Childhood

Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

How Do We Gain Weight?

Examining a Set of Lifestyle Practices, Pathologies, and Inherited Factors that Influence Body Weight

Dear Students: This document is an attempt to illustrate the many and varied behavioral and
biological factors that influence body weight. Although these factors are not insignificant,
remember from Intersession 1: Health Disparities and Health Equity that there are social and
policy factors that can have much greater impacts on health, including (and perhaps especially)
obesity. See, for example, the Consumption Junction article included in your readings. One of
our goals generally in Intersession 2 and specifically in the Childhood Obesity TBL is to illustrate
the challenges that many people encounter trying to make healthy lifestyle choices in the face of
significant environmental, financial, social and educational constraints.

Introduction – The Regulation of Body Weight

Animal studies have clearly demonstrated that body weights tend to be relatively stable over
time. The figure below, for example, illustrates that forced overfed rats (gavage fed) will gain
weight (Panel A), but will return to their normal weight once unrestricted (ad libitum)
feeding is restarted. Similarly, as shown in the figure below right, rats will lose weight when
caloric restricted, but regain their normal weight once ad libitum feeding begins.

Recovery of body weight by rats after

a period of caloric restriction.
Journal of Nutrition 127: 1875S (1997)

Figure legend at top of follow page

Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

Daily body weight (A) and weight of chow (B) consumed spontaneously during 8 h (B) in group of 7
gavage overfed (open symbols) and 5 control (closed symbols) rats. Solid bar represents period of
gavage overfeeding. Am J Physiol Regul Integr Comp Physiol 259:R1148-R1155, 1990

Data such as these has suggested that body weight is regulated around a set point using
homeostatic or feedback mechanisms.

In the classical model for a body weight set point shown below, body weight gravitates to one
stable weight. Above the stable weight, the control system kicks in and drops food intake
(Energy In) and increases calorie burning (Energy Out). This creates a net negative energy that
draws the body back to the stable weight. The classical model for a body weight set point is
frequently referred to as a thermodynamic model for body weight regulation, for it emphasizes
the calories-in vs calories-out equation for determining changes in body weight:

Combining the classical model for a body weight set point and evidence for homeostatic
mechanisms regulating around a body weight set point, one would have to conclude either that
(1) as energy intake (appetite) goes up, mechanisms would be activated to increase energy
expenditure (i.e. increase basal rates of metabolism), or (2) as body weight increases, appetite
will be inhibited, decreasing energy intake. The thermodynamic model argues, therefore, that
obesity develops only if energy intake, in the form of feeding, chronically exceeds total body
expenditure (physical activity, basal metabolic rate, and adaptive thermogenesis).

Although essentially accurate, more recent studies have made clear that the thermodynamic
model explanation for obesity is too simplistic, and that the regulation of human body weight is
far more complex and involves too many factors to be adequately modeled by a simple calories-
in vs calories-out equation, not because the basic premise is wrong, but because there are many
mechanisms that influence total calories-in or total calories-out, several of which we have little
or no conscious control over.
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

Most problematic is the obvious conclusion that if there are homeostatic mechanisms
responsible for regulating human body weight, they are not working; how else do you explain
the unprecedented increase in body weights over the past 25 years? The preceding figure charts
obesity trends among U.S. adults as part of the CDC Behavioral Risk Factor Surveillance Study
(BRFSS).

Part of our challenge in understanding obesity in general, and childhood obesity in particular, is
not only identifying mechanisms and practices that result in weight gain, but do so at a rate that
will explain how, over the course of 2-3 generations, greater than 30% of the population can now
be clinically diagnosed with obesity. Although part of the responsibility must be placed at the
feet of federal policies and food company marketing practices, it is also recognized that Western
civilization has generated more and varied mechanisms for weight gain, many of which hijack
and corrupt our understanding of the traditional thermodynamic model for weight gain. In the
remaining pages of this document, we will examine a subset of these mechanisms on the
following list, and discuss which of these mechanisms make significant contributions to
childhood obesity:

1. Common obesity
a. Carbohydrates, Glycemic Index, Metabolic Activity & Appetite
b. Processed Foods & Thermogenesis
c. Sugar Sweetened Beverages: perception of liquid vs solid food calories
d. BMI charts for children
2. Hypothalamic obesity
3. Genetic obesity
4. The Gut Biome
5. Breastfeeding (and the Gut Biome)
6. Antibiotics (and the Gut Biome)
7. Side-Effects of Prescription Medication
8. Placental Leptin Reprogramming
9. Human adenovirus-36 Infection
10. Insufficient Sleep
11. Circadian Rhythm Disruption
12. Brown Fat
13. Eating as an addictive behavior
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

1. Common Obesity
a. Carbohydrates, Glycemic Index, Metabolic Activity & Appetite

In the past three or more decades, American men have increased their caloric intake by 7%
and American women by 22%:

CDC Morbidity and Mortality Weekly Report, Feb 05, 2004

However, neither the NHANES nor other national data indicate an increase in caloric intake
among children and young adolescents (Third Report on Nutrition Monitoring in the United
States, Vol 2). Significant increases in caloric intakes appear in older adolescents (16–19 years)
and adults. And yet, obesity rates continue to increase for children. Reports largely focus, rightly
or wrongly, on one factor to help explain this trend: the general decrease in physical activity
among the young. This is significant, because physical activity has long been considered the only
aspect of our metabolic rate over which we have control:

Science 307: 530 (2005)

Total daily energy expenditure can be divided into three main components: resting metabolic
rate (RMR), thermogenesis, and the cost of physical activity, both planned (exercise; red) and
unplanned (NEAT; green). RMR represents 50 to 70% of daily energy expenditure and covers the
energy necessary for body maintenance, including cellular metabolism and whole-body
functions such as ventilation, circulation, and tissue oxygen uptake. Because humans have
evolved behavioral strategies (clothing, heating) to maintain body temperature in cold
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

environments, thermogenesis (yellow) accounts for only 10% of daily energy expenditure and
encompasses the energy required to digest, absorb, transport, and store ingested food. This
leaves 20 to 40% of daily energy expenditure for the most variable component, physical activity.
The energy cost of physical activity can be divided into planned physical activity, such as sport
and exercise, and spontaneous physical activity or NEAT, which includes all nonvolitional
muscle activities such as fidgeting, muscle tone, and maintenance of posture. When people
decide to increase energy expenditure for weight control purposes, usually only structured
exercise is included in their calculations. Science 307: 530 (2005)

Although data demonstrating an inverse relationship between exercise and weight gain remain
controversial, the data linking an increased sedentary lifestyle and weight gain are
underexplored. The 352 ± 65 kcal/day differential in the above example of NEAT can be the
difference between remaining lean and excess weight gain, suggesting that recommendations to
“remain active” need not mean running, biking, swimming and similar aerobic activities that be
very difficult for many people to enjoy or to do routinely. Recommendations to walk instead of
drive, take the stairs instead of the elevator, and to stand instead of sit, etc, might contribute
significantly to the exercise component of daily energy expenditure.

Although it is largely assumed that exercise is the only component of daily energy expenditure
over which we have control, we can influence the remaining components to a limited, but
important, extent. The main component of daily energy expenditure, resting metabolic rate
(RMR; or resting energy expenditure, REE), is influenced by dietary glycemic index, especially
during caloric restriction (dieting). Similarly, thermogenesis is influenced by the degree to which
our foods are whole or processed.

Reminder: Glycemic index (GI) is an empirically derived descriptor for how the carbohydrates in
our foods are digested and absorbed. A high GI food is one that is easily digested and the
resulting sugars quickly absorbed; whereas, a low GI food is slowly digested and the sugars more
gradually absorbed. This, of course, impacts the secretion of insulin. The rapid increase in blood
glucose levels resulting from the intake of high
High Glycemic Index Low Glycemic Index GI foods stimulates such a strong insulin
response that the resulting sharp decline in
blood glucose levels frequently overshoots into
a brief period of hypoglycemia. This, of course,
stimulates hunger and appetite, encouraging
snack consumption that simply repeats the
cycle. Low GI foods avoid this cycle with a
more moderate rise in blood glucose (and
insulin) that does not result in hypoglycemia.
Factors that influence a food’s glycemic index
are: how swollen (gelatinized) the starch (don’t
over-cook your pasta!), how much the food has been processed, and how much fat and fiber is in
the food, which govern how rapidly the food is digested.
The frequent cycles of insulin over-secretion with a high GI diet elevate circulating triglycerides
and greatly increase risks for insulin resistance and type 2 diabetes. For the purposes of this
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

discussion, however, these cycles entail consumption of extra calories that exacerbate weight
gain. Low GI diets keep hunger in check, and perhaps very importantly, prevent excessive
decreases in RMR during attempts at weight loss with dieting:

Changes in Resting Metabolic Rate

The figure above illustrates the results from a randomized parallel-design study of 39 overweight
or obese young adults aged 18 to 40 years who received an energy-restricted diet for 28 months
that was either a typical low fat, high glycemic load diet (glycemic load = GI x grams of
carbohydrate) or a low glycemic load diet. Although RMR decreases for all diets, it decreased
significantly less (80 kcal per day less) in those on a low GI diet, greatly facilitating weight loss
and decreasing perceptions of hunger during the diet. JAMA 292: 2482 (2004) The implications from
this study extend to non-dieting situations as well, perhaps most significantly at breakfast,
where a low GI meal containing protein, fat and fiber will delay the onset of hunger until lunch.

b. Processed Foods and Thermogenesis

The increase in metabolic rate that occurs during the digestion of foods is termed
thermogenesis. It is our investment in these catabolic processes from which we derive all energy.
Perhaps not surprisingly, as shown in the
following figure, it requires significantly more
energy to digest whole, minimally processed
foods (¨, 137 ± 14.1 kcal, 19.9% of meal energy)
compared to foods that are heavily processed (▲,
73.1 ± 10.2 kcal, 10.7% of meal energy). Thus, the
net calories absorbed for two calorically identical
diets is increased when consuming processed
foods (64 kcal in this example).
Food and Nutrition Research 54: 5144 (2010)

The above examples demonstrate that we can influence each of the four components of
metabolic rate, and not just physical activity, and that the consequences of avoiding a low
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

metabolic rate are very positive, both in terms of escaping weight gain, but, perhaps, facilitating
weight loss.

c. Sugar Sweetened Beverages: perception of liquid vs solid food calories

The consumption of only two food categories are statistically associated with weight gain: sugar
sweetened beverages (SSB) and more recently, pizza. Although part of the responsibility for this
relates to the issues described above: SSBs are an extremely high glycemic index food. Another
contributing factor, however, are the observations that SSB represent a significant source of
calories that are not accurately registered as such; therefore, adults and children fail to adjust
food intake to compensate for these calories:

On the left are the results from a cross-over design study in which 15 subjects are provided with
an extra 450 kcal/day for 4 weeks in the form of either jelly beans or a SSB (after a 4 week
washout period, the groups were switched). Free-feeding intakes were measured throughout the
day. For those consuming jelly beans, free-feeding intakes were significantly lower than baseline,
resulting in dietary compensation of -17% for the jelly beans. No decrease in intake was observed
for those drinking the extra calories, resulting in a positive energy balance. International Journal of
Obesity 24: 794 (2000)

On the right are similar results from a study in children in which the intake of solid food was
measured across an increasing range of SSB consumption. SSB intake contributed to an increase
in total daily calories that was not compensated by a commensurate decrease in solid food
calories, again resulting in a positive energy balance. Journal of Pediatrics 142: 604 (2003). Although
SSB represent a significant source of high-fructose corn syrup, which contribute additional risks
associated with increased circulating triglycerides and insulin resistance, it is the simple
observation that SSB represent pure added calories that factors most prominently in its
association with weight gain and obesity in children.

Somewhat unexpectedly, SSBs consumption contributes to increased blood pressure. Adolescents
who limited SSB consumption experienced significant declines in systolic and diastolic pressures.
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

d. BMI Charts for Children

Is BMI interpreted the same way for children and teens as it is for adults? No.
Although the BMI number is calculated the same way for children and adults, the criteria used to
interpret the meaning of the BMI number for children and teens are different from those used for
adults. For children and teens, BMI age- and sex-specific percentiles are used for two reasons:

• The amount of body fat changes with age.
• The amount of body fat differs between girls and boys.

The CDC BMI-for-age growth charts take into account these differences and allow translation of a
BMI number into a percentile for a child's sex and age. For adults, on the other hand, BMI is
interpreted through categories that do not take into account sex or age.

Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

Find the weight status category for the calculated BMI-for-age percentile as shown in the following
table. These categories are based on expert committee recommendations.

Weight Status Category Percentile Range
Underweight Less than the 5th percentile
Healthy weight 5th percentile to less than the 85th percentile
Overweight 85th to less than the 95th percentile
Obese Equal to or greater than the 95th percentile

See the following example of how some sample BMI numbers would be interpreted for a 10-year-
old boy.

Why can't healthy weight ranges be provided for children and teens?
• Healthy weight ranges change with each month of age for each sex.
• Healthy weight ranges change as height increases.

The CDC BMI-for-age growth charts are available at: CDC Growth Charts: United States.
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

2. Hypothalamic Obesity

A very rare "organic" form of obesity is seen in patients who suffer damage to an area at the base
of the brain called the hypothalamus. This area, the size of a fingernail, is home to the primary
function of regulating homeostasis, including the control of energy balance. Damage to this area
has long been known to promote excessive eating (hyperphagia) and weight gain, termed
"hypothalamic obesity." This form of weight gain is not responsive to diet and exercise, and
victims of this form of obesity continue to gain weight despite their best efforts.

glioma

Hypothalamic obesity is an unfortunate complication in some survivors of brain tumors,

especially those diagnosed in childhood. It is estimated that as many as one-third of all survivors
of craniopharyngiomas develop severe obesity after diagnosis and treatment. In a review of the
BMI curves of 148 children who survived brain tumors for at least five years, relations were found
between the development of obesity and: 1) tumor location (hypothalamus), 2) tumor histology
(craniopharyngioma and hypothalamic astrocytoma), 3) having had surgery (either a biopsy
and/or a gross total resection), 4) the amount of radiation directed at the hypothalamus (greater
than 51 Gy), and 5) the presence of hypothalamic hormone disturbances. Thus, we are led to
believe that obesity in this setting is due directly to damage to the hypothalamus, whether it is
from the tumor itself, or the surgery or radiation treatments thereof.

A rat model of hypothalamic obesity has been available for approximately 50 years; experimental
damage to an area of the brain known as the ventromedial hypothalamus (VMH) triggers non-
stop eating and weight gain. Even in the face of severe caloric restriction, animals with VMH
lesions continue to gain weight, because their metabolism is geared toward energy storage
instead of energy burning. Prior to the development of severe obesity, it has been shown that
VMH-damaged rats manifest increased insulin; however, investigators have also found that
cutting the nerve that leads to and from the brain to the pancreas (the vagus nerve) in rats
prevents the hyperphagia, insulin rise, and weight gain. Thus, it has been proposed that the
VMH may control energy balance by influencing insulin secretion through the vagus nerve.
These data also suggest a potential target for therapy.

Although weight gain via hypothalamic damage is very rare, and offers little practical advice for
pediatric patients seeking information on weight loss, the hope is that mechanisms of weight
gain learned from these patients will aid future researchers and physicians.
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

3. Genetic Obesity

Estimates of the heritability of BMI range from 30% to 70%. Adoption studies, for example,
demonstrate clearly that the body weight of adoptees much more closely mirror the BMIs of
their biological parents than of their adoptive parents (see below; BF and BM: biological father
and mother; AF and AM: adoptive father
and mother). NEJM 314: 193 (1986)

Studies of monozygotic and dizygotic

twins reared together or apart yield
similar data. Although the contributions
of environmental factors are far from
insignificant, one’s genetic background is
a very important factor to body weight. A
significant part of this genetic
background is the polymorphisms in
genes controlling appetite and
metabolism that predispose one to
obesity under certain dietary conditions.
More than 41 sites on the human genome
have been linked to the development of significant weight gain when a favorable environment is
present. For example, Fat mass and obesity-associated protein
in humans is encoded by the FTO gene located on
chromosome 16. Polymorphisms in FTO are strongly
associated with body fat estimates in populations of different
ethnic backgrounds or ages. It was estimated that each copy
of the FTO rs9939609 minor allele (ie, A allele) corresponds
to approximately 1.5-kg heavier body weight (figure at top
right). The prevalence of this risk allele in white individuals is
around 40%. Interestingly, adolescents meeting the daily FTO Polymorphisms
physical activity recommendations were able to overcome the
weight gain effect of the FTO polymorphism.
Arch Pediatr Adolesc Med. 164(4):328-333 (2010)

Another common obesity-predisposing genotype near the

INSIG2 gene is present in 10% of individuals (see at bottom
right). Science 312: 279 (2006)

Although each polymorphism contributes only a modest

amount of weight gain, it is unknown how multiple poly-
morphisms in any one person interact. t is possible that
certain polymorphism combinations may contribute to INSIG2 Genotype in Red
significant weight gain and a risk for obesity.
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

4. The Gut Microbiome

The distal human intestine can be viewed as an anaerobic bioreactor containing trillions of
bacteria and archaea, programmed to perform metabolic functions that we have not been
required to evolve on our own, including the ability to harvest otherwise inaccessible nutrients
from our diet. Gut microbiota in genetically obese mice has proven more effective at extracting
calories from food during digestion than are the microbiota from lean mice (see figure b, below).
Feces from obese mice contain fewer calories than
feces from lean mice. This trait is transmissible to
germ-free recipients, resulting in greater adiposity.
Transplantation of germ-free wild-type mice with
caecal microbiota harvested from obese donor mice
(ob/ob) results in a significantly greater percentage
increase in total body fat than colonization with
caecal microbiota from lean donors. Total body fat
content was measured before and after a two-week
colonization. These results raise the possibility that
the composition of the microbial community in the
gut affects the amount of energy extracted from the
diet. Nature 444: 1027 (2006)

Two groups of beneficial bacteria are dominant in the human gut, the Bacteroidetes and the
Firmicutes. To investigate the relation between gut microbial ecology and body fat in humans,
12 obese people were randomly assigned to either a
fat-restricted (FAT-R) or a carbohydrate-restricted
(CARB-R) low-calorie diet. The composition of their
gut microbiota was monitored over the course of one
year by sequencing 16S ribosomal RNA genes from
stool samples. Before diet therapy, obese people had
fewer Bacteroidetes (P<0.001) and more Firmicutes
(P=0.002) than did lean controls (see figure b at left).
Over time, the relative abundance of Bacteroidetes
increased (P<0.001) and the abundance of Firmicutes
decreased (P=0.002), irrespective of diet type.
Nature 444: 1009a (2006); PNAS 104: 979 (2007)

These findings indicate that obesity has a microbial

component, which might have potential therapeutic
implications, and tempt consideration of how we
might manipulate the microbiotic environment to
treat or prevent obesity. But questions about how
and why the composition of gut microbiota is
regulated will have to be answered first.
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

5. Antibiotics

Antibiotics, discovered in the early twentieth century, came into widespread use after the
Second World War, with substantial public health benefits. Additionally, for more than 50 years
now, we have known that the administration of low doses of antibacterial agents promotes the
growth of farm animals. In the United States, for example, the largest use of antibiotics and
related antimicrobial substances is within farms, with low doses fed to large numbers of animals
used for food production to increase weight gain by as much as 15%. Antibiotic use has increased
markedly, now approximating one antibiotic course per year in the average child in the United
States. Not surprisingly, therefore, there is increasing concern that antibiotic exposure may have
long-term consequences in children, including weight gain. Nature 488: 621 (2012)

To investigate this, a mouse model of early-life subtherapeutic antibiotic treatment (STAT) has
been developed. Mice were exposed at weaning to penicillin (P), vancomycin (V), penicillin plus
vancomycin (P+V), chlortetracycline (Ct), or no antibiotic (C) in their drinking water at levels in
the mid-range of US Food and Drug Administration (FDA)-approved levels for subtherapeutic
antibiotic use in agriculture:

After a 7 week exposure, there was no significant difference in overall growth between the STAT
and control mice; however, by dual energy X-ray absorptiometry (DEXA) scanning, total fat
mass was significantly higher in all four groups of STAT mice than in the control group (c).
Percent body fat also was increased in most STAT groups compared to controls (d). Lean weight
was not significantly different in the STAT mice (e). Interestingly, in both fecal and caecal
samples, the ratio of Firmicutes to Bacteroidetes was significantly elevated in the STAT mice
compared to controls (surprise!). Nature 488: 621 (2012); Cell Metabolism 3: 408 (2012)

The Avon UK Longitudinal Study of Parents and

Children (ALSPAC) looked at a cohort of 11,532
children, comparing their antibiotic exposure to
BMI. Antibiotic exposure during the first 6 months
of life was consistently and significantly associated
with increased BMI at 10 (p < 0.001), 20 (p < 0.001)
and 38 months (p < 0.029). Exposures beyond 6
months were inconsistent.
International Journal of Obesity 37: 16 (2012)
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

6. Breastfeeding

Adapted from CDC Research to Practice Series, No. 4 (July 7)

The beneficial effects of breastfeeding children are well documented and include a lower risk for
ear and respiratory infections, atopic dermatitis, gastroenteritis, necrotizing enterocolitis, type 2
diabetes, and sudden infant death syndrome (SIDS). Potentially there is still another benefit,
which involves pediatric weight status.

In 1981, it was reported that there was a significantly reduced risk for overweight among children
who were breastfed. Since that report, several studies have provided varying degrees of support
for this effect. This variation may be due in part to differences in study design, the populations
studied, sample size, definitions of breastfeeding and overweight, length of follow-up, reporting
bias, and control of confounding factors. In 2004 and 2005, three groups of researchers
published the results of meta-analyses that examined the relation between breastfeeding and
pediatric overweight using mostly studies conducted in developed countries.

Figure 1. Effect of breast-feeding

vs formula feeding on childhood
obesity: covariate-adjusted odds
ratios of nine studies and
pooled odds ratio.
Int J Obes Relat Metab Disord
2004;28:1247-1256

The duration of breastfeeding is inversely related to pediatric overweight. The greater the
duration of breastfeeding, the lower the odds of overweight. For each month of breastfeeding up
to age 9 months, the odds of overweight decreased by 4%. This decline resulted in more than a
30% decrease in the odds of overweight for a child breastfed for 9 months when the comparison
was with a child never breastfed.

Exclusive breastfeeding indeed appears to have a stronger protective effect than breastfeeding
combined with formula feeding, but more research is needed. Exclusive breastfeeding groups
showed a stronger protective effect compared to all their other studies. Exclusive decreased the
odds of overweight by 6% for each month of exclusive breastfeeding. The association between
breastfeeding and overweight appears to remain with increasing age of the child.

There are several possible explanations for why breastfeeding appears to reduce the risk for
overweight, but conclusive evidence is not yet available. It may be that mothers who breastfeed
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

choose a healthier lifestyle, including a healthy diet and adequate physical activity for
themselves and their children. This healthier lifestyle could result in a spurious relationship
between breastfeeding and reduced risk of overweight. The results of several studies, however,
suggest a true relationship between breastfeeding and reduced risk of overweight, because after
adjusting for potential confounding variables, significant inverse associations remained.

There are several biological mechanisms by which breastfeeding may reduce the risk of
overweight. First, because breastfed infants control the amount of milk they consume, their self-
regulation of energy intake, which involves their responding to internal hunger and cues that
they are full, may be better than that of bottle fed infants, who may be encouraged by external
cues to finish a feeding. A second possibility pertains to insulin concentrations in the blood,
which vary by feeding mode. Formula-fed infants have higher plasma insulin concentrations and
a more prolonged insulin response. Higher insulin concentrations stimulate more deposition of
fat tissue, which in turn increases weight gain, obesity, and risk of type 2 diabetes. Also, the high
protein intake of formula-fed infants may stimulate the secretion of insulin. A third possibility is
that concentrations of leptin (the hormone that is thought to inhibit appetite and control body
fatness) may be influenced by breastfeeding. One study found that after controlling for
confounding variables such as BMI, children who had the highest intake of breast milk early in
life had more favorable leptin concentrations relative to their fat mass. In conclusion, there are
several potential explanations for why breastfeeding appears to reduce the risk for overweight,
but more research is needed in this area.

The First Prebiotics in Humans

Human Milk Oligosaccharides

Given our discussion the importance of the human gut microbiome and its clear importance in
the regulation of body weight, we must present human breast milk in the same context.
Although there are many important differences between human milk, cow milk and formula, the
one that might be in the best position to influence body weight and gut health is the class of
oligosaccharides. Oligosaccharides are carbohydrates made up of 3-9 mono-saccharide units
Quantitatively, the third component of human milk, after lactose and lipids. They reach the
highest concentration in colostrum (more than 20 g/L) and then decrease, after about 2 weeks,
to approximately 12 to 14 g/L in mature milk. Cows’ milk, and many infant formulas, contains
less than 1 g/L oligosaccharides. J Clin Gastroenterology 38:S80–S83 (2004)

Among a variety of Bifidobacteria tested, only Bifidobacteria longum biovar infantis was able to
grow extensively on human milk oligosaccharides as sole carbon source. The genomic sequence
of this strain revealed approximately 700 genes that are unique to infantis, including a variety of
co-regulated glycosidases, relative to other Bifidobacteria, implying a coevolution of human milk
oligosaccharides and the genetic capability of select intestinal bacteria to utilize them.
Nestle Nutr Workshop Ser Pediatr Program. 2008; 62: 205–222

It remains possible, therefore, that part of the obesity-protective effect of breastfeeding is due to
the cultivation of a healthy gut Microbiome.
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

7. Side-Effects of Prescription Medications (Obesogenic Drugs)

Adapted from Ingrid Kohlstadt, MD, MPH, American College of Preventive Medicine

Not often considered in the list of risk factors for obesity, the medications taken by many people
are contributing to significant weight gain. Clinicians may hesitate to inform patients of the
potential of medications to alter appetite and weight for fear that a patient may conclude
erroneously that a drug caused weight gain, and therefore discount the importance of lifestyle
modification. Additionally, insufficient comparative effectiveness data are available to help
clinicians select medications that won't affect a patient's appetite. Perhaps discussion of a
medication's potential effect on appetite has simply fallen victim to the practical realities of
shorter office visits. Reasons to discuss potential effects of a medication on appetite include:

Patients who are obese are more frequently prescribed appetite-increasing medications.
Counseling on lifestyle may be indicated on the basis of US Preventive Services Task Force
recommendations. Children and people with mental illness are two groups at increased risk.

Informing patients of the possibility of appetite deregulation may prompt a joint decision to
choose another medication, use a lower dose, or modify environmental factors.

Collective decision-making can improve adherence to a treatment plan. Both public health
and clinical intervention approaches are available to modify the effects of appetite and avoid
weight gain.

Forewarned patients may be better able to recognize an increase in caloric intake and take
preventive measures before weight gain occurs.

Medications that promote adipose accumulation cross numerous disease and therapeutic
categories. The major drug categories that are implicated in weight gain are:

Medications for Type 2 Diabetes Mellitus

Medications for Hypertension
Antihistamines
Steroid Hormones
Anticonvulsants
Psychoactive Medications

Weight gain in children is especially concerning with psychoactive mediations because it

influences growth in ways not fully appreciated. Furthermore, 80% of obese children become
obese adults. Studies conducted under the legislation of the Pediatric Research Equity Act
and the Best Pharmaceuticals for Children Act demonstrated adverse metabolic effects
among children. When the study results were reviewed by the US Food and Drug
Administration's (FDA's) Pediatric Advisory Committee in December 2009, the committee
voted unanimously to strengthen the labeling about pediatric weight gain on an atypical
antipsychotic medication.
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

8. Placental Leptin Programming

Obesity is often associated with insulin resistance, dyslipidemia, and hypertension; thus, a
concept of metabolic syndrome has been proposed. As we discussed above, genetic factors
and/or environmental factors, such as a high-calorie diet in the Western life style, have been
considered to contribute the prevalence of obesity (although this explanation is simplistic).
Another possible explanation is the epidemiological and experimental evidence that intrauterine
undernutrition is closely associated with pediatric and adult obesity, giving rise to the concept of
“developmental origins of health and disease.” Although perinatal exposure to glucocorticoids in
the development of impaired glucose metabolism has been demonstrated, other more general
mechanisms of developmental origins of obesity have yet to be identified.

Leptin is an adipocyte-derived satiety factor that decreases food intake and increases energy
expenditure, thereby stabilizing body adiposity in many species, including humans. Leptin
deficient mice, such as the ob/ob mouse, and humans show marked obesity that is restored by
exogenous leptin treatment. Leptin exerts its biological activities through long-form leptin
receptors, expressed abundantly in the hypothalamus. Resistance to the satiety effect of leptin is
a trait of obese subjects, as circulating leptin levels are well correlated with body fat mass. It is an
intriguing hypothesis, therefore, that leptin resistance at the hypothalamus is associated with
the onset of obesity or metabolic disorders in children with intrauterine growth restriction.

In mice, plasma leptin levels rise transiently during the neonatal period, termed as “neonatal
leptin surge.” It is postulated, therefore, that the leptin surge is involved in the formation of
energy-regulation circuits in the hypothalamus. This has been tested in several mice models,
where intrauterine undernutrition in which premature leptin surge contributes to
developmental origins of obesity.
The fat-derived hormone leptin regulates energy balance in
part by modulating the activity of orexigenic neuropeptide Y
and anorexigenic proopiomelanocortin neurons in the
hypothalamic arcuate nucleus. To study the intrinsic activity
of these neurons and their responses to leptin, we generated
mice that express distinct green fluorescent proteins in these
two neuronal types (see figure at left). Leptin-deficient (ob/ob)
mice differed from wild-type mice in the numbers of excitatory
and inhibitory synapses and postsynaptic currents onto
neuropeptide Y and proopiomelanocortin neurons,
essentially favoring an orexigenic phenotype. When leptin
was delivered systemically to ob/ob mice, the synaptic density
rapidly normalized, an effect detectable within 6 hours, several
hours before leptin’s inhibitory effect on food intake. These
data suggest that leptin-mediated plasticity in the ob/ob
hypothalamus may underlie some of the hormone’s behavioral
effects.
Science 304: 110 (2004)
Childhood Obesity TBL 2018 Nutrition & Patient Health Thomas G. Sherman, PhD

In another study, a mouse model in which offspring with fetal undernutrition (UN offspring),
when fed a high-fat diet (HFD), developed pronounced weight gain and adiposity. In the
neonatal period, UN offspring exhibited a premature onset of neonatal leptin surge compared to
offspring with intrauterine normal nutrition (NN offspring). Interestingly, a premature leptin
surge generated in NN offspring by exogenous leptin administration also led to accelerated
weight gain with a HFD. Both UN offspring and neonatally leptin-treated NN offspring exhibited
an impaired response to acute peripheral leptin administration on a regular chow diet (RCD)
with impaired leptin transport to the brain as well as an increased density of hypothalamic nerve
terminals. These results suggest that the premature leptin surge alters energy regulation by the
hypothalamus and contributes to “developmental origins of health and disease.”
Cell Metabolism 1: 371 (2005)

Put more simply, these data indicate that human practices of over-consumptive under-nutrition
during pregnancy might promote a premature leptin surge that establishes in utero leptin
resistance in the fetus. This hypothesis argues that these children and adults have an artificially
high leptin set point, leading to obesity – much like an infection increases the set point for body
temperature, leading to fever.

Thus far, we have discussed the concept of a variable set point for human body weight, and the
contributions of genetic background and placental nutrition to pediatric and adult weight gain.
There is increasing evidence now that all of these factors may involve epigenetic mechanisms of
inheritance.

In a rat model, for example, it was recently shown that paternal high-fat-diet (HFD) exposure
programmed β-cell ‘dysfunction’ in rat F1 female offspring. Chronic HFD consumption in
Sprague–Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance
and insulin sensitivity. Relative to controls, moreover, their female offspring had an early onset
of impaired insulin secretion and glucose tolerance that worsened with time, and normal
adiposity. This observation could be explained as an epigenetic phenomenon, because paternal
HFD altered the expression of 642 pancreatic islet genes in adult female offspring; these genes
belonged to 13 functional clusters of enzymes and proteins. Hypomethylation of the Il13ra2
gene, which showed the highest fold difference in expression (1.76-fold increase), was
demonstrated. Il13ra2 is part of the Jak–Stat signaling pathway and is expressed in, and
modulates growth and invasion of, various pancreatic cancer cell lines and is upregulated by
TNF-α (Tnf).
Nature 467: 963 (2010)

This is the first report in mammals of non-genetic, intergenerational transmission of metabolic

sequelae of a high fat diet from father to offspring. Thus, evidence is accumulating that maternal
and paternal dietary patterns can directly influence their children’s body weight and health
other than via social mechanisms.