The Stubborn Fat Solution Patch 1.

1
A Pharmacological Approach to Manipulating Atrial Natriuretic
Peptide for Ultimate Fat Loss

by Lyle McDonald

This book is not intended for the treatment or prevention of disease, nor as a substitute for medical treatment, nor as an
alternative to medical advice. It is a review of scientific evidence presented for information purposes only. Use of the
guidelines herein is at the sole choice and risk of the reader.
Copyright: First Edition 2015 All Rights Reserved
This book or any part thereof, may not be reproduced or recorded in any form without permission in writing from the
publisher, except for brief quotations embodied in critical articles or reviews.
For information contact:
Lyle McDonald Publishing
1200 Hatteras Drive
Austin, Tx 78753
Email: lylemcdonald@bodyrecomposition.com

Table of Contents|
Foreword
Introduction
Chapter 1: Fat Cell Physiology
Chapter 2: Natriuretic Peptides and Lipolysis
Chapter 3: Natriuretic Peptides and Brown/Beige Fat
Chapter 4: Natriuretic Peptides and Appetite/Hunger
Chapter 5: Beta-Blockers for Fat Loss
Chapter 6: Beta-blocker Effects Chapter
7: Putting it All Together
Selected References
My Other Books

Foreword
As everyone was taught in high school, history has a tendency to repeat itself. My writing career certainly seems to work
this way. Way back in 1996, I finished my first book, a tediously technical book called The Ketogenic Diet that was THE
comprehensive be-all, end-all book on low-carbohydrate diets. While many people raved about it, I was never really happy
with it. That's not relevant but what few know is that finishing that book nearly killed me, it was not the right project to start
my career and it was a nightmare at the end to actually complete.
Over the next two years, I would attempt to start new projects but anxiety over the nightmare that was finishing the first
book would stop me in my tracks. I'd get 75% of the way through the new project and start to have issues and go start
something else. I have folders of partially finished stuff from that time period.
Finally, in 1998, I published an odd little booklet called Bromocriptine: A New Use for an Old Drug. Probably my least
well-known and least successful project, it was a weird little drug booklet that mostly dealt with the topic of body weight
regulation; it just turned out that this 30 year old drug seemed to fix a certain problem that I had been working on. But given
that I'm known for training and nutrition, a drug solution to anything just wasn't really consistent with 99% of what I wrote
about.
Time passed and I wrote more books but, apparently at the 10 year mark it was time for my next nightmare project. Around
2006, I was working on another monstrously tedious technical book called The Protein Book. It was THE comprehensive
be-all, end-all book on the topic of dietary protein for athletes. As with The Ketogenic Diet, it was a horror to finish,
months of writers block and a complete inability to complete the damn thing were just another horrible chapter in my
writing career; finally, I finished it.
In 2008, I published The Stubborn Fat Solution. And going by my rough history, I should have started my next little drug
booklet shortly thereafter. And I actually did. But, as I'll talk about in the introduction below, I sort of abandoned it for a
while (about 6 years) only coming back to it as part of research for another recent project. No, it is not the Super Secret
Project (TM) I've been talking about for about the same amount of time. As the title suggests, it sort of follows up on The
Stubborn Fat Solution and a topic that I discussed but couldn't elaborate on at the time.
This is another weird little side project for me, another drug booklet that is really outside of what I usually write about. But
it's just so damn cool. Enjoy.

Introduction
If you're at all interested in the topic of fat loss (and outside of that small percentage who stay perpetually lean without
much effort, everyone is), odds are you've read my other books on the topic. In all likelihood, this includes my last book
The Stubborn Fat Solution (or SFS as it's usually abbreviated).
The SFS was the culmination of a decade long project examining the topic of stubborn body fat loss. Men's abs and low
back and especially women's thighs are more stubborn than other areas to get rid of. There are a myriad number of reasons
for this and, as is my way, I covered all of them in SFS. I spent chapters detailing everything there is to know about body fat
including what makes certain fat cells more stubborn than others to empty and get rid of.
Of course, I provided solutions in the form of the SFS protocols, 4 different targeted protocols that can be integrated with
other diets to get rid of stubborn body fat. Some specific supplements were mentioned as well. Although I didn't talk about
specific diets, I did discuss how the protocols would best fit with certain types of diets (e.g. low- vs. high- carbohydrate).
In that book, I had a chapter discussing the impact of hormones on body fat and such and in that chapter, almost as an
afterthought, I mentioned a relatively 'new' fat mobilizing hormone called Atrial Natriuretic Peptide (ANP) that might have
promise in terms of fixing the stubborn fat problem in a bit less effort intensive way than than the SFS protocols.
At the time I had some of the data on what ANP did and it certainly looked promising; I'll discuss that in a later chapter. But
there was no meaningful way to manipulate it that I had come across. The only things I was aware of just wasn't terribly
applicable. It was interesting but ultimately a dead end.
But, as is so often the case, a few months later I came across some fascinating research, a pharmaceutical way of
manipulating ANP in a useful fashion. Yes, a drug. I guess I could have revised SFS with that new information but, frankly,
it tends to be a losing battle.
Not only do I kind of not like to revisit projects (I'd rather learn about/write about something new), drug discussion is
polarizing. The people who are interested in such topics (either intellectually or practically) are generally far overwhelmed
by the people for whom drug discussion turns them away. Whether it's the general public (who are often selectively antidrug) or athletes who compete drug-free, it's just often a problem.
In my experience, when you talk about drugs in a non-drug oriented book, you tend to lose a lot of readers; this is just
reality. The guys willing to use any and all drugs aren't happy because there isn't more drug information and the anti-drug
people aren't interested at all. By trying to be all things to all people, you end up making everybody unhappy. So even if I
had been aware of what this book talks about, I wouldn't have included it in SFS.
Admittedly, what I'm going to talk about in this book really isn't anything that problematic from a legality standpoint. You
will need to combine it with some other compounds but with the exception of a couple, they are all either mostly legal
(depending on where you live) or at least in that gray-market area.
Now, I originally started this book when I found the original research, probably in 2009. Then for reasons I am not entirely
clear on, I got distracted. I don't know if I lost interest or had more problems to solve but I just put it away, partially written.
But then, in 2015, I started researching a new book project. And in doing so came across more literature relating to Atrial
Natriuretic Peptide. Exciting literature that simply did not exist when I started the project in 2009 or whenever I gave up. So
here was a place where my disorganization and probably laziness benefitted me. Basically I'm glad that I didn't finish this
back when I did.
And on with the show.

Chapter 1: Fat Cell Physiology

Ah the fat cell. Originally thought to be nothing more than an inert storage depot for excess energy, we now know that it is
highly active, contributing immensely to overall human physiology. With dozens and dozens of chemicals that it produces
(such as leptin and adiponectin), it is truly an enormous player in the human body. You'll have to forgive me for waxing a bit
poetic, I've written a lot about the fat cell and have to keep myself interested.
But the interesting physiology of the fat cell doesn't change the fact that it's kind of a pain in the ass. Whether for lean
dieters trying to get very lean or even the obese carrying too much of it, finding ways to get rid of (ideally permanently) fat
has been a goal for years.
Liposuction has been around for a while but does some weird things. A new approach called Cryo-Lipolysis looks
promising, it may actually cause fat cells to die (with the application of extreme cold). Both tend to be limited in how much
fat they can realistically remove anyhow. And while I'm not suggesting that this book will allow one to get rid of fat cells
forever (I gave up on the fat cell apoptosis/death project years ago) it does represent an entirely new way of stripping fat off
the body. Yes, new. But to understand why this is new, I have to look at what has been thought up until this point and look at
the basics of fat cell metabolism, with a focus on fat mobilization.

The Basics of the Fat Cell

Fat cell number varies enormously in humans as does their size. Big and small fat cells actually turn out to have somewhat
different physiologies (it's harder to get fat out of the small ones) and people with more but smaller fat cells are at a
disadvantage in terms of fat loss. Of course even bigger fat cells shrink on a diet which is part of why getting rid of the last
of them becomes more problematic (trust me there are a LOT more reasons than just this).
The primary component fat cells is lipid, also called triglyceride (TG). This is the combination of three fatty acid chains
bound to a glycerol backbone ("tri" means three and "glyceride" refers to the glycerol). Fatty acids chains vary in structure
in both their length (short, medium, long) and saturation (just accept that this is an organic chemistry thing).
When people talk about saturated, monounsaturated and polyunsaturated fats, they are really talking about the structure of
the fatty acid chains. There are actually some differences in how readily the different types of fat are stored or mobilized.
Saturated fats and longer chains are harder to get out of fat cells, for example (trivia: stubborn fat tends to store more
saturated fats, another reason they are stubborn).
Somewhere between 85-90% of a fat cell is composed of TG. One pound of fat is 454 grams, if 85-90% of that is TG that's
roughly 400 grams of fat or so. When burned each gram of fat provides 9 calories of energy and that's 3600 calories. That's
where that old value of 3,500 calories to lose one pound of fat comes from. It doesn't work quite that cleanly for reasons I
won't discuss here.
The other 10-15% of the fat cell is water and the cellular machinery that does all of the things that a fat cell does. Producing
leptin, adiponectin, the other dozens of chemical messengers. Of course, there are enzymes and such involved in both the
storage and mobilization of fat within the cell. Let's talk about those.

Lipoprotein Lipase (LPL) and Hormone Sensitive Lipase (HSL)

The key players in fat storage and mobilization are LPL and HSL, two enzymes that, respectively store fat and mobilize it.
There is also another molecule in the fat cell called Acylation Stimulation Protein that is hugely important for fat storage.
Discovered in the 80's, it's actually more important for fat storage than LPL. And, a fact ignored by most, ASP activity can
be turned on simply by fat in the bloodstream, without the hormone insulin present or increased. Take that Gary Taubes.
But since we're talking about fat loss, let's focus on HSL. HSL is regulated predominantly by something called cyclical
Adenosine Monophosphate (or cAMP) in the fat cell. When cAMP is low, HSL activity is low; when cAMP activity is high
HSL activity is high.

Burning Fat
The process of "burning fat" can get as complicated as you want to make it but I tend to focus on three primary steps:
mobilization, transport and oxidation (burning). I discussed all three in some detail in The Stubborn Fat Solution but will
only focus on mobilization in this book.
Mobilization is the step we're concerned with here. When HSL is activated, stored TG in the fat cell is broken down and the
fatty acids are released into the bloodstream as is the glycerol backbone (sometimes scientists just measure glycerol release
with the assumption that fatty acids are being released in a ratio of 3:1). This process is called lipolysis ("lipo" = fat, "lysis"
= breakdown).

These fatty acids can actually then just be stored again (a process called re-esterification) but if blood flow is sufficient, they
get carried away (transported) elsewhere in the body. Eventually they run into a tissue such as skeletal muscle or liver or
heart where they are oxidized (burned) for energy. That's ultimately what the process of losing fat is:
mobilize the fatty acids, transport them away from the fat cell, burn them off for energy. I discuss the above in excruciating
detail in The Stubborn Fat Solution but for now that's all you really need to know.
And as I mentioned above, the hormone HSL is the key to fat mobilization and HSL activity is increased when cellular
cAMP goes up. So we want to raise cAMP. Some readers may remember the supplement forskolin that was popular years
ago. It was shown to raise cAMP in cells (at least when done in a petri dish or infused) but it more or less crapped out as an
oral supplement.
So what, you ask, controls cAMP in the fat cell?

A Tale of Two Hormones: Insulin and the Catecholamines

Before talking about the key hormones involved in fat cell metabolism, I should mention that others play important but
ultimately secondary roles. Testosterone, progesterone, estrogen, thyroid, cortisol, growth hormone, leptin and others all
impact on fat cell metabolism.
GH and small cortisol pulses help to mobilize fatty acids for example. In contrast, chronically elevated cortisol, especially in
conjunction with elevated insulin levels can cause fat storage. Thyroid affects overall metabolism and the drop in thyroid on
a diet is part of why metabolism slows down; note that too much thyroid can burn off muscle tissue and cause other
problems.
Testosterone can impact on the levels of HSL and LPL (not so much the activity) and impacts on something called
adrenoceptors that I'll discuss below. The female hormones, estrogen and progesterone are too schizy to get into: in some
parts of the body, they help fat loss, in others they hurt and they interact in a complex way (that changes throughout the
menstrual cycle).
But the two key hormones when it comes to fat mobilization have been, for decades, considered to be primarily insulin and
the catecholamines. Since insulin is simpler, and I suspect most readers know what it is, let's talk about it first to get it out of
the way.
Insulin is the primary inactivator of HSL (it is also part of what turns on fat storage), inhibiting fatty acid mobilization from
fat cells. Insulin goes up in response to both protein and carbohydrate consumption and is usually thought of as "bad" when
it comes to fat loss. Certainly there is some truth to this.
As above, it's very incorrect as thinking that insulin is the only thing that affects fat storage (as many are now claiming),
ASP that I mentioned above works just fine without it when fat is consumed even if insulin levels don't go up (that is, fat
stimulates it's own storage). But for now you can think of insulin as the "bad guy" for fat mobilization (and thus loss).
Insulin acts, by binding to insulin receptors on the surface of the fat cell, to decrease cAMP. This insulin inhibits fat
mobilization.
But what about the catecholamines. Known as adrenaline/noradrenaline or epinephrine/norepinephrine depending on what
part of the world you live in (I'll use adrenaline/noradrenaline), the catecholamines are key players all around the body with
a lot of different functions.
For the record, adrenaline is released from the adrenal gland into the bloodstream and it tends to act very globally in the
body, affecting most tissues. In contrast, noradrenaline is released from nerve terminals and tends to only affect the tissue
that the nerves are close to (innervates in anatomical terms).
And, just as insulin was thought to be the only player in fat storage (it's not), the catecholamines were thought to be the only
mobilizers of fat from the fat cell (they aren't). Before expanding on that, let's talk about how these hormones work. To
understand that, I need to talk about something called adrenoceptors (or adrenoreceptors).

All About Adrenoceptors

Just as insulin has it's own receptor on the surface of cells (and actually every hormone has it's own specific receptor), the
catecholamines have their own receptors called adrenoceptors. There are two primary classes of adrenoceptor called alpha
and beta and each one has a number of subtypes. The ones we are concerned with here are alpha-1 receptors (that kind of
don't matter for fat cell metabolism), alpha-2 receptors (which matter hugely), beta-1 receptors (not critical for fat cell
metabolism), beta-2 receptors (hugely important) and beta-3 receptors.
Let me talk about the beta-3 receptor briefly. Originally found in animals, in something called Brown Adipose Tissue, beta-3
receptors were hoped for a while to be the key to obesity treatment. In animals, beta-3 activating drugs caused massive fat

loss and it was just awesome. Obesity was cured.

But as so often happens when trying to go from animal research to humans, it didn't pan out. When beta-3 activator drugs
were tried in humans they had either a very small or pretty much no effect (the reasons why aren't relevant). They were
abandoned and keep that in mind when you hear of some supplement company that claims to have a beta-3 product that
works. When companies with potential multi-billion dollar profits stop researching something or can't make it work, the
idea that a supplement company has figured it out is about nil.
So what about the other adrenoceptors? Again I'll focus on alpha-2 and beta-2 for the time being since they are key players
in the fat cell. You can think of alpha-2 receptors as a "brake" on fat cell mobilization. Despite being activated by the
catecholamines, they lower cAMP and inhibit fat mobilization. Think of beta-2 receptors as "accelerators", when activated
they raise cAMP levels and stimulate fat mobilization. Alpha-2 receptors bad, beta-2 receptors good.
Some of the hormones I mentioned above can impact on alpha-2 and beta-2 receptor density. Testosterone often lowers
alpha-2 receptor number, helping with fat loss. Estrogen can raise alpha-2 receptor number, hurting it (again, estrogen is
way more complicated than this).
So why does this matter? As it turns out, different depots of fat in the body can have vastly different ratios of alpha-2 and
beta-2 receptors. Women's hip and thigh fat, for example, has a very high ratio of alpha-2 receptors to beta-2 receptors and
this is a big part of why it's so difficult to mobilize and get rid of. Men's ab/low back fat isn't quite as bad but can still be
stubborn and as you sort of move up the body, things get a lot easier. Visceral fat, found surrounding the organs is very easy
to mobilize due to it's adrenoceptor ratios and incredibly high blood flow.
This actually explains the "order" in which people lean out. If they are carrying visceral fat, they lose that first. They don't
look much better outside of a flatter stomach but they feel leaner. Then fat loss is sort of top down. Upper body leans out
first, women and men get ripped, veiny delts and chest long before anything else.
The abs come in next (and even upper and lower abdominals come in at different rates). For women, who often carry a lot
of lower bodyfat, abs often get ripped fairly early in the process and end up with a ripped upper body and relatively fat hips
and thighs. Lower body fat is simply always the last place people lose fat. Men, who generally do not have a lot of fat in
their lower bodies have abs and low back as the typical problem areas. Some men do have a more "female" bodyfat
patterning and they have the same problems with lower body fat as women do.
There are actually some solutions to the alpha-2 adrenoceptor issue. The supplement yohimbe/yohimbine is a natural alpha2 blocker; it takes the "brake" off of fat loss. Very low-carbohydrate diets for a few days also naturally inhibit alpha-2
receptors as well. I imagine most know about ephedrine or clenbuterol both of which hit the beta-2 receptors (ephedrine
actually activates both beta-1 and beta-2 receptors but that is neither here nor there for now). Exercise causes the release of
hormones that may or may not mobilize fat depending on the area you're looking at.
There are also ways to modulate exercise to work around the problems above, I outlined all of them, diet, supplement and
training in The Stubborn Fat Solution and won't detail them again here since that's not what this book is about. But so
far none of the above is really that exciting if you've read much in recent years (or any of my books). Insulin is bad, the
catecholamines have variable effects, you can lower carbs, exercise or take some supplements to try and fix the issue.
I should mention in closing that insulin pretty much always "wins" against the catecholamines in the battle for fat cell
metabolic control. When insulin is high, it's anti-fat mobilization effects will suppress the fat mobilization effects of
adrenaline/noradrenaline. Do realize that it's somewhat unusual to have high levels of both at the same time. Generally
when insulin is high, catecholamines are low and vice versa.
But clearly I wouldn't be writing this book if I was just going to repeat the same tired information. This book is about
something new and exciting. Because above I made it sound like insulin and the catecholamines are the only players in fat
cell mobilization, certainly this was thought for decades.
But, to quote Star Wars and show my nerdiness: There is another.

Chapter 2: Natriuretic Peptides and Lipolysis

So now you have the basics of fat cell mobilization as well as why stubborn fat is stubborn: a preponderance of alphareceptors compared to beta-receptors make fat cell mobilization more difficult. There are other issues related to things like
insulin sensitivity, blood flow, etc. that I'm not going to get into here.
For now let's just focus on the beta/alpha adrenoceptor issue that I talked about last chapter. Just remember that insulin is
bad, catecholamines are variable and a high alpha to beta receptor density makes fat mobilization more hard. It can be
worked around but what if there was another way. A New Hope perhaps (sorry).

The New Millennium

In the year 2000, society did not collapse due to Y2K and programmers not realizing that years need to have 4 digits. It's a
shame since I was running a big credit card debt and was hoping it would get wiped out when all of the computers crashed.
Ah well. Neither did the Messiah return and for the most part, the whole thing was nothing more exciting than watching the
numbers change; kind of like watching the odometer of your car turn over from 99,999 to 100,000. Whoop de doo.
However, something cool did happen, at least if you define cool relative to being a big nerd on the fat loss front. Which I do.
Because in 2000, a nifty little review paper came out titled Millennium fat-cell lipolysis reveals unsuspected novel tracks.
that described an entirely new fat mobilizing pathway.
As I mentioned in the last chapter, for the previous decades, insulin and the catecholamines were the primary hormones
directly affecting lipolysis, there were a bunch of secondary hormones but that was basically it. And that limited what could
be manipulated. Drop carbs, hit the beta receptors with exercise of drugs, take yohimbine or use a low-carb diet.
But this paper discussed an entirely new pathway to mobilizing fat, that worked outside of or at least around the classical
insulin/catecholamine pathway. Recall from last chapter that both insulin and the catecholamines work to mobilize (or
inhibit) mobilization of stored fat by affecting cAMP levels (which affects HSL activity). Low cAMP and you get sluggish
fat mobilization, high cAMP and it increases.
When insulin or the catecholamines bind to their receptors, they ultimately affect cAMP through something called
downstream signalling. Basically the hormones bind, something happens, something else happens and 6 other somethings
happen and finally something useful or important happens. Sometimes it's good (increased cAMP in this case) and
sometimes it's not (decreased cAMP in this case).

The Natriuretic Peptides

ANP stands for atrial natriuretic peptide and is actually one of a class of natriuretic peptides. There is also b-type (or brain)
natriuretic peptide and a c-type natriuretic peptide. Respectively they are called ANP, BNP and CNP. In this book I will
predominantly focus on ANP although BNP plays a role that is actually fairly important during dieting.
All three of these compounds are released from the heart and the original purpose of them was thought to be mainly related
to water balance in the body (natriuretic is a fancy word referring to something that causes natriuresis which is the loss of
minerals and the urine; this pulls water out of the body).
As people get sick or obese, they often start holding a lot of water and this tends to increase blood pressure (and other
things). The body, being very smart, then releases a host of compounds including the NPs in an attempt to get things back to
normal. The natriuretic peptides are a big part of that.
So when people are in heart failure or suffering from massive hypertension (again, often secondary to obesity), NP levels go
up in an attempt to get blood pressure back down and things back to normal. It's actually more complicated than that, of
course but the details are not particularly relevant here.
But here's an interesting tidbit, ANP turns out to have another major role in the body, one that might not have been
predicted. It mobilizes fat. If you think about it, it makes a certain weird kind of sense in evolutionary terms. If obesity and
fat gain are causing some negatives to occur (such as high blood pressure), ANP increases could be part of what helps to
burn the fat off. There are a host of other adaptations as well, leptin goes up, fat cells become insulin resistant, etc. This
happens due to becoming obese in a (generally futile) attempt to reverse the situation.
Clearly, mind you, it doesn't work that well or there wouldn't be any issues with obesity or high blood pressure. It actually
turns out that obese people often have lower ANP levels than leaner people; it appears that their bodies degrade ANP more
effectively or excrete it through the kidneys. So a pathway that should rightfully work to help with fat loss seems to have
become dysfunctional for whatever reason. This is also not unusual in obesity: systems that are meant to work at lower
levels or be very effective go screwy as people get obese.

In any case, ANP levels often go up when blood pressure or what have you occur and in addition to its other effects, ANP
stimulates fat mobilization. But of far more interest to this book and the issue of stubborn body fat, not only does ANP
mobilize fat, it works through a completely different pathway than insulin and the catecholamines. Like those other
hormones, ANP has it's own receptor on the fat cell but when ANP binds, it does something different.
Because while insulin and the catecholamines work by modulating cAMP, atrial natriuretic peptide works through a cGMP
mechanism (cGMP stands for cyclical guanadine monophosphate which those of you who remember high school or college
chemistry may be familiar with). In the same way that cAMP is a downstream signalling molecule, cGMP is too.
This has a number of consequences not the least of which is that ANP's effects are not impacted directly by insulin or
catecholamine levels. They are working completely separately. Let me say that again: ANP mediated effects on fat
mobilization are not impacted by insulin or the catecholamines; they don't actually interact at all. So while insulin and the
catecholamines may be "fighting it out" for the control of fat cell metabolism (with insulin usually winning), ANP just does
an end-run and works through a completely different pathway.
Quite in fact, ANP is even more interesting in that it can simulate lipolysis even when insulin is high which is something
that the catecholamines can't do. I'll come back to this later in the book in terms of practical applications.
As I mentioned above, like all hormones, ANP has it's own specific receptor to bind to and very preliminary research (not
much has been done) suggests that ANP doesn't show the same density differences in different areas of the body. So in
addition to working when insulin is high, ANP may get around the whole alpha/beta receptor issue that makes some types of
fat so damn hard to get rid of.
On that note, however, it has been shown that fat mobilization in females may be mediated more by ANP levels than in men,
in premise, some of what I'm going to discuss in this book may help women more than men in terms of getting rid of
stubborn body fat. It's really about time; women are screwed in terms every other aspect of fat loss. Finally, something may
be going their way.
So now you're thinking, I'm sold, bring on the ANP and I'll watch the fat (stubborn and otherwise) melt right off. As usual
there is a catch.

So What's the Problem?

Mind you, when I wrote The Stubborn Fat Solution I already knew most of the above and I expressed that in the short
section of that book on ANP. The problem was that I hadn't found any useful way to raise ANP levels and I stated that
clearly. Clearly getting high blood pressure is out of the question, and I would have found it difficult to sell heart failure as a
way of getting ripped (bodybuilders would have done it).
In most of the research at that time, when they examined ANP it was with infusion. Since ANP is a protein based hormone,
you can't take it orally, it will simply get digested in the gut. And I doubted bodybuilders, crazy as they are, would infuse
ANP during morning cardio. They might, mind you but it didn't seem terribly practical for most.
Most of what I had seen to raise ANP that wasn't the above involved massive hyper-hydration. But not just "drinking extra
water". It was gallons of water with a saline infusion and hormones like cortisol and aldosterone to make the body retain
fluids Hardly practical. I would note that at least one contest prep guru has been suggesting very high sodium intakes during
diet prep and I do wonder if this isn't affecting ANP levels by causing body water to go up. Maybe.
Another approach was to use something called a tilt table. This is a table that takes people from lying flat to a head down
position; this spikes blood pressure and this causes ANP to go up at least acutely. Exercise in the prone position (laying
down) seemed to raise ANP as well. While I can imagine some creative cardio machines that flip you upside down every
five minutes to raise ANP, it didn't seem that useful either. One study found that ANP went up more in response to exercise
in the water but it didn't affect fat mobilization more than doing the same exercise on land.
Doing exercise under hypoxic conditions (no, NOT training masks, we're talking the inhalation of hypoxic air) also had a
profound impact on raising ANP but that's hardly practical.
I would note that exercise per se does increase ANP and this is part of the overall fat mobilizing process; as I mentioned
above this effect seems to be more pronounced in women. Intensity may be a key to this. One study found that ANP went up
(in women more than men) after sprint exercise for example.
I do wonder, in hindsight, if part of the benefit of the stubborn fat protocols aren't related to this (since they involve high
intensity intervals to start or finish the exercise bout). But perhaps this whole inane fascination with high intensity aerobic
activity for fat loss isn't totally misguided. If youre wondering about resistance training and ANP release, there is almost
literally no research on it. Ive found one study and it showed no ANP response so this looks to be a cardio thing only.

One study found that performing two bouts of exercise an hour apart saw a big increase in ANP levels during the second
bout. Perhaps this lends some credibility to the idea that cardio morning and evening is better than a single session; I don't
know if the effect is still seen with 12 hours between sessions but maybe the bodybuilders weren't nuts to do it this way.
But for the most part, none of this was really as useful as I wanted it to be. It's generally bad idea to do high-intensity
exercise daily (your legs tend to fall off) especially on a diet. The hyper-hydration thing is interesting but there's still no real
indication that anything but the most extreme levels reliably impact on ANP levels. And raising blood pressure deliberately
doesn't seem like a good idea.
Again, I knew all of the above when I wrote The Stubborn Fat Solution but just sort of left it sitting there. As I mentioned
in the foreword I found another approach and started writing this book before getting bored and doing something else. And
in hindsight I'm glad I did because as it turns out, there's way more interesting stuff coming out of the ANP literature now
and this book gets to be a lot cooler because of my inability to get it finished in the first place.
So before I tell you about the method I'm going to suggest to jack up ANP and take advantage of the fat mobilizing effect,
let me tell you about some other things ANP (in conjunction with other things) appear to be able to accomplish.

Chapter 3: Natriuretic Peptides and Brown/Beige Fat

In the first chapter of this book, I mentioned b-3 receptors and how they worked amazingly in animals but seemed to not do
much in humans. This chapter will address part of why that was. Now part of the reason is simple, when receptors are
activated they often get downregulated, that is they decrease in number.
Humans don't have a huge number of b-3 receptors to begin with and what we do have is downregulated very quickly in
response to stimulation. So even if b-3 drugs worked for a little while, they quickly stopped working. The drug clenbuterol
(a beta-2 agonist) often stops working for the same reason, the constant stimulation of the beta-2 receptors causes them to
decrease in number and clen loses it's effectiveness.
Ephedrine, which also activates the beta-2 (and beta-1) receptors doesn't do this since it doesn't hit the receptors as hard.
You also don't take it 24 hours/day (clen stays in the system for 36 hours after a dose) so the b-2 receptors get a "rest" at
night. One study even suggested that chronic ephedrine use could increase it's effects. But the general problem with b-3
receptors wasn't just due to this. Rather it was due to a fairly fundamental difference between rats/mice and humans.

WAT and BAT

In addition to the different areas of fat I talked about a little bit last time (i.e. visceral, abdominal, hip/thigh) there are
actually two (and now three) actual types of fat in humans. The type I was talking about earlier in this book is called White
Adipose Tissue or WAT. It's the primary type of fat in humans and one of it's major purposes is energy storage. It has a lot of
stored triglyceride, a bit of cellular machinery and, of relevance to this chapter, has few mitochondria.
Mitochondria (aka the powerhouse of the cell) are found all over the body and burn both fat and glucose for energy (and
they burn mostly fat). In doing this, they produce energy for the body to use (strictly speaking, ATP or adenosine
triphosphate which is the "currency" the body uses for energy); a side effect is that mitochondria also throw off heat.
And while WAT has very few mitochondria (making it fairly bad at burning fat for energy), a different type of fat called
Brown Adipose Tissue (BAT) is effectively the opposite. It contains very little stored TG and has lots of mitochondria. And
it's primary role, as you might imagine, is burning fat for fuel. And it generates a lot of heat doing this.
In small animals (mice and rats for example), in which BAT was first found, this helps with thermoregulation. That is, by
generating heat, BAT helps to keep animals warm. And because of the crucial role of BAT in those animals, b-3 receptors
were critically important (their activation turned on the BAT). So why didn't this pan out in humans?
For years, it's been felt that adult humans didn't have much BAT (babies, who are bad at regulating their body temperature
have a good bit of BAT but it was always thought to go away as they got older). What little adult humans was found
between the shoulder blades and in the neck but there didn't seem to be much of it and what we did have didn't seem to do
much. For years nobody was quite sure why. This was thought to be another reason that b-3 activator drugs crapped out in
humans. If their primary role was to activate BAT and humans didn't much BAT, it made sense that the drugs that activated
BAT wouldn't do much. Which they didn't.
And this stance, that humans don't have enough BAT to worry about, was held for years, I've echoed it in some of my earlier
books. But in the last 10 years or so, there has been essentially revolution and renewed interest in BAT. Almost purely by
accident (i.e. they were looking for tumors in a PET scanner), researchers managed to find that some people had quite a bit
of BAT. There was a huge variability in how much though. It also turned out that the amount of BAT present was related to
how easily or not people kept lean; more BAT, relatively is correlated with a lower bodyweight.
So why hadn't earlier studies found BAT? Or, rather, why did the new research find it? It turns out that cold exposure is one
of the primary activators of BAT and the earlier studies were always looking at normal room temperatures. The only way to
really study BAT or even to see how much humans had was to look at it in the cold. I'm not talking about freezing here,
temperatures around 19C (around 66 F).
For many, that's fairly chilly (and this also causes shivering which burns calories) but it's still enough to get BAT, if it's there
to perk up activity wise. In that vein, it's been suggested that the fact that humans avoid both cold and hot temperatures (we
have central heat and air and clothes) may be contributing to obesity as both cold exposure and heat exposure can raise
energy expenditure. But since most don't like being too hot or too cold, we use clothes and technology to stay in a more
midrange zone for comfort.
In any case, when studied under colder conditions, it turns out that some people have quite a bit of BAT but the amount can
vary about tenfold between people (and we're talking gram levels here, maybe 36 to 360 grams of total BAT so not even a
pound of the stuff). It's currently unclear how relevant this really is in the big picture.
Some have suggested that with full activation, reasonable amounts of BAT could burn off 9-20kg per year with the latter

value being a pretty enormous estimation and probably way too high. It would tend to require constant cold exposure (and
it's interesting to note that lumberjacks who do undergo chronic cold exposure had been found to have more BAT than
others) and you have to compensate for the hunger that occurs.
In one study for example cold exposure did increase energy expenditure by like 150 calories per day. But the folks, allowed
to eat without control, ate more than that. So it's a double edged sword. Certainly if food intake is controlled, cold exposure
has potential to burn some extra calories and certainly there has been some interest on the Internet for using cold packs or
cold exposure for this. But it only works if calories are controlled.
In any case, BAT is back and appears ready to stay. And interest in finding ways to increase and/or activate BAT has been
equally renewed. Preferably pharmaceutical means given that most will simply not put up with the inconvenience and
discomfort or being cold all the time.
But even more recently, the whole BAT thing has become more complicated. By another tissue that should also be called
BAT.

Enter Beige Adipose Tissue

One of the reasons that I'm glad I didn't finish this booklet in 2008 is that I wouldn't have been able to talk about this topic:
beige fat (also called "brite fat" in the research). Like most of this it was first discovered in animal models (rats and mice).
It's thermogenic like BAT and is thought to be somewhere between regular white fat (WAT) and classic BAT in terms of
what it does (as well as in it's color, hence beige fat).
And it's now thought that most of what was considered BAT in adult humans is actually what is being called beige fat in
animals. Basically while human children have true BAT, which is then lost; some adults appear to have beige fat in the areas
that were once thought to be true brown adipose tissue. That is, adult human brown adipose tissue isn't really brown, it's the
beige fat. Confused yet?
This might also help to explain why the drugs that activated brown adipose tissue in animals crapped out in humans. Our
brown adipose tissue was really beige (on top of the difference in b-3 receptor function) and was presumably responding to
a different stimulus.
From here on out, let's forget about brown adipose tissue and use BAT to refer to beige adipose tissue. Mind you, the end
result is basically the same but this is more accurate. It's also thought that research on animal beige fat may actually transfer
over to human beige fat since they seem to be an identical tissue. Time will tell and maybe this will be one of the few times
where mouse/rat physiology actually translates into something useful for humans.

Where Does BAT Come From?

Since it's clear that we lose brown adipose tissue after babyhood, a question is then were beige adipose tissue comes from.
Without getting into excruciating details, realize that there are precursor cells in the body, think of them as baby cells that
have to get a signal to mature and turn into adult cells.
For a while it's been wondered if cells could be "transformed" from one type to another. That is, there was brief interest in
"turning" white fat cells into brown fat cells, again with the hopes of treating obesity. It's not as if there aren't enough of
them. Researchers call this the "browning" of white tissue. Basically turning them more into beige fat cells.
But it looks like this doesn't really happen. And while there was some early question about whether beige fat came from
white fat precursor cells (which got a different message when they were told to mature), it looks like there are actually beige
precursor cells that, given the right stimulus can mature into beige adipose tissue.
So in premise, given the right stimulus, there should be some way to increase the amount of beige fat. If so, in premise it
can be activated and burn off extra fat calories like the original brown adipose tissue was supposed to. At least one of these
is already known: chronic cold exposure.
Cold has its effects in the body by generating a sympathetic nervous system response and the beta receptor activation seems
to be part and parcel of how it activates beige fat either acutely or to cause it to increase. In this vein, increased beige fat has
been found in people suffering from a pheochromocytoma, a type of tumor that chronically produces adrenaline and
noradrenaline. Essentially they have a chronic hormonal condition that is just like cold exposure.
Of course, exercise, ephedrine and clenbuterol all do the same and it was suggested early on that chronic use might cause
increases in human brown adipose tissue. But without a good way to measure BAT (remember: you have to look for it in the
cold), it was never proven.
But we know this: beta-receptor activation increases fat mobilization. Under certain conditions to make beige fat more
active as well. And may have the ability to get the body to produce more beige fat. All this was known and still relevant.

Early on it looked like a compound released by muscle, called irisin, might play a role in all of this. But the significant
results in mice/rats were rather inconsistently replicated in humans. Most studies in humans showed no increase in irisin
with exercise (and the ones that did found only a small increase). Of some interest, one study of sprint training (4-8 sets of
30" all out) for 3 weeks found that women saw an increase in irisin but men a decrease. The reason for this gender
difference is unknown as are the real world effects.
Related to this, an early study found that sprint training caused a significant increase in ANP at the end of 10 maximal
sprints and that the effects were also greater in women. I might suggest that the high-intensity protocols in my own
Stubborn Fat Solution are working partially through this mechanism.
Another compound called BAIBA (beta-amino butyric acid), released from skeletal muscle may hold more promise. It not
only appears to be involved in the "browning" of white fat but the single study done to date shows that 20 weeks of
endurance training increases BAIBA levels by 17% but at the current time no more is known about what regulates BAIBA.
What role this actually plays in terms of the acute stimulus of beige-fat recruitment/activation is unknown but, going
forwards this may represent another pathway of interest to "turn on" or "make more" beige fat". I include it only for
completeness.
Thyroid hormone is also key here. Not only does it increase energy expenditure and thermogenesis but may be involved in
the overall recruitment and cell program that produces beige cells. There are a few other activators of beige fat but I won't
get into them: for now they aren't modifiable in any way I am aware of. But it turns out that there are other compounds that
appear to not only activate beige fat but possibly increase the amount of it. Compounds that we can actually control. Can
you guess why I'm talking about this?

The Return of ANP

Knowing the above, that beta-receptor activation has the effects above and stimulates lipolysis, and knowing (as per the last
chapter) that ANP stimulates lipolysis, a seemingly logical question/leap was whether or not ANP (or the natriuretic peptides
in general) could either activate or get the body to make more beige fat. That is, if they share the effect of increased
lipolysis, might they also share the effect on beige fat.
And the answer seems to be yes although the research is preliminary. In both animals and humans, exposure of isolated fat
cells to ANP (for 6 hours) led to significant increases in the genes responsible for fuel use, mitochondrial biogenesis and
activation of the cell program that causes beige fat cells to mature from their precursors. Yet, it was in vitro (in a test tube),
and looked mostly at genes.
But the researchers also found an increase in mitochondrial content (meaning the fat cells could burn more fatty acids for
fuel). They also found that ANP raised oxygen consumption in the cells (indicative of fuel use) by 250%. These results were
similar to that caused by a generic beta-activating compound. In this vein, ANP has been shown to improve the oxidative
capacity (essentially the ability to burn fat for fuel) of skeletal muscle.
Following that, the researchers wanted to see if the combination of beta-activation followed by ANP had the same, less or a
greater effect than either activator alone. In this case, not only did the beta-activating drug raise oxygen consumption, etc.
when ANP was then added, the effect was increased further (and went higher than either compound alone).
Finally, the combination of a beta-activator and ANP was shown to induce the program that "browns" fat. That is, it
appeared to turn on the mechanism for making more beige fat. It's important to realize that both compounds worked at
concentrations that are found under normal circumstances. Often studies of this sort use concentrations that are impossible
to achieve outside of the test-tube. That is not the case here: this occurred at levels of the hormones that can occur in the
body.
And irrespective of the irisin issue above, it's interesting to postulate that regular exercise (which raises levels of both the
catecholamines and ANP) could be increasing beige fat cell number and activity. This hasn't been studied to my knowledge
but is interesting to consider if long-term exercise isn't having an effect on beige fat (possibly making it easier to stay leaner
in the long-term).
Regardless of that, a few things are clear:
1. Like beta-receptor activation, ANP by itself seems to activate a lot of good things in terms of energy expenditure,
mitochondrial content and may be able to both activate and make more beige fat.
2. Beta-receptor activation does the same by itself.
3. The combination of the two, beta-activation and an increase in ANP has a greater effect than either by itself.
4. A newly found compound called BAIBA released from skeletal muscle appears to brown white fat.
5. Thyroid hormone appears to play a role in the overall production and activation of beige fat.
So what, outside of exercise, has the potential to accomplish the above? Beta-activation is fairly easy, ephedrine, clenbuterol

both do it. But what about ANP? I need to talk about one last interesting thing.

Chapter 4: Natriuretic Peptides and Appetite/Hunger

I know readers are waiting for me to get to the point but I have one more brief topic to cover. Once again, had I written this
booklet back in 2008, this research wouldn't have existed. That said, please note that what I'm going to talk about in this
chapter is fairly preliminary with studies showing some often contradictory results (some of this is probably due to
differences between human and animals models) and is probably the least important part of this book. But I'm still going to
talk about it.
Now, a population that is known to have elevated levels of natriuretic peptides is individuals in the midst of heart failure.
You'll actually hear more about them in the next chapter. Along with this comes a cachexia, essentially weight loss and
"wasting" that occurs in these patients.
Some readers may be familiar with the term "cancer cachexia" which refers to the fact that people fighting cancer often find
their weight dropping with an inability to eat (this is one therapeutic use of marijuana by the way, stimulating appetite in
these folks). The hormone TNF-alpha (an inflammatory hormone that goes up under certain conditions) was originally
called "cachexin" as one of its roles is to blunt hunger in the brain.
But the fact that folks in the midst of progressive heart failure start to waste away raises a question of what is causing this.
Certainly some of the effect is probably mediated by what I talked about in the previous chapters: increases in energy
expenditure, thermogenesis, etc. But is there more?
As it turns out, some preliminary research suggests that the natriuretic peptides, and especially the b-type (BNP) may be key
players in regulating hunger and appetite, decreasing both. Once again, the research on this is fairly new but, in the
aggregate it appears that they are playing a role in reducing hunger. This ties into something I talked about in an earlier
chapter, the body often undergoes a variety of adaptations in response to obesity or other disease states that look like they
are trying to fix the problem.
An increase in BNP with obesity might be an attempt by the body to reduce food intake to bring things back to normal
though why this would occur in heart failure is obscure to me. Once again, clearly it doesn't work so well and there is,
again, evidence that the obese may have a malfunctioning system, or just clear the natriuretic peptides to a greater degree.
One study for example, found that infusion of BNP both decreased subjective ratings of hunger (cutting them to one third)
and reduced levels of ghrelin. Ghrelin is the gut hormone responsible for inducing hunger, going up before meals as well as
when individuals lose fat. It has other metabolic effects but keeping ghrelin from going up as high, or from going up on a
diet, would be very beneficial to keep hunger from going off the rails.
In confusing contrast, another study found that natriuretic peptides reduced leptin levels in the brain which would be
expected to make overall hunger worse (primarily by making other hormones involved in hunger regulation work less well).
But none of that changes the overall effect of reduced hunger and weight loss in heart patients and the suggestion that
raising natriuretic peptides (specifically BNP) seems to blunt hunger.
Natriuretic peptides also have been shown to impact on the metabolic effects to eating a meal. One study looked at the
effects of the NPs on metabolism after a high-fat meal and found that both lipolysis and fat oxidation were maintained to
some degree during the meal. Importantly, this occurred despite the increase in insulin (which usually shuts off both
processes) which typically "wins" the battle over fat metabolism as I mentioned before.
The researchers noted that this isn't automatically a good thing. The increase in fat oxidation was less than the increase in fat
mobilization which means that there might have been excessive fatty acids floating around in the bloodstream. This can
cause problems, sometimes these rogue fatty acids are put somewhere they don't belong like the liver or pancreas (this is
called ectopic fat storage). Mind you this shouldn't be an issue if someone is on a calorie restricted diet (and avoiding very
high-fat meals in the first place).
The main point of this is that ANP may help to keep fat burning and mobilization going during a period (right after eating)
when it tends to be shut down. For someone on a diet, this might give potentially the best of all worlds: eaten calories go
into muscle, body burns off fat (dietary or bodyfat) for fuel. Double win.
And finally with all of that out of the way, it's time to get to the punch line and tell you how I suggest manipulating the NP's
to enhance fat loss. And understand going to this that it will initially make no sense.

Chapter 5: Beta-Blockers for Fat Loss

Ok, this chapter is going to be very short since it's basically a bridge between the stuff I bored you with in the previous
several chapters and the stuff that you're really interested in. To get to the main thrust of this book, I'm going to quickly
walk through everything I've discussed so far.
In Chapter 1 I talked about some basic fat cell physiology along with the two primary hormones long thought to have the
only real impact on whether fat was mobilized well or not. Those two were insulin which inhibits fat mobilization
(lipolysis). I also talked about the issue of alpha and beta adrenoceptors and how their different densities/numbers in
different areas of the body make it relatively harder or easier to mobilize fat when they are stimulated by the
catecholamines.
This led into a discussion in Chapter 2 of an entirely "new" (as of the year 2000 or so) fat mobilizing pathway that works
completely independently of insulin and the catecholamines. This pathway was activated by a hormone called Atrial
Natriuretic Peptide (ANP, one of three natriuretic peptides) and it worked through an entirely different mechanism than the
other hormones.
ANP was released in folks with high blood pressure and in obesity, presumably in an attempt to drop body water and
potentially reduce bodyfat. Exercise reliably released ANP as does hyper-hydration (involving gallons of water and
hormone infusion) and some of the previously made observations regarding multiple exercise bouts or even high intensity
exercise may be explained by increases in ANP.
In Chapter 3, I talked about brown adipose tissue first. Brown adipose tissue mainly exists to burn calories for heat and is
involved heavily in thermoregulation. Previously thought to be found in small or insignificant amounts in adult humans,
recent research has suggested that brown adipose tissue may be more relevant to human physiology.
But more recently, a midway type of fat cell called beige (or "brite") fat has also been identified and it actually appears that
the supposed brown fat in humans is this beige fat. Mind you, beige fat is still thermogenic, burning off calories and fat for
heat and is probably what the early studies of brown adipose tissue were looking at. Until recently, the primary activator of
beige fat was cold exposure, primarily through the hormonal effect that it has on adrenaline and noradrenaline. Individuals
who overproduce those hormones chronically have elevated levels of beige fat so this all fits so far.
Unfortunately none of this was terribly useful information for most people. It's difficult to increase levels of
adrenaline/noradrenaline around the clock because it makes it so you can't sleep. As well, in modern society, most prefer
comfort to being chilly all the time; we use clothing and technology to stay in what's called The Thermoneutral Zone. Most
are unlikely to put up with being chilly all the time though if you gradually acclimate (by moving the thermostat down a
little bit at a time), it's not too awful.
But it also looks like beige adipose tissue can both be activated by and possibly increasing the amount by ANP for even
short periods (6 hours). Beta activation increases this effect by ANP and the combination of the two (as might be seen with
exercise) is more potent than either in combination. Thyroid hormone also seems to play a key in this, being involved in
both thermogenesis and gene expression. Thyroid can't be easily manipulated without drugs, though.
Finally, Chapter 4, I briefly looked at the possibility that the natriuretic peptides, especially BNP may be involved in hunger
and appetite control in the brain. Individuals with elevated NP levels often show a wasting (called cachexia) possibly driven
by increases in thermogeneis but also related to decreased food intake.
While the research is preliminary as hell, infusions of BNP lower subjective hunger and decrease ghrelin release. Acutely,
ANP has been shown to maintain both fat burning and mobilization even in the face of increased insulin when a high-fat
meal. This alone shows how ANP is working via a different pathway for all of this; normally insulin wins in the battle to
control fat mobilization (stopping it). But ANP stimulated lipolysis and fat oxidation was unaffected by insulin.

Let's Back Up and Talk about Receptor Antagonism

In the first chapter of this book I talked about the catecholamines and how they activate their own receptors (the
adrenoceptors). In technical terms, this is called receptor agonism. This simply refers to when a hormone or compound
binds to a receptor and causes it to do whatever it normally does.
But there is another class of compounds called a receptor antagonist. As you might imagine, this compound either blocks or
stops the normal behavior of the receptor. I told you about one already, yohimbe/yohimbine.
An alpha-2 receptor antagonist, yohimbine blocks the normal effect of the alpha-2 receptor (which is to slow fat
mobilization). It's effect is thus to increase fat mobilization. It's a double negative essentially: inhibiting the inhibitor has the
end result of increasing whatever is supposed to happen.

But let's follow that train of logic and think about what a beta-antagonist (also called a beta-blocker) would do. So first,
recall that beta-agonist drugs like clenbuterol and ephedrine tend to increase fat mobilization, etc. and they do this by acting
as agonists at the beta-receptor (they raise heart rate and blood pressure as well).
But what if you wanted to lower blood pressure, as in someone with hypertension? You might guess that you could use a
drug that was an antagonist to the beta-receptor. That is, if beta-agonism raises blood pressure, beta-antagonism would
lower it. And this class of drugs exists and does exactly that, they are called beta-blockers.
Beta-blockers reduce heart rate and blood pressure and are often used by people before a big performance or speech to help
folks keep from spazzing out. Athletes such as archers and pistol shooters use beta-blockers too to slow their heart rate; they
actually try to fire between heart beats so that their aim is less twitchy.
But what else might a beta-blocker do in the body? If we know that beta-activation stimulates lipolysis, we'd expect a betaantagonist/blocker to shut down lipolysis. Which should be a distinctly bad thing. So why am I talking about this at such
length?

How Was the ANP Pathway Discovered?

Earlier in this book I mentioned that researchers had somehow (you probably assumed magic) discovered this brand
spanking new fat mobilizing pathway involving ANP but I didn't explain what even stimulated them to go looking for such.
Or how they found it. Because that would have ruined the punchline of this chapter which some of you may have already
guessed.
Because the ANP pathway was originally discovered, or at least suggested to exist in studies of, drum roll, heart
failure/hypertensive patients taking beta-blockers. Wait, what?
As I discussed above, beta-blockers should more or less eliminate fat mobilization by blocking the primary (and at the time,
sole discovered) pathway that stimulated it. But it was seen in these subjects that while fat mobilization was certainly
reduced, it was not eliminated completely. But as above, a beta-blocker if it's the only pathway of relevance should block
lipolysis. Yet there was still some going on.
Now after nearly 100 years of data, researchers figured that they had the fat metabolism and lipolytic pathways pretty well
figured out. And yet here was this weird-assed observation that didn't make sense: how could the body maintain fat
breakdown in the face of complete beta-receptor blockade? So they went looking for an explanation.
And what they discovered was this: not only do these patients have already raised levels of ANP but many of the betablocker drugs that these patients are given further raise ANP. And they looked further into it they found not only natriuretic
peptide receptors on the fat cell but were able to figure out that ANP binding stimulated lipolysis by a previously
undiscovered, non-catecholamine related, non-insulin related, non-cAMP related pathway. And that through this ANP
pathway, could stimulate fat breakdown.
Mind you, when I wrote The Stubborn Fat Solution, I only had half of the picture on all of this. I knew what ANP was,
what the pathway was but outside of exercise and the fluid stuff I talked about, I hadn't found any meaningful way to raise
ANP levels. But as I mentioned in the introduction, a few months later I'd come across the research that filled in the missing
pieces: beta-blockers raised levels of ANP (and the other NPs) and gave it some potential to utilize this pathway. I spent a
while looking into it, started this booklet and then walked away from it.
Again, I'm kind of glad given the new research into beige fat, appetite and everything else I've discussed. Because after
several chapters of introduction, I'm going to discuss is the use of beta-blockers, a drug that should pretty much do nothing
but bad for fat loss, and how they can help on a diet. By increasing lipolysis, by possibly increasing beige fat, by helping to
control hunger and appetite (maybe).
Am I nuts? Possibly but read on, in the next chapter I'll discuss some of the issues and problems that exist and how, by
being crafty, we can side step them completely and do some nifty things.

Chapter 6: Beta-Blocker Effects

Ok, last chapter seems to have taken quite the left turn from what I first described in this book. Somehow I reached the
conclusion that a beta-blocker a drug that should hurt fat loss can actually be useful, by raising ANP (and BNP) levels in the
body and cause a number of good things to happen.
So boom, everyone will run out and get a beta-blocker and lose fat, right? Women will be able to lose lower body fat easily
(because ANP receptors don't appear to be related to fat depots meaning that we can side step the normal problems with
lower body fat) and all will be good with the world. Well, not exactly.
There's usually a catch with this stuff and that's the topic of this chapter. Because if it were as simple as taking betablockers for fat loss, then you'd expect all of those hypertension and heart failure patients to be super lean and that's
generally not the case. Sure there is the weird cachexia/wasting that occurs in heart failure patients but that could just as
easily be due to decreased food intake.
If anything, patients on chronic beta-blocker therapy tend to have problems losing fat and issues with slight weight gain; yet
another reason that what I'm proposing in this book seems to make so little sense. And now I'm going to explain the reason
to you and how we can work around it.

More About Beta-Blockers

As a general rule, to eliminate variables, researchers tend to only look at drugs in isolation (although in disease states, often
they are stacked for therapeutic reasons) and beta-blockers by themselves clearly do NOT cause fat loss.
While lipolysis is maintained to some degree with beta-blockers, it is still lower than what is seen without them so this is not
surprising. As I mentioned, the patients would certainly mobilize more fatty acids without the beta-blockers than they do
using the drugs in isolation.
Given the role of beta-receptors in overall metabolism, there is also often a small reduction in metabolic rate with chronic
beta-blocker use. It's not huge, one study found 2.7% decrease in 24 hour energy expenditure while on the drugs (other
studies suggest a larger effect). For someone with a maintenance level of 2700 calories per day, that's about 70 calories
which you can burn with 10 minutes on the treadmill. It's not a huge amount of course but it all adds up in the long term.
Things that slow metabolic rate are, by and large, not a good thing when the goal is fat loss/you are dieting.
In that vein, there is often a small long-term weight gain for patients on long-term beta-locker therapy. In any case, the
weight gain is small, perhaps 2-3 kg (4-6 pounds or so) over about 5 years. Hardly anything to worry about on a short-term
diet but it does point out that these drugs lower metabolic rate and have a generally negative impact.
Confusingly, the effect depends a lot on which beta-blocker is being looked at (there are two primary classes of betareceptors). Like most drugs in the same class, there are different kinds of beta-blocker drugs. Certainly these effects don't
seem to fit well with the rest of this book where I crowed on about how awesome ANP appears to be.
There is also some indication that beta-blockers may negatively affect protein synthesis which could lead to muscle loss.
Sufficient protein and an exercise program have both been suggested and, once again, this is only an issue when the drugs
are used long-term by themselves.
Ultimately, using beta-blockers to improve any aspect of fat loss or whatever seems insane and you may be wondering if
I've lost it. And it would be absolutely true if all you were looking at was using beta-blockers by themselves. In isolation,
beta-blockers would be expected to hurt things, ANP be damned. But the key to that sentence is the phrase "In isolation."
Because a key aspect of making what I'm going to describe work is realizing that beta-blockers have to be taken with at
least one other compound (and I'll describe some stacks from mild to wild in the last part of this book) to be effective. Let
me put that more directly: if you go get ahold of some beta-blockers and start taking them and them alone, they
might actually make you gain fat or at least slow your diet results. And if you don't get anything else out of this booklet,
please read that sentence 5 or 6 more times and let it sink in. I really don't want emails from people that they took betablockers by themselves and it hurt their diet efforts.
But to understand how to make beta-blockers work through ANP, I need to get into a bit more detail on the issue of betareceptors an talk about some of the details I skirted in earlier chapters.

Beta-Adrenoceptor Redux
As I mentioned earlier in the book, there are actually three primary subtypes of beta-receptors, beta-1, beta-2, and beta-3.
Beta-3 aren't that relevant in humans, we don't have many and the ones we do seem to go away quickly when stimulated.

Now, from a physiological standpoint, part of the reason the body has different types of receptors is so that the same
hormone (or hormones) can do different things in different places in the body. A good example is the brain chemical
serotonin as there are about 15 different types of serotonin receptors. So serotonin can have vastly different effects in
different parts of the body depending which receptor type (or types) is present, in what ratios they are present, etc. This is
really just an efficiency thing for the body: rather than having 15 different hormones, it has one hormone and 15 different
kinds of receptors.
Beta-receptors are the same way, by having different types in different parts of the body, it allows a chemical (or in this case
two related chemicals: adrenaline and noradrenaline) to have different effects at different places. I already mentioned how
the ratio of beta-2 to alpha-2 receptors impact enormously on whether or not fat is easy or difficult to mobilize and the same
thing is seen elsewhere in the body.
Thankfully, compared to serotonin receptor subtypes, beta receptors aren't nearly as complicated as there are really only two
we need to worry about: beta-1 and beta-2 receptors (as above, the beta-3 receptor isn't that relevant to human physiology).
And although they have nothing to do with beta-receptor agonism or antagonism, we only have to worry about alpha-2
receptors in terms of fat cell metabolism.

Receptor Affinity: A Primer

As I noted above, the body has an efficient way of getting things done by using the same hormone or chemical to do
different things in the body based on what kind and how many of of specific receptor subtypes there are. Beta-receptors are
no different and beta-1 and beta-2 receptors are found in differing amounts in different parts of the body.
In addition to giving the body itself more precise control over various processes, this has one more important implication: it
allows us more control in how we manipulate different processes.
As it turns out, certain drugs can have relatively more or less affinity (a scientific term referring to how well or poorly a
given compound binds to a receptor) for one or the other receptor. So, for example, ephedrine is a general beta-agonist, it
hits beta-1 and 2 receptors pretty evenly; in contrast, the drug clenbuterol is much more specific for the beta-2 receptors.
Clenbuterol is said to have higher affinity for the beta-2 receptors.
I'd note that beta-blockers can also be relatively more or less specific for one or the other beta-receptors. I mentioned above
that there are multiple classes of beta-blockers; in this case there are two specific types: general beta-blockers (which affect
both beta-1 and beta-2 receptors) and specific beta-1 blockers. There are no beta-2 blocker drugs in use for some reason.
And, As you'll see, choice of drug to make this work is important to make sure we are hitting the right receptors with the
right compounds to achieve the desired results.
Specifically, by being creative, we can use this type of selectivity to get the benefits of certain compounds without the
drawbacks. This will make more sense shortly.

Back to Beta-1 and Beta-2 Receptors

Relevant to this book, the heart has both beta-1 and beta-2 receptors but, relatively speaking, beta-1 receptors are more
prevalent and more relevant to heart function. In contrast, fat cells tend to have more beta-2 receptors (there are beta-1
receptors too). This actually explains the difference between ephedrine and clenbuterol in terms of both good and bad
effects.
Since ephedrine activates both beta-1 and beta-2 receptors, it affects heart function more, that's why you get more wired and
heart rate and blood pressure go up to a greater degree. Basically, ephedrine has greater side effects due to its relative nonspecificity for beta-receptors.
Clenbuterol, by being more beta-2 specific has less effects on the heart (which has fewer beta-2 receptors) and more effects
at the fat cell. So clenbuterol mobilizes fat more effectively with far fewer side effects (you don't get as wired and heart rate
and blood pressure doesn't go up as much).
A drawback of this is that clenbuterol rapidly reduces the number of beta-2 receptors. It hits them so well and for so long
(clen stays in the system for a good 36 hours) that they decrease in number. And clen usually stops working after about 2
weeks. It's been suggested that anti-histamines (think Benadryl) and specifically Ketotifen might prevent the normal
reduction in beta-2 receptors by clenbuterol to keep it working beyond those couple of weeks..
As I noted above, different beta-blockers also can be relatively more or less specific and there are two major types of betablockers in use. The first are general beta-blockers which antagonize both beta-1 and beta-2 receptors (examples include
Pindolol and Propranolol). The second are beta-1 receptor specific drugs. (examples include Atenolol and Metoprolol).
Again, there aren't any beta-2 specific blocker drugs.

I'd note that both general beta-receptor blockers and beta-1 receptor blocker drugs reliably raise ANP at rest and during
exercise and they do this in both hypertension/heart disease patients AND healthy individuals. The latter is key, some drugs
that do wonderful things in disease states don't do the same in healthy folks but three different studies show that betablockers raise ANP in healthy folks.

Specific Drugs for Specific Effects

Now, as it turns out, looking at the effects on metabolic rate in response to beta-blockers, the observations based on current
research is a bit confusing. In those studies, metabolic rate and weight gain was tested in response to either general or
specific beta-blockers. Contrary to what would be expected, the general beta-blockers had the least impact on metabolic
rate (keep in mind that the effect is small regardless). Unfortunately, nobody seems to know why this would be the case
since it should be the other way around. The
researchers had some hypotheses but, so far, nobody seems to have gotten to the bottom of why things would work this way.
I'd only note again that the impact of beta-blockers on metabolic rate and weight gain is very small, a few percent drop in
daily metabolic rate and a weight gain of a few kilograms over years; additionally it is only seen when the drugs are used in
isolation. Which, at the risk of beating this particular dead horse a bit more, is not what you'll be doing.
And while this would seem to suggest that a general beta-blocker drug would be the better choice from the standpoint of
metabolic rate and the other effects discussed in this book, I'm actually going to be recommending beta-1 specific betablockers for the remainder of this book.
Let me walk you through the logic:
1. We know that beta-blockers, although they raise ANP, result in less total lipolysis than not using beta-blockers.
2. We know that the primary beta-receptor in heart is the beta-1 and that beta-1 specific blockers reliably raise ANP. We
don't need to block the beta-2 receptors in the heart to raise ANP.
3. We know that the primary beta-receptor on fat cells in terms of stimulating lipolysis are beta-2 receptors which can be
targeted with exercise, ephedrine or clenbuterol.
So we can combine a selective beta-1 blocker to raise ANP (which will have less impact on the fat cell) and then combine it
with a beta-2 activating compound to get the best of both worlds. You get beta-2 receptor activation of lipolysis, you get
ANP mediated activation of lipolysis and you don't get any problems with stuff fighting with other stuff. The effect on heart
rate and blood pressure won't be as profound either since the beta-agonist will help to offset the effects of the beta- blocker
to some degree.
And even with the small reduction in metabolic rate from the beta-1 antagonist, this small effect can and will be readily
overcome by whatever you use to activate beta-2 receptors. Ephedrine and caffeine easily raises metabolic rate by more than
the small drop in metabolic rate from the beta-blocker and clen is more effective still. Even a paltry 10 minutes on the
treadmill will more or less overcome any negative effect. You get double benefit with less side effects.
And that's basically it: I'm going to suggest stacking a beta-1 specific beta-blocker with something that activates the beta-2
receptors in the fat cells. Alpha-2 antagonism (such as from yohimbine) can be useful here too. Lest we forget, the
combination of beta-2 agonism and ANP stimulated effects appear to be higher than either compound in isolation. Mind
you, exercise and/or a caloric deficit is still going to be required to get any benefit, so that the now mobilized fatty acids are
burned elsewhere for energy.
I already mentioned that several studies in normal, healthy individuals show that beta-blockers enhance the ANP response to
exercise which should be a double plus. I should mention that beta-blockers do hurt exercise performance (tested at high
intensities in terms of time to fatigue) but the exercise I'll recommend is low intensity; also we're looking at fat loss here,
not performance enhancement. Beta-blocker use in an endurance athlete would be a disaster.
As well, by using a pharmaceutical approach (which will maintain ANP longer than exercise), we can mimic the studies
showing that beige adipose tissue activity and amount are increased. Recall that that takes 6 hours of exposure and with
proper dosing and compound choice, that's doable. With proper drug choice it may even be possible to get longer term
stimulation of beige adipose tissue, almost mimicking some of the chronic cold exposure effects.
Finally, this combination should do a real number on appetite. Ephedrine is known to decrease hunger and appetite
(clenbuterol less so) and that combined with the BNP increase from the beta-blocker should help as I talked about in
Chapter 4.
Basically, so long as you don't use beta-blockers by themselves and make sure to combine them with something (or more
than one something) that increases beta-receptor stimulation, the only outcome should be positive. Any negatives of the
beta-blocker is more than overcome by the use of a beta-agonist compound. So let's look at some potential stacks.

Chapter 7: Putting it All Together

Ok, some of you are probably wondering why I didn't just release this chapter with a couple of pages introduction but
anybody who has read my work knows that that's just now how I do things. I needed to explain to you the why behind the
what and wherefore. This chapter is all about that.
Here I want to talk a bit about the compounds we have to work with, some of their pros and cons, and then look at some
suggested stacks. The stacks will increase in intensity (or insanity) and potential problems as we go.

Beta-Blocker Choice
As per the last chapter, I recommend picking a beta-1 specific blocker as this will have it's primary impact at the heart in
terms of raising ANP and BNP. Some drugs to consider are one of the following:
Atenolol (trade name Tenormin)
Betaxolol (trade name Kerlone)
Bisoprolol (trade name Zebeta)
Celiprolol
Esmolo (trade name Brevibloc)
Metoprolol tartrate (trade name Lopressor)
You can use the links above to get specifics about dosing, how long they stay in the body, etc. for the different drugs. For
example's sake, I'll focus on metoprolol since it's one of the oldest, the side effects and dosing is exceedingly well
established and has been shown to reliably raise ANP in healthy individuals, etc. Metoprolol comes in both a short and longacting form and the choice of one versus the other depends on what else you intend to take with it. It's also inexpensive and
can be ordered online.
Dosing can range from 100-450 mg/day (remember that this is for heart failure patients) and 100-200 mg is probably plenty
for the application in this book. The beta-blocking effects of the drug will be seen within an hour of taking it. Depending on
how quickly an individual metabolizes the drug, it can stay active from 3 to 6.5 hours in the body and this is dose dependent
as well (a 100 mg dose was still 50% active after 6.5 hours). In heart failure or for hypertension treatment, the drug is
typically dosed twice daily due to it's fairly short effects but that's not what we're using it for.
There is also a long acting form of metoprolol called Metoprolol ER (extended release) or Toprol XL. This form releases the
drug into the body over a slower time course (dosing is typically once/day) but also results in lower levels of the drug. Beta1 activation is still roughly the same. Given the lower levels achieved compared to metoprolol, taking about twice as much
(200-400 mg) of the extended release would be a good rue of thumb. But you only take it the once per day.
Recall from a previous chapter that while effects such as fat mobilization are relatively rapid, any of the long-term effects
on things like beige fat probably take longer. So choice of metoprolol versus the ER version will be related to that. It will
also depend on the type of thermogenic chosen to accompany it.

Ephedrine/Caffeine
Ephedrine has been around for decades and despite some deaths (invariably related to excessive intake), is extremely safe.
Ephedrine is combined with caffeine in ratios of 20mg ephedrine to 200mg caffeine and taken anywhere from 1-3 times per
day (generally first thing in the morning, at lunchtime and perhaps at 4pm; some people have trouble sleeping when they
take the third dose). It stays active in the body for about 4 hours and has a small (about 5%) thermogenic effect in addition
to it's appetite blunting and fat mobilizing effects.

Green Tea/Nicotine
Of late, it's been harder to get ephedrine and there are other potential compounds that are at least similar in terms of their
effect and could be substituted. One is green tea although technically the active ingredient is epicatechin gallate.
Recommended doses are 300 mg and it should be taken with caffeine for maximum effect.
Another compound to consider is nicotine. Combined with caffeine, it also has thermogenic effects and helps to mobilize
fat. It also tends to suppress appetite via a brain mechanism. A patch or nicotine gum would be suggested with a 2mg dose
being sufficient. Clearly I'm not recommending smoking as a source of nicotine. Note that the majority of negative effects
are due to the other chemicals in cigarettes, nicotine in and of itself does not carry the same risks (and may actually be
protective against Alzheimer's and Parkinson's disease.

Clenbuterol
Clenbuterol started life as a livestock drug but athletes quickly got ahold of it when they found out about its amazing effects

in animals. A very specific beta-2 agonist it is known for some pretty amazing transformations, seeming to cause fat loss
while muscle is gained. This is especially true if it's combined with thyroid and the combination has profound effects
on the body, at least for as long as it works. The problem is that it stops working very quickly. Clenbuterol stays in the body
for a solid 36 hours and that, along with it's high binding affinity for beta-2 receptors, causes the effects to be rapidly lost.
Clenbuterol typically comes in 20 mcg pills and the effective dose is 100-140 mcg (5-7 pills) per day for men and 80- 100
mcg (4-5 pills) per day for women. Some suggest starting with 1-2 pills and ramping up slowly to check for side effects. But
they tend to be so much lower than ephedrine in the first place, along with the fact that their use with a beta- blocker should
eliminate any small effects that I see no reason to ramp up like this.
Many have suggested taking an anti-histamine such as ketotifen at 1mg/day starting in the second week of regular clen use.

Yohimbine
While not a true thermogenic, yohimbine is still important for fat loss since it's blocks those pesky alpha-2 receptors in
stubborn fat. Yohimbine tends to raise heart rate and blood pressure and combining it with ephedrine can cause a double
whammy (but see below). Many still think that yohimbine affects testosterone because it gives people boners but this is just
a blood flow thing.
Yohimbine is dosed at 0.2 mg/kg so a 180 pound/81 kg lifter would need 16 mg. Yohimbine HCL (the drug version which
has less side effects than the herbal) comes in 2.5 mg pills so that would be 7 pills for our 180 pound lifter. Caffeine helps of
course but yohimbine is completely inactivated by insulin and must be used fasted (ideally before cardio to help burn off the
calories). Yohimbine should NOT be used by anyone with a propensity to anxiety attacks as, in high doses especially, it can
trigger them (researchers actually use yohimbine to research anxiety attacks).

Thyroid
Unlike the previous entries, thyroid is made within the body and comes in two primary forms: T4 and T3 with the thyroid
gland releasing them in roughly an 80:20 ratio. T4 is essentially a storage form of thyroid and it's conversion to T3 in places
like the liver is really the key. T3 increases metabolism, affects protein synthesis, and is involved in gene expression for a
lot of things.
When folks diet, the conversion of T4 to T3 goes down in the liver, this is called Euthyroid Stress Syndrome (ESS). Despite
tons of literature on this, some doctors don't believe that it exists and will only give T4 for people suffering from "low
thyroid". True hypothyroid and ESS actually show distinctly different patterns in the body when you get blood work done.
True hypothyroid is marked by low T4 and T3 and high TSH (thyroid stimulating hormone). The body is trying to produce
enough thyroid but since the gland isn't responding, it jacks TSH to try to compensate. In ESS, you see normal TSH, normal
T4 and low T3. This indicates that the gland is working just fine, it's the conversion from T4 to T3 that is impaired.
Certainly T4 helps for someone who is truly hypothyroid, when the thyroid gland isn't doing it's job. But for ESS T4 doesn't
help much at all. For that folks need to use straight T3 (a common trade name is Cytomel). Some people have also gotten
good success with Armour thyroid, a natural form of (pig) thyroid that is a mixture of T4 and T3.
T3 used to be used for weight loss back in the day but it sort of crapped out. In high amounts it causes a racing heart and a
lot of muscle loss. There is even a small chance of something called thyroid storm. It's use was fairly rapidly discontinued.
However, T3 is interesting for our purposes for a number of reasons. The first is that thyroid and things like ephedrine and
clenbuterol interact synergistically. Beta-agonist drugs like ephedrine and clen increase thyroid conversion and activity and
thyroid sensitizes the beta-receptors such that beta-agonist drugs work that much better. Clen plus thyroid has profound fat
loss effects and this is likely the cause.
As above, too much thyroid is as bad as too little and some folks get a little bit nuts. 25-50 mcg of thyroid is a full
replacement dose and there's little to no reason to take more. Even 12.5 mcg has been shown to have positive effects. More
is not better. Most will be fine with 25 mcg if they use it all, bigger boys may want to use 50mcg but without anabolic
steroids, more than that just causes muscle loss.

DNP
And that brings us to the king of all thermogenics, DNP which is an abbreviation for di-nitro-phenol (to help the organic
chem nerds visualize it). While a thermogenic, DNP works through a completely different mechanism than everything I've
talked about before.
You may recall my mention of mitochondria (the powerhouse of the cell) in previous chapters. Well rather than impacting
on beta-receptors like the above compounds, DNP works on the mitochondria. Specifically it does something called

uncoupling. Now, normally mitochondria take glucose and fatty acids and burn them for energy (also generating heat).
DNP blocks this process, it uncouples mitochondrial function from energy production. That is, the normal energy
production from burning glucose and fat can't happen when DNP is in the system. So the mitochondria just keeps burning
more and more fuel in its futile attempt to provide the cell with energy. Again, the consequence of this is the generation of a
lot of heat.
Even low doses of DNP ramp up metabolic rate drastically, a small 100mg dose will raise metabolic rate by about 10%. So
someone with a daily energy expenditure of 2700 calories might burn 270 more from DNP alone. That's nearly 30 minutes
on the treadmill. Higher doses have an even bigger impact and it's possible to get a 50% boost in metabolism. Big boys with
high metabolic rates can get enormous fat losses at higher doses.
Fantastic, right? Well, yes and no. The end result of this is the generation of a lot of heat. At even moderate doses, DNP
users feel like they are running a fever. Unlike most drugs, DNP has no upper limit of activity, the more you take the more
of an effect you get in terms of both metabolic rate increase and temperature increase. Beyond a certain point, body
temperature goes up above a critical point and you cook yourself and your brain from the inside out. Overdose on DNP and
you can very readily kill yourself and this is no exaggeration.
And if this happens, there is no help to be had. DNP stays in the body for a solid 36 hours and if you take too much you just
have to wait it out. The hospital will give you an ice water enema and stick you in an ice bath in an attempt to keep you
from poaching from the inside out and there have been a few nasty cases recently where bodybuilders took way too much
and ended up cooking their brains.
To say that DNP is THE most dangerous compound (insulin is close) that people could consider using is an understatement.
Most things give you some wiggle room with dosing but one massive DNP screwup leaves you dead or wishing you were.
DNP was insanely popular in the early part of the 20th century and found it's way into the, then unregulated, diet industry.
Unfortunately, this caused people to take too much and there was unpleasantness. There was a slight increase in cataracts
and between that and side effects, DNP was pulled and regulated.
Later on, DNP made a comeback by a weight loss doctor who combined it with thyroid hormone for a potent fat loss
combination for obesity treatment. He was eventually discovered by notorious drug guru Dan Duchaine who re-popularized
it in the bodybuilding subculture in the late 90's.
Thankfully, given that high doses make people feel miserable and have some potential risks, the current trend for DNP use
is lower doses for long periods. Even 100-200 mg/day can ramp metabolic rate by 10-20% (and given DNP's half-life the
amounts sort of build up) without causing folks to feel like they want to die.
I honestly don't expect many people to even consider using DNP. It's hard and expensive to get (if you don't know how, you
don't need to be using it) since it's not actually thought to be for human consumption. It's actually used as a bug poison
(burns them up from the inside) and researchers use it to study and/or kill yeast.
It can be sourced online, usually someone gets ahold of a bottle, caps it and sells it at exorbitant prices (like $1 per pill). If
you can find a bottle of it, $20 worth will last pretty much your entire life but you have to know how to cap it yourself. It's
messy, stains your hands orange and is a big hassle. But it works like nothing else.
Everything else, ephedrine, clenbuterol, thyroid and even beta-blockers can all be ordered far more easily from online
pharmacies (I won't give you sources in this book).

Diet
Readers may note that I didn't talk much about diet in this booklet which is kind of rare for me. Surprisingly, there is simply
not a lot of work on how diet or nutrition impacts on ANP or any of these processes. What little exists is invariably in heart
failure patients or rats (who have a very different system for the NP's).
I would point out that none of this stuff in terms of fat mobilization, etc. will work unless you are in a caloric deficit. The
only way to ultimately burn fat off the body is a deficit and mobilization is only part of that equation. You need to burn the
fatty acids by reducing total food intake below maintenance, by increasing exercise (see below) or both. At least a 15- 20%
caloric deficit should be used and you can see articles on my site about how to set up a basic fat loss diet.
http://www.bodyrecomposition.com/fat-loss/the-fundamentals-of-fat-loss-diets-part-1.html/
http://www.bodyrecomposition.com/fat-loss/the-fundamentals-of-fat-loss-diets-part-2.html/
I would offer that due to it's tendency to lower blood pressure in and of itself, a very-low carbohydrate diet will be a
mistake. Beta-blockers can reduce BP and there is real concern over dropping it too low (of course folks who already have
high BP don't have to worry about this much). Certainly carbs can be moderated to reduce calories and insulin and such but

don't go to ketogenic (less than 100-120 grams of carbs per day) or very low carb levels.
Beta-blockers can have an effect on protein synthesis but this can be overcome with sufficient dietary protein and resistance
training (which should be part and parcel of any diet anyhow).
Lean athletes won't have any problem with getting enough protein but many general dieters simply don't eat enough protein.
Leaner individuals should get at least 1 gram of protein per pound and sometimes even 1.5 g per pound is needed.
Fatter individuals can get away with less, perhaps 0.75 g/lb of protein per day. Given that protein helps to blunt hunger,
eating more than that won't hurt and may help on a diet even if it's not absolutely required.

Exercise
I should probably mention aerobic exercise here. Because while all of the above is incredible in terms of thermogenic
effects and fat mobilization, we still need to optimally burn off the fatty acids being mobilized. With the exception of DNP,
which more or less makes exercise superfluous, I'd recommend anybody trying the stacks I'm going to describe combine it
with some form of aerobic exercise. Low intensity is fine, some research shows that higher intensity raises ANP more but
you shouldn't need that.
Just pick an intensity that is challenging but not impossible and put in your 30-60 minutes. You could even try one of the
higher intensity stubborn fat protocols, just realize that your heart rate may not go as high as you think it should due to the
beta blocker. You should generally wait at least an hour after taking whatever stack you end up taking to do your cardio.
None of these drugs are immediately acting and you want to wait for fatty acids to build up before burning them off.
And while fasted cardio has recently gotten crapped on in a literature review, at least some of the compounds above work
best when insulin is low. Certainly it's nice that ANP sidesteps the insulin issue but most of the above will still work
optimally in a low insulin state. So wake up, take what you're taking, wait an hour and get to the gym or outside.
I'd also add that heavy resistance training should be included for anyone dieting to spare muscle loss (remember that
resistance training appears to do nothing for ANP but there is almost no research on the topic). A minimum of twice per
week is recommended and I imagine most athletes will do more than that. You can read my suggestions for weight training
on a diet in the following articles.
http://www.bodyrecomposition.com/training/weight-training-for-fat-loss-part-1.html/
http://www.bodyrecomposition.com/training/weight-training-for-fat-loss-part-2.html/
So let's look at potential stacks from simple to insane.

Stack 1: Short-Acting Beta-blocker plus Exercise

While I went on and on about not taking a beta-blocker alone, the hormonal effects of exercise should be sufficient to get
the effects we're looking for: the beta-blocker will raise ANP, exercise will hit the beta-2 receptors along with burning off
the mobilized fatty acids. For this approach I'd recommend a fast acting beta-blocker.
Take it an hour before you exercise with some caffeine (100-200 mg) and put in your 45-60 minutes of low-moderate
intensity cardio. This is unlikely to have much effect on beige fat and will only impact on hunger for a short period but if
you're not going to use a beta-agonist for a more sustained effect, you won't be getting beige fat activity anyhow. A second
dose of the beta-blocker at lunch should help to stave off diet induced hunger.

Stack 2: Short-Acting Beta-blocker plus Ephedrine/Caffeine

I anticipate this being the stack that many readers will be most comfortable with. It ramps things up a notch from the
previous stack but really isn't too far out there. I'd probably still recommend a short acting beta-blocker here, taken at least
once first thing in the morning with 20 mg ephedrine/200 mg of caffeine. Once again wait an hour and then go hit some
cardio.
This will give at least a good 3-4 hour duration of ANP and beta-receptor stimulation. A second dose of each taken at lunch
would extend this for another 3-4 hours. This not only continues the fat mobilizing effect of the combination but now gets
us into the time frame to activate/make more beige fat (hopefully). It will also work to control hunger most of the day.
If it doesn't keep folks awake, a third dose of each could be taken in the early afternoon. 4pm is usually the latest most can
get away with for this and even that may keep some people up. That extends the ANP/beta-receptor activation for nearly 12
hours, surely sufficient to affect beige fat and also control hunger all day.
You could also take a long-acting beta-blocker in the morning and then just add the second and third doses of EC. It would
save you swallowing a couple of pills I suppose.

If ephedrine is unavailable, consider using 300 mg of ECGC/green tea or 1-2 mg of nicotine (patch or gum) with a200mg of
caffeine.

Stack 3: Beta-blocker plus Ephedrine/Caffeine plus Yohimbine

Now we're getting serious. By adding yohimbine to the beta-blocker/EC combination we're now adding alpha-2 receptor
antagonism to the mix. This doesn't help with calorie expenditure, thermogenesis of beige fat recruitment but does help to
overall mobilize fatty acids.
Now, normally I recommend against the combination of EC and yohimbine. The mixture of the two tends to jack up heart
rate and blood pressure and, in some people, it's simply not safe. However, due to the addition of a beta-blocker, this
risk is removed. This is an odd stack, you feel wired but somehow calm at the same time. I used to joke that when you take
uppers and downers you reach middle and this is kind of like that.
Regardless of you're dosing of the beta-blocker and EC (i.e. once or multiple times daily), you should only take yohimbine
(0.2 mg/kg) all at once an hour before fasted cardio. And I mean fasted, even small amounts of insulin block yohimbine's
effects completely. You can, as above, take EC and a beta-blocker later in the day to get the long term effects.
Again, ephedrine is unavailable, consider using 300 mg of ECGC/green tea or 1-2 mg of nicotine (patch or gum) with the
200mg of caffeine.

Stack 4: Long-Acting Beta-blocker plus Clenbuterol

I tend to think this stack will be a line that many are not willing to cross for some reason. I could be wrong. Recall from
above that clenbuterol is far more potent than ephedrine and stays in the system far longer. Combining it with anything but a
long-acting beta-blocker would make no sense and that's what I would recommend here. So you're looking at 80-120 mcg of
clenbuterol and 100-200mg of Metoprolol ER. Just take it first thing ever morning and be done with it.
Users would expect a chronic beta-agonist and ANP response to occur from this stack as both are being ramped up pretty
much 24/7. I'd still recommend some morning cardio to burn off fatty acids but clen does a pretty good job. Remember that
clenbuterol stops working pretty quickly, petering out in 2-3 weeks with regular use. Either use the above for a blast type of
fat loss cycle (use a larger deficit, perhaps 25-30% but plan to end your diet after 3 weeks) or be prepared to add ketotifen at
1 mg/day about a week in to keep it working longer than that.

Stack 5: Long-Acting Beta-blocker plus Clenbuterol plus Thyroid

Identical to the stack above but you can get metabolism and everything else really raring with the addition of 25mcg (50mcg
is the absolutely maximum) of T3 per day. So 80-120 mcg clenbuterol, 100-200 mg of Metoprolol ER and 25- 50mcg of
thyroid. It can all be taken once per day since at this point we're looking at long-term effects. Again, some cardio at some
point helps to burn off the fatty acids.

Stack 6: Long-Acting Beta Blocker plus Clen plus DNP plus Thyroid
At this point we're going all in for what will either be the most amazing or most lethal combination. We've got a long- acting
beta-blocker (i.e. Metoprolol ER) to keep ANP elevated and trigger lipolysis. To that add clenbuterol for some nice beta-2
agonism for all of the effects described in this book (lipolysis, thermogenesis, beige fat activation/recruitment, and appetite
suppression). Throw in some DNP at 100-200 mg/day (tops), the mother of all thermogenics to burn off all of those fatty
acids.
This won't help with anything but burning off the fatty acids being mobilized from the fat cells but you pretty much won't
need cardio if you do it this way. Throw in a bit of thyroid at 25-50mcg per day to potentiate the clen and plan on ketotifen
at 1 mg/day if you even need to diet longer than 2-3 weeks. To say this will make you a fat burning machine would be an
understatement.

Variations on a Theme
And I imagine creative readers can come up on other variations on this theme. Just keep the primary goal of all of this in
mind. Raising ANP with a beta-blocker either acutely (for fat mobilization effects) or longer term to activate/hopefully
create more beige fat.
Add to that a beta-agonist such as EC or clen for exactly the same reason. Small amounts of thyroid can have it's place,
yohimbine helps with fat mobilization (less so with the other effects), DNP is the mother of all thermogenics that most
people are probably better off not messing around with.

Selected References
Since the reality is that most don't care about full reference lists (and the ones who do can generally look up what they need
themselves, especially if you give them a place to start), I'm not going to provide a complete reference list for this booklet.
Rather, I'm going to give some selected references, focusing on some of the major points I addressed in this book. I'll make
short commentary on them so you know what they are dealing with.

Fat Cell Physiology

Lafontan M Adrenergic regulation of adipocyte metabolism. Hum Reprod. (1997) 12 Suppl 1:6-20.
One of many reviews on adrenoceptors and how they modulate fat cell metabolism.
Cianflone K et. al. Acylation stimulating protein (ASP) an adipocyte autocrine: new directions. Seminars in Cell
Developmental Biology (1999) 10: 31-41.
The paper that everyone still locked into the 20 year old insulin/LPL model of fat storage should read, detailing the role of
ASP in fat cell metabolism and fat storage.
Jensen MD. Cytokine regulation of lipolysis in humans? J Clin Endocrinol Metab. (2003) 88:3003-4
A short review looking at the major hormones impacting on lipolysis.
Meek SE. et. al. Insulin regulation of free fatty acid metabolism. Diabetes (1999) 48: 10-14.
A paper showing distinct differences between the types of fat and how insulin affects fatty acid metabolism.
Fielding BA and KN Frayn. Lipoprotein lipase and the disposition of dietary fatty acids. Br J Nutr. (1998) 80:495-502.
An excellent review of the role of LPL in fat cell metabolism.

ANP and Fat Mobilization

Langin D et. al.Millennium fat-cell lipolysis reveals unsuspected novel tracks. Horm Metab Res. 2000 Nov-Dec;32(1112):443-52.
This is the first paper I can recall talking about ANP and how it represented a new fat mobilizing pathway.
Moro C et. al. Atrial natriuretic peptide contributes to physiological control of lipid mobilization in humans. FASEB J. 2004
May;18(7):908-10.
Another paper showing that the NP's control fat mobilization in humans.
Moro C et. al. Atrial natriuretic peptide stimulates lipid mobilization during repeated bouts of endurance exercise. Am J
Physiol Endocrinol Metab. 2006 May;290(5):E864-9. Epub 2005 Nov 15.
The paper showing that two 45' bouts of exercise with an hour rest caused ANP to have a greater fat mobilizing effect.
Moro C et. al.Differential regulation of atrial natriuretic peptide- and adrenergic receptor-dependent lipolytic pathways in
human adipose tissue. Metabolism. 2005 Jan;54(1):122-31.
Yes, Moro has quite the interest in ANP. This paper clearly showed that ANP worked outside of the beta-receptors; also
showed that while insulin inhibited beta-receptor function it did NOT block ANP stimulated lipolysis.
Moro C et. al. Sex differences in lipolysis-regulating mechanisms in overweight subjects: effect of exercise intensity. Obesity
(Silver Spring). 2007 Sep;15(9):2245-55.
A paper showing that overweight women might be more dependent on ANP stimulated lipolysis than men.
Nagashima K1 et. al. Relationship between atrial natriuretic peptide and plasma volume during graded exercise with water
immersion. J Appl Physiol (1985). 1995 Jan;78(1):217-24.
An odd little paper showing that ANP increases at a lower exercise intensity during water exercise (walking on a treadmill
believe it or not) compared to walking on land.
Lafontan M. et. al. Control of lipolysis by natriuretic peptides and cyclic GMP. Trends Endocrinol Metab. 2008 MayJun;19(4):130-7
The French are fascinated by fat metabolism and Lafontan has done endless studies; this is another showing that the NP's
affect lipolysis by a cGMP mediated mechanism.
Birkenfeld AL et. al. Lipid mobilization with physiological atrial natriuretic peptide concentrations in humans. J Clin
Endocrinol Metab. 2005 Jun;90(6):3622-8.
Showing that the fat mobilizing effects of ANP occur in the physiological range, this isn't something requiring massive
increases.
Birkenfeld AL Atrial natriuretic peptide induces postprandial lipid oxidation in humans. Diabetes. 2008 Dec;57(12):3199204.

The paper showing that ANP increases fat oxidation and mobilization with the consumption of a high-fat meal.
Bouissou P et. al. Effects of propranolol and pindolol on plasma ANP levels in humans at rest and during exercise. Am J
Physiol. 1989 Aug;257(2 Pt 2):R259-64.
Another paper showing that beta-blockers raise ANP in humans at rest and during exercise.

Brown/Beige Fat
van Marken Lichtenbelt Brown adipose tissue and the regulation of nonshivering thermogenesis. W Curr Opin Clin Nutr
Metab Care. 2012 Nov;15(6):547-52.
One of the papers discussing the rediscovery of human brown adipose tissue (before the realization that it was beige).
Wu J et. al. Genes Dev. 2013 Feb 1;27(3):234-50. Adaptive thermogenesis in adipocytes: is beige the new brown?
A recent paper looking at the shift in concept for brown adipose and beige adipose tissue in humans.
Schlueter N Metabolic actions of natriuretic peptides and therapeutic potential in the metabolic syndrome. Pharmacol Ther.
2014 Oct;144(1):12-27.
A paper suggesting that the NP's may be useful for combating obesity, etc. by increasing lipolysis, fat burning and
mitochondrial function.
Whittle AJ1, Vidal-Puig A. NPs -- heart hormones that regulate brown fat? J Clin Invest. 2012 Mar;122(3):804-7.
One of several papers suggesting that the NP's regulate brown function and activity (now beige) fat.
Bordicchia M Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and
human adipocytes. J Clin Invest. 2012 Mar;122(3):1022-36.
The paper showing that NP's both by themselves and in conjunction with beta-2 receptor activation can induce
mitochondrial density, oxygen consumption and the gene program that activates/makes more beige fat.
Elsen M Browning of white fat: does irisin play a role in humans? J Endocrinol. 2014 Jul;222(1):R25-38.
One of many papers examining the role of irisin in humans and beige fat.
Scalzo RL et. al. Regulators of human white adipose browning: evidence for sympathetic control and sexual dimorphic
responses to sprint interval training. PLoS One. 2014 Mar 6;9(6):e90696.
A paper looking at sprint training which found that women but not men increased irisin in response to sprint training which
might play a role in making more beige fat.
Brooks S et. al. The hormonal responses to repetitive brief maximal exercise in humans. Eur J Appl Physiol Occup Physiol.
1990;60(2):144-8.
The paper showing that sprint training raises ANP, more in women than men, at the very end of the sprinting.
Roberts LD et. al. -Aminoisobutyric acid induces browning of white fat and hepatic -oxidation and is inversely correlated
with cardiometabolic risk factors. Cell Metab. 2014 Jan 7;19(1):96-108.
The paper showing that BAIBA is involved in the browning of white fat and that a 20 week exercise program raises BAIBA
to similar levels as seen in mouse/rat models.
Obregon MJ. Adipose tissues and thyroid hormones. Front Physiol. 2014 Dec 11;5:479.
A nice review of the role of thyroid on fat cells including it's role in inducing beige fat.

Energy Balance, Appetite and Hunger

Berkseth KE et. al. A role for natriuretic peptides in the central control of energy balance? Diabetes. 2013 May;62(5):137981.
A review paper examining the potential role of NP's in the brain in terms of controlling energy intake and output.
Costello-Boerrigter LC. Cardiac natriuretic peptides: contributors to cardiac cachexia or possible anti-obesity agents or
both? Diabetes. 2012 Oct;61(10):2403-4.
A paper examining the effect of NP's on the wasting in heart disease as well as their potential for obesity treatment.
Vila G, et. al. B-type natriuretic peptide modulates ghrelin, hunger, and satiety in healthy men. Diabetes. 2012
Oct;61(10):2592-6.
The paper showing that BNP infusion reduced hunger and ghrelin levels.

Beta-Blocker Effects
Sharma AM et. al. Hypothesis: Beta-adrenergic receptor blockers and weight gain: A systematic analysis. Hypertension.
2001 Feb;37(2):250-4. Meta-analysis of studies on the topic showing a slight weight gain with chronic beta-blocker use.

Buemann B A 24-h energy expenditure study on reduced-obese and nonobese women: effect of beta-blockade. J Clin Nutr.
1992 Oct;56(4):662-70.
The study showing a 2.7% reduction in metabolic rate with beta-blockers. Other studies have shown a greater impact.
Luchner A Augmentation of the cardiac natriuretic peptides by beta-receptor antagonism: evidence from a populationbased study. J Am Coll Cardiol. 1998 Dec;32(7):1839-44.
Paper showing that beta-blocker drugs reliably raise NP levels.
Gordon RD et. al.Effects of felodipine, metoprolol and their combination on blood pressure at rest and during exercise and
on volume regulatory hormones in hypertensive patients. Blood Press. 1995 Sep;4(5):300-6.
One of a few papers in non-hypertensive, non-heart failure patients showing that beta-blockers affect natriuretic peptides.
Tsai RC et. al.Effect of beta-adrenergic blockade on plasma levels of atrial natriuretic peptide during exercise in humans. J
Cardiovasc Pharmacol. 1988 May;11(5):614-8.
An early paper showing that beta-blockers led to an increase in ANP both during and after exercise.
Deray G et. al. Beta-adrenoceptor blockade potentiates exercise-induced release of atrial natriuretic peptide. Eur J Clin
Pharmacol. 1990;38(4):363-6.
An early study in healthy individuals showing that beta-blockers, both generic and specific, increased the ANP release
during exercise.
Berlin I Beta-adrenoceptor blockade potentiates acute exercise-induced release of atrial natriuretic peptide by increasing
atrial diameter in normotensive healthy subjects. Eur J Clin Pharmacol. 1993;44(2):127-33.
Another paper showing that beta-blockers raise ANP in conjunction with exercise.
Berlin I Tertatolol potentiates exercise-induced atrial natriuretic peptide release by increasing atrial diameter in healthy
subjects. Cardiology. 1993;83 Suppl 1:16-24.
A paper by the same group showing that beta-blockers increase exercise related ANP release.

Stacks
Lanfontan M et. al. Alpha-2 adrenoceptors in lipolysis: alpha2 antagonists and lipid-mobilizing strategies. Am J Clin Nutr
(1992) 55: 219s-227s.
An early paper looking at the role of alpha-2 adrenoceptor antagonist (such as yohimbe) and how they might help with fat
loss.
Astrup A.Thermogenic drugs as a strategy for treatment of obesity. Endocrine. 2000 Oct;13(2):207-12. Review.
One of many reviews on the ephedrine/caffeine stack.
Harper JA et. al. Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Obes Rev. 2001
Nov;2(4):255-65.
A great paper comparing thyroid hormone and DNP on metabolic uncoupling and raising metabolic rate. Concluding that
DNP is safer than thyroid in many ways.

MY OTHER BOOKS
Depending on what your typical reading materials are, you may or may not be familiar with my other books (I mean beyond
my endless mentioning of them in the text of this booklet) so I thought Id bring them to your attention in case you are at all
interested in what else I have written. All of them can be ordered through my website at http://www.bodyrecomposition.com
THE STUBBORN FAT SOLUTION (PUBLISHED 2008)
The book that this booklet adds a little bit to, The Stubborn Fat Solution was a decade long project, this expands on some of
the information found in The Ultimate Diet 2.0 with a focus on the physiological reasons that men and women both suffer
from stubborn body fat areas (specifically the abs/low back in men and hips/thighs in women).
Along with a complete discussion of all the reasons that cause stubborn fat to be stubborn, the book provides 4 distinct
training protocols along with diet and supplement recommendations to help folks strip stubborn fat from their body. Like
The Ultimate Diet 2.0, The Stubborn Fat solution is aimed at people who are already lean; unlike The Ultimate Diet 2.0, The
Stubborn Fat Solution Protocols do not require that training and diet be completely overhauled; rather the protocols can be
used within the diet and training program that the reader is already on.
THE RAPID FAT LOSS HANDBOOK (COMPLETELY REVISED AND UPDATED IN 2008)
The Rapid Fat Loss handbook describes a low-carbohydrate, low-calorie crash diet capable of causing total weight losses of
10-20 pounds and actual fat losses of 4-7 pounds in only two weeks. How to set up the diet, how optimally to train, in
addition to many chapters dealing with coming off the diet present an integrated system of training and nutrition for the
most rapid fat losses possible.
THE PROTEIN BOOK: A COMPLETE GUIDE FOR THE ATHLETE AND COACH (PUBLISHED 2007)
Similar to my first book on the ketogenic diet, The Protein Book is a comprehensive look at the topic of dietary protein for
athletes. Every topic from basic protein metabolism, protein requirements, nutrient timing around training and supplements
is discussed. As well, each whole food protein and protein powder is examine in terms of its pros and cons for athletes. Of
course, how to put all of the information together for different kinds of athletes (strength/power, endurance, physique) is
included. The book is over 200 pages and includes over 500 scientific references.
A GUIDE TO FLEXIBLE DIETING (PUBLISHED 2005)
The Guide to Flexible Dieting is not a diet or diet book per se, rather it deals with the behavioral issues behind dieting
failures. Addressing in some detail how bodyweight is regulated, along with how diets can fail dieters and dieters can fail on
their diets, it deals with the idea that being more flexible with ones diet, by allowing free meals, refeeds and even full diet
breaks can make them work better in the long-run.
BROMOCRIPTINE: AN OLD DRUG WITH A NEW USE (PUBLISHED 2002)
My second booklet is sort of incorrectly named. Ostensibly its about a drug called Bromocriptine (which has been used for
the treatment of Parkinsons disease for about 30 years) but it really delves into the details of body weight regulation in
some detail. I dont even mention the titular drug until about chapter 6, the first 5 chapters are all about body weight
regulation. This booklet is fully referenced and written in a more conversational and readable style than my first. It is
available only as an e-book.
THE KETOGENIC DIET: A COMPLETE GUIDE FOR THE DIETER AND PRACTITIONER (PUBLISHED
1998)
This was my first project and its a monster. Its 325 pages of information dense text with over 600 scientific references. To
say that it is the be-all, end-all guidebook for low-carbohydrate/ketogenic diets is an understatement. Theres really no other
book in its category. I should note that it is written in a very different style than this booklet or my others; its somewhat dry
and very technical. It covers nutritional and exercise physiology and gives recommendations for three different types of
low-carbohydrate diets, as well as sample exercise programs from beginner to advanced. It is really for the hardcore lowcarbohydrate dieter who truly wants to know everything that is going on in their body when they are in ketosis.

You can read more of my work on my website at

http://bodyrecomposition.com