Adrenergic

Peter

receptor

function

Amer

ABSTRACT
tionally

All classical

expressed

appear

adrenoceptor

in fat cells.

to be present

adrenoceptor

receptors.

regulation.

They

subtypes

However,

in all types

reserve

are spare

offat

only
cells.

in fat cells; -50%

Beta adrenoceptors

are regulated

treatment.
during
in the

Alpha
infancy,
function

There

and

is a decrease

noceptors

in receptor

after exposure
and function
of

expression.

are situated

at the level

WORDS

renoceptors,

fect

different

mechanisms

to homologous

in the peripheral
surface
adrenoceptors
renoceptor
function

Adrenoceptor

old

and

/32

classification
must

termed

tions

2285

and

adrenoceptor
mechanisms

Catecholamines

through

a1 receptors

concentration
is increased,
kinase
C. All /3-adrenoceptor

(2+

so

which leads
subtypes

to activation

mediate
their effects via the same cyclic AMP mechanism.
It is
not yet known
which subtypes
are present
in brown
adipose

lipolysis,

/3 adrenoceptor,

a ad-

role

in

the

fat cell

regulation

of

metabolism.

several

The

first

case

in brown

focuses

on obesity

and

of protein

tissue. However,
when recent data are summarized
(5) it appears
that fl and $, but not /32, are functionally
expressed
in brown
adipose
tissue.
There
are important
species
differences
in the functional
role

of adrenoceptor

subtypes

As mentioned

D are described.

into

a1

in two

a2,

surveys

In addition,

/3

species
selectivity
of hormone
action.
A
may provide
a means
for better
underselectivity
of a particular
catecholamine
subtypes
of action

in brown
of these

Am

fat cells,

receptors

J C/in Nuir

fat cells.

are

the funcsumma-

l992;55:228S-36S.

In humans

only for thermogenesis

fat cells that produce
though
data suggest

fat cells
role

in adult

ofthese

ditions
paper

subtype

as well

/33-agonists

pathophysiological
regulation

and

oflipolysis.

fat cells

have

synthesis

other

From

the Department

Medicus
Bromma.
3 Address
reprint
Huddinge
Hospital,
Printed

in USA.

ofMedicine,
from

Swedish

Huddinge
Medical

Association

are less well

Hospital,

Karolinska

Research

requests
to P Arner,
Department
5-141 86 Huddinge,
Sweden.

1992 International

effects

or on transport

and metabolism
ofglucose).
These effects, however,
characterized
and will not be considered
further.

Institute,
Stockholm.
2 Supported
by grants

in this

in white fat cells is to

to free fatty acids and

Catecholamines
on lipid

the
con-

fat cells.

in white

of adrenoceptors
of triglycerides

(for example

discussion
in white

function

(7-9),
human

the remaining

on adrenergic

by means

on fat cells

to be of importance

selective

and

Therefore,

focus

The major function

regulate
the breakdown
glycerol

by using

in normal

is unclear.
will

they appear

in infants;
adults
have only a few brown
minor
effects
on thermogenesis
(6). Althat it may be possible
to activate
brown

man

cells

Adrenoceptor

fat cells

adrenoceptor
has recently
been cloned
(3). The function
of these
new adrenoceptor
subtypes
is unclear.
The major
subclasses
(a1,
a2 /3) are coupled
to different
effectors,
which
provide
a mech-

effect.
As regards

G, protein.

be in-

be reevaluated.

anism
for organ
and
further
subclassification
standing
of the tissue

through

via inhibition

J Clin

in the latter

A, B, C, and

production

is mediated

Am

( 1 , 2) there seems to be a family of a receptors;

at least two
different
a1 receptors
termed
A and B and four different
a2 receptors

via dis-

by stim-

may

action
ofcatecholamines
is binding
to cellin target cells. This review
deals with adin fat cells under
normal
and pathophysi-

subtypes

production

is mediated

AMP

hydrolysis

ef-

between

obesity.

a major
including

ological
conditions
and
obesity-related
disorders.

the

balance

transcription,

of brown

step

cyclic

through

phosphoinositide

that the intracellular

the

heat

a2 effect

heat

of gene

catecholamines

play
body,

and

inhibitory

pathway

regulate

inhibit

net thermogenic

upon

1). The /3 effect

cyclase
The

may

the

of regional

Adipocyte,

Adrenoceptors
processes
in the

The

same

stimulate

Thus,

which

(Table

ofadenylate

of the

Introduction

/3

ulation

catecholamines

is dependent

receptors,

the G protein.

in brown

As noted in another
survey
are involved
in this process. The

a2 receptors.

of catecholamines

crete

of adrenoceptors

ofcatecholamine-stimulated
heat production
and the remaining
part through

In addition,

these

/3 adre-

role

/3adrenoceptors

through

except

In addition,

are sensitive

production

alterations
fasting,
when

to changes

principal

thermogenesis.

/3adrenoceptors

part (80%)
through

a1 adrenoceptors.

andro-

by nutritional
beta-blocking

developmental
and during

1. The

and

, a2,

major
occurs

to agonists.
Site variations
in the
/3 and a2 adrenoceptors,
which
in

volved
in the development
Nutr l992;55:228S-36S.

KEY

less sensitive

but not a2 adrenoceptors

desensitization
expression

part

are

when there are marked

of a2 adrenoceptors,

in Table

(4) a1

is a substantial

estrogens,

rized

fat cells is to regulate

offl and a2 adrenoceptors

are subject
to intensive

by insulin,

receptors

are func-

/3 adrenoceptors

gens as well as by thyroid

hormones
and are altered
factors,
diabetes,
autonomic
neuropathy,
and

there

in fat ce0s13

Council

and

of Medicine,

for the Study

of Obesity

ADRENOCEPTORS
TABLE
Function

IN

FAT

2295

CELLS

1
and effector

mechanisms

for adrenoceptors

in fat cells
Function

Receptor

subtype

Effector

functions

white

fat cells

ulate

and

and

a2 receptors

same

latter

mechanisms

way

inhibit

lipolysis

fat cells

( 12)

fat cells

in human

a2 A subtype

(15).

The

/3

fat cells, on the other

have fully functional

appear

to have

all three

The

stim-

mechanisms

the

14); the

to be predominantly

cells
(17),

also
but

have
receptors

contain
not a

of the

present

/3

in all

a /32 receptor
receptor
(18).

no /32 receptors
(20). Hamster

subtypes

by an

addition,

between

adrenoceptor

(19) but
fat cells

fectors,
much

total

The

The

relationship

between

by a hormone

to a combination
creased
concentration

the

number

the

final

and

of decreased
causing

and

by a decrease

in hormone

a large

ceptor
function.
hibition

decrease

dual

stimulate

for the
occupancy

receptor
and

of cellular

TABLE 2
Species differences
fatcells

(maximum
numbers

appear

to be the

inhibit

cellular

of receptors
The

erate

As regards
in vivo

has

because

only

receptors

to be occupied

(24).

natural

occurring

of this
classes

the administration

of
than

ef-

/3 and

by
dual

to obtain
of a
by

cells
can

that
either

a2 receptors,

effect

remains

of receptors
ofbeta

by

inactivation
is accompanied

sensitivity

cyclase

In

in fat cells, there

Only
50% of the

ie, catecholamines

role
both

hormone.

amplification

are accompanied

Furthermore,
in fat cells

adenylate

lipolysis,

more

relationship
(23, 24).

function,

functional

are

for

seem

blockers

unto op-

or alpha-

be

response
due

is altered

that

relationship
is essential

receptor-effector

response

are

can

The

of the

number
sensitivity.

in catecholamine

adrenoceptors

or

hormone

effect).
In the latter
is accompanied
only

the responsiveness

number
reserve.

In a one-to-one

that

response

there

in receptor
in hormone

adrenoceptor

in the

rate
rate

by spare receptors
(Fig 1).
in receptor
numbers
leads

sensitivity;
in the

of receptors
cellular

Because

of dual

Fat cells

increase

lipolysis
lipolysis
?

hormone
sensitivity
(ie, an inhalf maximum
effect)
and de-

creased
hormone
responsiveness
case a small decrease
in receptor

threshold

role

an

a means

of /3 or a2 receptors

decrease

Increase
Decrease

concentration
provide

catecholamine
response.
number
of these receptors

respectively.

either
one-to-one
or be characterized
In the former
case a small reduction

after

signal.

fraction

a large

clear.
occupied

by

fat cells

receptors
are present,
however,
the
for a moderate
decrease
in recep-

in the

receptors

small changes
larger changes

a full
small

(2 1, 22).

occupancy

heat production
heat production
heat production

overcome

increase
spare

hormone

have

Relationship
response

be

White

As regards
the receptor-effector
is clear evidence
of spare receptors

2). The presence

easily in human

is probably

/3 receptor

of the
(10).

cannot

fat cells

concentration.
When
spare
organ can always
compensate
tors

expression

( 1 3,

number

The
in

elucidated

in rat adipocytes

receptor

hand,

role

in the

fat cells(Table
much more

seems

fl

functional

differences

than

fat cells

species.
However,
human
fat
(16), which
is fully functional
Rat
they

the

has not yet been

species

ofadrenoceptor
subtypes
in white
ofa1 or a2 receptors
is demonstrated
a2 receptor

through

fat cells.

considerable

( 1 1 ) or hamster

in

-receptors

production
in brown
fat cells.
can be activated
by a1 receptors

as in brown
in white

are

ofadrenoceptors
1 . Beta

in Table

for heat
pathway

receptors

There

ofaction

are summarized

described
above
phosphoinositide
the

Increase
Decrease
Increase

Stimulation
of adenylate
cyclase and cyclic AMP through G,
Inhibition
of adenylate
cyclase and cyclic AMP through
G
Increased
Ca2
and protein kinase C through
phosphoinositide
hydrolysis

Beta 2.3
Alpha2
AlphaC

The

Brown

mechanism

bypass

the

between

re-

relationship,

to a small

one

for hormone

decrease

the

to

one

in-

in receptor

a)
in the expression

Receptor

Easy detected

Beta1
Beta2
Beta3
AlphaC
Alpha2

All species
Human,
hamster
Rat, hamster
Human,
hamster
Human,
hamster

ofadrenoceptor

Hardly

subtypes

detected
-

Rat
Human
Rat
Rat

in white

or absent

0
010

of

total

FIG 1 . Relationship
between
logical effect of catecholamines

receptors
adrenoceptor
in fat cells.

occupied
occupancy

and

the bio-

ARNER

2305
TABLE 3
Effects of hormones

and other

endogenous

substances

on catecholamine

Substance

action

Catecholamine
Increased
Decreased
Increased
Increased

sensitivity
sensitivity
sensitivity
sensitivity

Insulin
Lactate
Prostaglandine
adenosine

Decreased
Decreased
Decreased

sensitivity
sensitivity
sensitivity

2 blockers
causes
lipolytic
activity
tions

of normal

effect

on lipolysis

a decrease
in humans
or altered

acid,

and an increase,
respectively,
who are investigated
under
sympathetic

activity

by catecholamines

(25,

in humans

26).

fat cells

effect

Thyroid hormones
Estrogens
Androgens
Glucocorticoids

E, nicotinic

in white

Major

Decreased
G expression
Inhibited
catalytic
component
of adenylate
Increased
/3-adrenoceptor
number
Multiple
effects on the /3-adrenoceptor-adenylate
cyclase complex
/3-Adrenoceptor
translocation
/3-Adrenoceptor
internalization
Decreased
fl-adrenoceptor
agonist affinity

of the
condi-

zation

A dual

cells

is puzzling,

be-

has been

described

desensitization
(35).

The

a2 receptor

to desensitization.

antilipolytic
action
of catecholamines.
It has been suggested
that a certain
degree
of catecholamine
inhibition
is necessary
in human
fat cells because
unrestrained

in fat cells, although

has been described

lipolysis

may

proceed

at an almost

maximal

rate

(28).

receptor
will be the major
lipolysis-regulating
catecholamines
and modulate
the lipolytic
effect
tors. Alternatively,
the dual receptors
may operate
conditions
suggest
receptors

in man.

Recent

in situ

studies

that a2 receptors
modulate
modulate
lipolysis
during

lipolysis
physical

Several

whereas
(29).

/3

desensitization

The exposure
of cells to hormones
often leads to a rapid loss
ofreceptor
responsiveness.
This tachyphylaxia
can be subdivided
into homologous
and heterologous
desensitization.
Homologous
desensitization
a particular

is specific
receptor
and

desensitization
the desensitization
The

the

and refers to processes

that only affect
its specific
agonist.
During
heterologous

action
through
of several
other

one type of receptor

causes
types of receptors
as well.

desensitization

of/3

homologous

characterized

in detail

(30).

Within

adrenoceptors

the

exposure,
/3 receptors
are sequestered
away
into a membrane-associated
compartment,

after

(and probably
change
is that

the receptor
becomes
functionally
The /3 receptor
is phosphorylated,

uncoupled
from
which
impairs

interreact

there

with

G.

degradation
and
Catecholamine
The

/3 receptor

At later

stages

are

also

sensitive

to desensitization.

ofcells
in vitro (3 1) and in vivo (32) to /3-agonists
by a rapid decrease
in /3-adrenoceptor
number
ness. The mechanisms
behind
desensitization
clarified.
distal
The

It appears,
to cyclic

uncoupling

the effector.
its ability
to

changes

synthesis
of /3 adrenoceptors.
tachyphylaxia
has been investigated
is very

however,

AMP

that

accumulation

of i3 adrenoceptors

there

in the

in fat cells.
The

exposure

is accompanied
and responsivehave
not been

are no regulatory

in desensitized
from

agonist

from the cell surface

which
is not acces-

sible to hydrophilic
ligands,
such as isoprenaline
also not to the natural
catecholamines).
A second

G, during

of fat cells

in fat

to natural

in vivo,

or function

and

catin situ

in fat cells

on a1-receptor

(32,

desensitization

homologous
desensitization
in other tissues
(39).

hormones

expression

(Table

for this

changes

fat cells

(33).

desensiti-

and

and

3). Some

by hormones

other

endogenous

function

have

permissive

sensitivity,

whereas

receptor

It has been

in a review

other

substances

effects
others

effect of thyroid
established,
but

stated

and

of adrenoceptors

ceptor
function.
The permissive
sensitivity
is well

may

in white

and

increase

inhibit

alter

fat cells

the cate-

catecholamine

re-

hormones
on catecholamine
the mechanisms
are unclear.

(10) that thyroid

hormones

do not

alter a2- or /3-adrenoceptor

number
in animal
adipocytes;
here
the major
mode
of action
appears
to be localized
at the level of
G expression
(40, 41). However,
there may be species
differences
in thyroid
hormone
action,
since the in vivo administration
of
these

hormones

number

has been

a few minutes

number

Heterologous
described

to be less sensitive

in vitro,

are no reports

of adrenoceptors
substances

cholamine

Adrenoceptor

a2-receptor

alter

Regulation
endogenous

microdialysis

at rest,
exercise

a2-agonist

As yet, there

(34).

appears

the exposure

or selective

cyclase

If so, the

receptor
for
ofthe
/3 recepunder different

using

not

36-38).

fat cells

has also been

in fat cells

Thus,

echolamines
does

in brown

of/3 adrenoceptors

cause only these hormones

cause pronounced
lipolytic
activity
in adult
man (27). In most other species
several
additional
hormones
are markedly
lipolytic
and may, therefore,
overcome
the

a2

mechanism

Estrogens
cells.

to

humans

This

reduce
cannot

or a2 receptors
ponent

(43).
increase
may to

the lipolytic
Instead,

testosterone

action

(44).

increased

of catecholamines

estrogens

cyclase

an

(42).

to changes

the lipolytic
some
extent

number
of /3 adrenoceptors
may also alter a2-receptor

by

in adipocytes

be attributed

of adenylate

effects
and
The latter

on

is accompanied

of /3 adrenoceptors

in the

inhibit
Androgens

in fat

number

the catalytic
have

/3

of
com-

permissive

sensitivity
of catecholamines.
be due to an increase
in the

in fat cells (45), although

andogens
function
in adipocytes,
at least when

is administered

in vivo

(46).

Glucocorticoids
also produce
catecholamine-permissive
lipolysis
in fat cells. The mechanisms
behind

this

effects
phenom-

enon
are not clear and may be multifactorial.
An increase
in
the numbers
of total /3 adrenoceptors
plus the enhanced
action
of G and of the catalytic
component
of adenylate
cyclase
have
been

described

/3 adrenoceptors
glucocorticoids
reduce

(47).

In addition,

the effect

may be subtype
specific.
promote
the expression

the expression

of/31 adrenoceptors

ofglucocorticoids

on

In 3T3-Ll
adipocytes,
of/32 adrenoceptors
and
(48).

This

may

involve

ADRENOCEPTORS
glucocorticoid
steroid
per

effects

hormone

se may

Apart
hormone

also

fat cells

through
and

renoceptor
nism that

cause

(49,

resistance

insulin

been shown

through
a translocation
sensitivity;
this may

that hormones

through

through

G may

interactions

with
with

of/3-agonist

by pertussis

(54).

also
13-ad-

mechabe an im-

This

It
in-

by a decrease

in

their

Catecholamine-induced
lipolysis rate

Factor
Fasting

Increased

Exercise

Increased

Infancy

Decreased

High age

Decreased

Sex

Increased

efficacy

toxin,

which

sug-

(54).

adaptation

Major

of adrenoceptor
evidence
that
to physiological

need

lipolysis
the

for free fatty

is increased.

lipolytic

acid

adrenoceptor
regulation

action

function
and leads

the sex ofthe

of catecholamines.

subject

There

(55) and epinephrine

(56).

plain the increased

lipolytic
activity
mans,
since there is only a moderate
catecholamine
concentration
during
Fasting
that

presumably
mediate

crease

of a2 receptors

effect
This

(66,

67).

are

multiple

effects

catecholamine-induced

sensitivity

to catecholamines

It is well established
including
is observed
training
(63).

changes

that

in part

cx-

the

chain
The

in-

during

fasting

(57,

ofthe

until

hormone

and

mechanism

occurs

ofhormone-sensitive

lipase;

in the stoichiometric

properties

there

is accompanied
in human

30 mm
due
seems

to be little

of adrenoceptors

influence

Regional

increase

in the

number

fat cells

Human
gional

This

may

been

(69).

be due

a2 adrenoceptors
function

the

to a difference

in males

it is difficult

on adrenoceptor

as com-

to determine

because
activity

there
that

are

are also

in adrenoceptors

adipose

tissue

variations

(68).

is a heterologous

in the

described

activity

since

of several

this

tissue

metabolic

organ;

metabolic

pathways

began

re-

to be investigated

.-30
y ago. As noted
in a review,
the effect of catecholamines
on lipolysis
differs
markedly
between
and within
human
fat depots

(72).

Visceral

subcutaneous
peripheral
variations

fat cells

are

more

responsive

than

fat cells, which

are much
more
(ie, gluteal
or femoral)
subcutaneous
have important
applications
to clinical

abdominal

responsive
fat cells.
medicine.

than
These
Since

exercise

mass in different
adipose regions. Visceral fat has direct contact
with the liver via the portal system.
As discussed
(73, 74), an

or no change

increase

during

and

rat

owing

effectiveness
exercise

almost
no lipolytic
effect in vitro because
of
responsiveness
(65). The latter may be due
ofan

(29).

/3 and

variations

-50

seems
to differ
between
of increased
catecholamine-

(70, 7 1). However,

ofsex

constitute

variations
lipid may

the coupling

>

in the delivery

catecholamine

the

95%

in synthesis
be involved

fat cells may cause

Recently,

to a combination

in women

with females

are

gradually

regional
of this

Developmental
aspects
of adrenoceptor
function
have been
investigated
in detail in humans
(Fig 2). Shortly
after birth,
cathave
a2-receptor

in aging
function
evidence

between

subjects

decreases

of hormone-sensitive
lipase
decrease
in catecholamine-induced

observed

lipolysis

the

then

triglycerides

(61-64).

echolamines
increased

thyroid-

This
effect of

of physical

to increased

by

infancy,

fat cells,

action
of catecholamines.
subjects
(6 1, 62). The

within

is probably

exercise
oflipolysis

been

cell adrenoceptor
There
is indirect

have

58).

early

marked
regional
variations
in adrenoceptor
influenced
by sex, as discussed
below.

of events

observed

high-carbohydrate
or highfunction
in fat cells of nor-

physical

in the regulation

an increased
lipolytic
in male and female
is rapid

The

the
of

(59, 60).

subjects

adaptive

on

lipolysis.

has

Fat
sexes.

pared

marked

hormones.
sensitivity

may

lipolysis

in the balance

that occurs
in fasting
huincrease
in the circulating
caloric
deprivation
(55, 56).

On the other hand,

overfeeding
with
fat diets does not alter adrenoceptor
mal

This

also

During

of catecholamines

effect

a reduction
in the activity
A similar
post-adrenoceptor

induced

influences

/3-adrenoceptor
number
and the decrease
in a2-adrenumber
in fat cells may contribute
to the enhanced

in

noceptor
lipolytic

has

(Table
4).
there
is an

lipolysis
when

developmental
changes
in the latter action
of the
Fasting
increases
markedly
the in vivo lipolytic
norepinephrine

in
to

as a fuel, catecholamine-induced

In addition,

mechanism

stimulating
hormone
appears
to be the major
regulatory
hormone oflipolysis
in man (27). There
is a gradual
increase
in the
lipolytic
effect ofcatecholamines
during
infancy,
which
reaches
an adult effect at -2 y ofage
(65). Thereafter,
there is a constant
ofage.

function

adaptive
changes
in catecholamine-induced
In fasting
and in connection
with exercise,
increased

fat cells

Increased
fl-adrenoceptor
number
and decreased
a-receptor
number
Increased
hormone
sensitive
lipase activity
Increased
cs2-receptor
number
and coupling
Decreased
hormone
sensitive
lipase
Different
fl-a2 receptor
balance
between the sexes

in women

to

There
is increasing
white fat cells is subject

in white

Thus,

lipolytic

Physiological

function

antilipolytic

prostaglandin
E, nicotimc
by a decrease
in /3-adrenodecrease
in lipolytic
sensitivity

is reversed

effect

(52).

/3adrenoceptor.

the

in

ofcatecholamine

and parahormones

produce

the stimulation
ofhuman
fat cells
acid, or adenosine
is accompanied
ceptor
affinity
and a concomitant
a G-mediated

adaption

re-

interactions
cell surface

for the antilipolytic

effect of insulin
lactate
can also stimulate
/3-adrenoceptor

lipolysis

partly

action

23 lS

CELLS

TABLE 4
Physiological

regulatory
that cat-

(5 1 ). However,

in fat cells, which

is accompanied
sensitivity
of catecholamines
(53).

inhibit

cells

FAT

50).

inhibit

insulin

number
in fat cells
reduces
catecholamine

It has recently

although

of 3T3-Ll

that insulin-/3-adrenoceptor
Insulin
can acutely
reduce

portant
mechanism
is noteworthy
that

gests

activity,

insulin
is the major
It is well established

/3 adrenoceptors,

thereby

ternalization
the lipolytic

gene

differentiation

be of importance

cent data suggest

occur
in fat cells.

action

on the

from catecholamines,
for fat cell metabolism.

echolamines,

that

on /3-adrenoceptor

effects

IN

ofthe

total

offree

fatty

acids

hypertriglyceridemia
mechanisms

sensitivity

fat cell volume,

and breakdown
in the regulation

to the liver

been

from

and glucose

underlying
have

intersite
partly

small

(through
lipolysis)
of the total fat

visceral

intolerance.
variations

elucidated.

and women
the major
contributing
mechanism
is a regional
difference
in the expression
of/3 adrenoceptor
(75, 76). The order
of magnitude
for the number
of /3 receptors
in vitro is omental
> subcutaneous

abdominal

>

subcutaneous

peripheral.

in

In men

Regional

2325

ARNER

100

:
4
IL

0
(/)
>-

0.5

AGE
2. Developmental

FIG

HSL

variations

There

abdominal
regional

function

(29). In women,
activity
within

is a higher

in men (29,
13-adrenoceptor

a2-receptor

circulatory,

possible

separate

affinity

genes

that

fat cells
cells.

been

described

in peripheral

than

may explain
why
lipolysis
within

in
the
the

responsible
in human
and

in different

Marked

stromal

regions

regional

for regional
adipose
tissue,
factors.

are

derived

variations

encoding

for
gluteal
to the

and

renoceptors
in the former
cells
of the glucocorticoid
receptor
encoding
fat depots

cells

from different
where
metabolism

132

fat cells
increase
(78).
gene

It is

The

attractive

obesity
has been
postadrenoceptor

the subactivity

in abdominal
been described,
number
of /3 ad-

transcriptional
the mRNA

activity
expression

described,

also differ in the submay suggest

that fat

that

there

is a lipolysis

frequently.
A few obese
in catecholamine-induced

defect

in

patients
with a
lipolysis
have

the

in obese
however,
littermates,

adrenoceptor.

a2

lipolysis

ofoverweight

As mentioned,
with young lean

defect

is impaired
(83).
of 13 adrenoceptors
(84,

85).

rats

has

been

ber

latter

and

from
obese

findings

dogs

number

findings

obese

in obese

dogs

action

sensitivity

of catecholamines

(88).

a2-

The

cholamines

and

on

obese

humans

larger

than

(89).
those

has

not

human

in vivo

The

of nonobese

catecholamines
in human

When
considered

the

has

A normal
been

have,

is

reported

demonstrated

subjects

There

ifanything,

of

cate-

to be normal

function

(9 1). The

catlipolytic

actions

/3-adrenoceptor

activity

This

concerning

fat cells.

subjects.

have

a2-receptor

seem
num-

elucidated.

of obese

fat cells

tion

been

are

fat cells

increased

There

animals.

published

in vitro

fat cell size and adrenoceptor

that

of these

been

between

an

87).

to the

a decreased

/3-adrenoceptor-mediated

lipolysis

model

in f3-adrenoceptor
affinity
in
the possible
influence
of age

have

on obese

(86,

/i

it is difficult

mouse

and

fat cells

between

However,

receptors

in the

(82).

by /3-agonists

interaction

are conflicting
ofa2

few studies

oflipolysis

the

the monogenic
human
state.

in obese

Surprisingly

effeci

frequently.

due to obesity

cyclase.

counterbalanced
by an increase
obese dog adipocytes.
Moreover,
on the

reported

to a decrease
in the number
of the /3 subunit
of the G

impairs

adenylate

/3 adrenoceptors

of

be involved
lipolytic

old obese
rats have been compared
so that it is not possible
to distinguish

may be due
and an excess

The

to extrapolate
multifactorial
The

This

may

(8 1). A blunted

between
changes
due to age and those
In genetically
obese mice, stimulation

decreased

in obesity

a2

in whom

catecholamines

of

echolamine

regions
represent
separate
cell populations,
is regulated
differently
at the level of gene

hypothesis

fat cells.

to be an increased

adrenoceptors

for lipoprotein
lipase
(79, 80). These
data

tested
block

in human

in the development

from

in the activity

expression.

Adrenoceptors

lipolysis

adrenoceptors,

has recently
in the total
The
and

50

SCALE

been

regional
variations
fat depot
(71,

genes have recently

been described
within
fat depots.
An increase
in the transcription

as compared
with
which
corresponds

ofthe
gene
cutaneous

also

LOG

protein
mechanisms
expression
paraendocrine,

precursor

of regulatory
cutaneous
ofthe

have

adipose
tissue is more pronounced
in women
than
75). It is note worthy
that site variations
in a2- and
distribution
have also been observed
in the adi-

pose tissue ofdogs

(77).
There
may be several
variations
in j3-adrenoceptor
including

in catecholamine-induced

there are also

the subcutaneous

subcutaneous
fat cells, which
variation
in catecholamine-induced

subcutaneous

also

changes
lipase.

hormone-sensitive

in /3-adrenoceptor

in vivo recently
in a2-receptor
75).

(YEARS),

are

is a relationship

in humans.
activity

latter

in

usually
Large

(90)

findings

and

indicate

an increased

lipolytic

ac-

laboratory

animals

are

obesity.

findings

together

in humans
there

is no

and
evidence

of a major

alteration

ADRENOCEPTORS
TABLE 5
Catecholamine-induced

lipolysis

IN

Lipolytic

effect of catecholamines

Obesity
Pheochromocytoma
Cushing syndrome
Hyperthyroidism

Normal (?)
Decreased
Decreased
Increased

Hypothyroidism

Decreased

Type I diabetes mellitus

Autonomic
diabetes neuropathy
Chronic /3 blockade

Increased
Increased
Increased

of obesity

adrenoceptor
function
a possible
role ofthese
in certain

iological

adaptation

hormones

may

ceptor
term

individuals.

be associated
are

but

have

of time.
inhibition

obese Pima Indians

non-obese
subjects
changes

not

small

possible

during

The

on the adipose

decrease

infancy

one

review

(72),

adaptation
is associated

during
with

rate

This

are

also

therapeutic
a decrease
but

may

over

to the findings
developmental

may

be

in

not

further

variations

in fat

abdominal,

promote

subcutaneous
the

development

(100).

A prolonged
the

administration

up-regulation

blockers.

Long-term
agents

in

cell

gain

Catecholamine

action

disorders
(Table
in patients
with
mechanisms
(93,

in fat cells

to obesity

is altered

in several

these

alterations

have

not

been

96),

although

postadrenoceptor

changes

level ofphosphodiesterase)
are also involved
(97).
to be no change
in a2-receptor
function
in hyperroidism
(95, 96).
It is well known
sympathetic

nervous

that

type
activity.

I diabetes

is associated

In fat cells

from

type

patients
there is increased
/3-adrenoceptor
sensitivity
an enhanced
coupling
between
these receptors
and G
total amounts
ofG
in type I diabetes

with

in the

an increase
explain

in /3-receptor

why

the /3-adrenoceptor

beta-

number

there

is little

blockade.

Conclusions
Adrenoceptors

play

metabolism.
classical

role

are unique

adrenoceptor

species

a major

Adipocytes

subtypes,

differences

in this

in the

regulation

because

they

although

respect.

The

there

effects

of fat cell
express
are

all the

important

of catecholamines

and

to

Hormones,

physiological

nutritional
and

ing infancy

common

elucidated

(ie, at the

There
appears
and hypothywith

patients
increase

sensitive

The lipolytic
effect of catecholamines
is increased
in hyperthyroidism
and decreased
in hypothyroidism.
This is attributed
to an increase
and a decrease,
respectively,
in /3-adrenoceptor
(95,

during

and
partly

beta

adipose

94).

number

may

the

of

be modulated
in fat cells at the level
Beta adrenoceptors
are particularly

5). Catecholamine-induced
lipolysis
is decreased
pheocromocytoma
or Cushings
syndrome;
the

behind

This

cause

withdrawal

ofhypertensive
by an

is followed

may

on fat cell metabolism

can
of adrenoceptor
molecules.

of gynoid

related

after

in fat cells
(101).

increased
I diabetic
owing
to
(98). The

and adenylate
cyclase activity
are not altered
(98, 99). In type I diabetics
with autonomic

changes
There

The

influence

Alpha

when

pathophysiological

beta-blocking

in obesity.
expression

undergo

marked
change

On the other
hand,
site
and a-receptor
affinity,

in the development

importance

of regional

of subclasses

and

are less adaptable,

receptors

a2 receptors

adaptation.

treatment,

the expression

in expression
and function.
is no evidence
of an overall

function
/3-receptor
volved

factors,

diabetes

/3 adrenoceptors.

not

treatment

/3 adrenoceptors

disorders,

in disorders

phenomenon

is accompanied

responsiveness

agents
this

Fasting
lipolysis

obesity.

Adrenoceptors

ofbeta-blocking

of /3 adrenoceptors;

rebound

blocking
of

sensiof /3

in
ac-

for the development

regional
variation

regional

there
is a further
increase
in /3 adrenoceptor
reflects
an additional
increase
in the number

or no weight

involved

fasting
in obese subjects.
in catecholamine-induced

neuropathy
tivity,
which

sympathetic

the subcutaneous
fat depots
may be in(gynoid)
type of obesity.
As mentioned
in

there

in peripheral,

tissue.

mass

by

is associated
lipolysis
in

mechanism

Unknown
Unknown
Increased
13-adrenoceptor
number
and decreased
phosphodiesterase
activity
Decreased
13-adrenoceptor
number
and increased
phosphodiesterase
activity
Increased
coupling
between 13-adrenoceptor
and G5
Increased
fl-adrenoceptor
number
Increased
fl-adrenoceptor
number

adrenoceptors

short-

in hormone-sensitive-lipase

tivity in elderly people

may be ofimportance
of obesity
during
this period
of life. The
within
female

during

Major

or

in adreno-

to detect

an impact

phys-

fasting,

alterations

(92), which
is in contrast
discussed
above.
Pathological

obesity.

adrenoceptors
volved
in the

an altered
diets,

For example,
overfeeding
of/3-adrenoceptor-mediated

in adrenoceptors

childhood

example,

to exercise,

with

which

observations

a long period
with marked

in obesity.
However,
this
receptors
in the development
For

of adipocytes

function,

233S

CELLS

in clinica 1 disorders

Condition

of adipocyte
does exclude

FAT

forms

within

133-agonists

and

a2-antagonists

in adrenoceptor
variations
which

occur
in
may be in-

of obesity.

/3 adrenoceptors

may

of

except durdevelopmental

adrenoceptors
for fat cell metabolism
remains
unclear.
it may be feasible
to develop
drugs with super-selectivity
these adrenoceptor
subtypes
in the treatment
ofobesity.
ticular,

thyroid
function

and a2
However,
towards
In par-

#{163}3

be useful.

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ADRENOCEPTORS
44.

45.

46.

47.

48.

49.

50.

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