2285 Am J C/in Nuir l992;55:228S-36S. Printed in USA. 1992 International Association for the Study of Obesity

Adrenergic receptor function in fat ce0s13

Peter Amer

ABSTRACT All classical adrenoceptor subtypes are func-tionally expressed in fat cells. However, only /3 adrenoceptors

appear to be present in all types offat cells. There is a substantial

adrenoceptor reserve in fat cells; -50% offl and a2 adrenoceptors

are spare receptors. Beta adrenoceptors are subject to intensiveregulation. They are regulated by insulin, estrogens, and andro-

gens as well as by thyroid hormones and are altered by nutritional

factors, diabetes, autonomic neuropathy, and beta-blocking

treatment. Alpha receptors are less sensitive to changes except

during infancy, when there are marked developmental alterations

in the function of a2 adrenoceptors, and during fasting, when

there is a decrease in receptor expression. In addition, /3 adre-noceptors but not a2 adrenoceptors are sensitive to homologous

desensitization after exposure to agonists. Site variations in the

expression and function of /3 and a2 adrenoceptors, which inpart are situated at the level of gene transcription, may be in-volved in the development of regional obesity. Am J Clin

Nutr l992;55:228S-36S.

KEY WORDS Adipocyte, lipolysis, /3 adrenoceptor, a ad-renoceptors, catecholamines

Introduction

Adrenoceptors play a major role in the regulation of several

processes in the body, including fat cell metabolism. The first

step in the peripheral action ofcatecholamines is binding to cell-

surface adrenoceptors in target cells. This review deals with ad-

renoceptor function in fat cells under normal and pathophysi-

ological conditions and in the latter case focuses on obesity and

obesity-related disorders.

Adrenoceptor subtypes in brown fat cells

The old classification of adrenoceptor subtypes into a1 , a2,

/3 , and /32 must be reevaluated. As mentioned in two surveys

( 1 , 2) there seems to be a family of a receptors; at least twodifferent a1 receptors termed A and B and four different a2 re-

ceptors termed A, B, C, and D are described. In addition, a /3adrenoceptor 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-

anism for organ and species selectivity of hormone action. A

further subclassification may provide a means for better under-

standing of the tissue selectivity of a particular catecholamine

effect.

As regards adrenoceptor subtypes in brown fat cells, the func-

tions and mechanisms of action of these receptors are summa-

rized in Table 1. The principal role of adrenoceptors in brown

fat cells is to regulate thermogenesis. As noted in another survey(4) a1 , a2, and /3adrenoceptors are involved in this process. Themajor part (80%) ofcatecholamine-stimulated heat production

occurs through /3adrenoceptors and the remaining part througha1 adrenoceptors. In addition, catecholamines may inhibit heat

production through a2 receptors. Thus, the net thermogenic ef-

fect of catecholamines is dependent upon the balance between

these different receptors, which regulate heat production via dis-

crete mechanisms (Table 1). The /3 effect is mediated by stim-ulation ofadenylate cyclase and cyclic AMP production through

the G protein. The inhibitory a2 effect is mediated via inhibitionof the same pathway through the G, protein. Catecholamines

stimulate phosphoinositide hydrolysis through a1 receptors so

that the intracellular (2+ concentration is increased, which leadsto activation of protein kinase C. All /3-adrenoceptor subtypes

mediate their effects via the same cyclic AMP mechanism. It isnot yet known which subtypes are present in brown adiposetissue. However, when recent data are summarized (5) it appears

that fl and $, but not /32, are functionally expressed in brownadipose tissue.

There are important species differences in the functional role

of brown fat cells. In humans they appear to be of importance

only for thermogenesis in infants; adults have only a few brown

fat cells that produce minor effects on thermogenesis (6). Al-

though data suggest that it may be possible to activate brown

fat cells in adult man by using selective /33-agonists (7-9), therole ofthese cells in normal and pathophysiological human con-

ditions is unclear. Therefore, the remaining discussion in thispaper will focus on adrenergic regulation in white fat cells.

Adrenoceptor subtype and function in white fat cells

The major function of adrenoceptors in white fat cells is to

regulate the breakdown of triglycerides to free fatty acids andglycerol by means oflipolysis. Catecholamines have other effects

on fat cells as well (for example on lipid synthesis or on transport

and metabolism ofglucose). These effects, however, are less well

characterized and will not be considered further.

1 From the Department ofMedicine, Huddinge Hospital, Karolinska

Institute, Stockholm.2 Supported by grants from Swedish Medical Research Council and

Medicus Bromma.

3 Address reprint requests to P Arner, Department of Medicine,Huddinge Hospital, 5-141 86 Huddinge, Sweden.

one to one

0010 of total receptors occupied

ADRENOCEPTORS IN FAT CELLS 2295

TABLE 1

Function and effector mechanisms for adrenoceptors in fat cells

Receptor subtype Effector mechanism

Function

Brown fat cells White fat cells

Beta 2.3 Stimulation of adenylate cyclase and cyclic AMP through G, Increase heat production Increase lipolysis rate

Alpha2 Inhibition of adenylate cyclase and cyclic AMP through G Decrease heat production Decrease lipolysis rate

AlphaC Increased Ca2 and protein kinase C through

phosphoinositide hydrolysis

Increase heat production ?

The functions and mechanisms ofaction ofadrenoceptors in

white fat cells are summarized in Table 1 . Beta -receptors stim-

ulate and a2 receptors inhibit lipolysis through the mechanisms

described above for heat production in brown fat cells. The

phosphoinositide pathway can be activated by a1 receptors in

the same way as in brown fat cells. The functional role of the

latter receptors in white fat cells has not yet been elucidated (10).

There are considerable species differences in the expression

ofadrenoceptor subtypes in white fat cells(Table 2). The presence

ofa1 or a2 receptors is demonstrated much more easily in human

( 1 1) or hamster ( 12) fat cells than in rat adipocytes ( 1 3, 14); thea2 receptor in human fat cells seems to be predominantly of the

a2 A subtype (15). The /3 receptor is probably present in all

species. However, human fat cells also contain a /32 receptor

(16), which is fully functional (17), but not a /3 receptor (18).Rat fat cells, on the other hand, have no /32 receptors (19) but

they have fully functional fl receptors (20). Hamster fat cellsappear to have all three /3 receptor subtypes (2 1, 22).

Relationship between adrenoceptor occupancy and

response

The relationship between the number of receptors that are

occupied by a hormone and the final cellular response can be

either one-to-one or be characterized by spare receptors (Fig 1).In the former case a small reduction in receptor numbers leads

to a combination of decreased hormone sensitivity (ie, an in-

creased concentration causing half maximum effect) and de-

creased hormone responsiveness (maximum effect). In the latter

case a small decrease in receptor numbers is accompanied only

by a decrease in hormone sensitivity; the responsiveness is altered

after a large decrease in the number of receptors that bypass the

threshold for the receptor reserve. The relationship between re-

ceptor occupancy and cellular response is essential for hormone

function. In a one-to-one receptor-effector relationship, the in-

hibition of cellular response due to a small decrease in receptor

TABLE 2Species differences in the expression ofadrenoceptor subtypes in whitefatcells

Receptor Easy detected Hardly detected or absent

Beta1 All species -

Beta2 Human, hamster Rat

Beta3 Rat, hamster HumanAlphaC Human, hamster Rat

Alpha2 Human, hamster Rat

number cannot be overcome by an increase in the hormone

concentration. When spare receptors are present, however, the

organ can always compensate for a moderate decrease in recep-

tors by an increase in the concentration of the hormone. In

addition, spare receptors provide a means for amplification of

the hormone signal. Because there are more receptors than ef-

fectors, small changes in receptor number are accompanied by

much larger changes in hormone sensitivity.

As regards the receptor-effector relationship in fat cells, there

is clear evidence of spare receptors (23, 24). Only - 50% of the

total fraction of /3 or a2 receptors has to be occupied to obtain

a full catecholamine response. Furthermore, inactivation of a

small number of these receptors in fat cells is accompanied by

a large decrease in catecholamine sensitivity (24).

The role of dual adrenoceptors

Fat cells appear to be the only natural occurring cells thathave dual adrenoceptor function, ie, catecholamines can either

stimulate or inhibit adenylate cyclase by /3 and a2 receptors,respectively. The functional role of this dual effect remains un-

clear. As regards lipolysis, both classes of receptors seem to op-

erate in vivo because the administration ofbeta blockers or alpha-

U

a)

FIG 1 . Relationship between adrenoceptor occupancy and the bio-logical effect of catecholamines in fat cells.

2305 ARNER

TABLE 3Effects of hormones and other endogenous substances on catecholamine action in white fat cells

Substance Catecholamine effect Major mechanism

Thyroid hormones Increased sensitivity Decreased G expressionEstrogens Decreased sensitivity Inhibited catalytic component of adenylate cyclaseAndrogens Increased sensitivity Increased /3-adrenoceptor numberGlucocorticoids Increased sensitivity Multiple effects on the /3-adrenoceptor-adenylate

cyclase complexInsulin Decreased sensitivity /3-Adrenoceptor translocationLactate Decreased sensitivity /3-Adrenoceptor internalizationProstaglandine E, nicotinic acid, Decreased sensitivity Decreased fl-adrenoceptor agonist affinity

adenosine

2 blockers causes a decrease and an increase, respectively, of the

lipolytic activity in humans who are investigated under condi-

tions of normal or altered sympathetic activity (25, 26). A dual

effect on lipolysis by catecholamines in humans is puzzling, be-

cause only these hormones cause pronounced lipolytic activity

in adult man (27). In most other species several additional hor-

mones are markedly lipolytic and may, therefore, overcome the

antilipolytic action of catecholamines.

It has been suggested that a certain degree of catecholamine

inhibition is necessary in human fat cells because unrestrained

lipolysis may proceed at an almost maximal rate (28). If so, the

a2 receptor will be the major lipolysis-regulating receptor for

catecholamines and modulate the lipolytic effect ofthe /3 recep-

tors. Alternatively, the dual receptors may operate under different

conditions in man. Recent in situ studies using microdialysis

suggest that a2 receptors modulate lipolysis at rest, whereas /3

receptors modulate lipolysis during physical exercise (29).

Adrenoceptor 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 is specific and refers to processes that only affect

a particular receptor and its specific agonist. During heterologous

desensitization the action through one type of receptor causes

the desensitization of several other types of receptors as well.

The homologous desensitization of/3 adrenoceptors has been

characterized in detail (30). Within a few minutes after agonist

exposure, /3 receptors are sequestered away from the cell surface

into a membrane-associated compartment, which is not acces-

sible to hydrophilic ligands, such as isoprenaline (and probably

also not to the natural catecholamines). A second change is that

the receptor becomes functionally uncoupled from the effector.

The /3 receptor is phosphorylated, which impairs its ability to

interreact with G. . At later stages there are also changes in the

degradation and synthesis of /3 adrenoceptors.

Catecholamine tachyphylaxia has been investigated in fat cells.

The /3 receptor is very sensitive to desensitization. The exposure

ofcells in vitro (3 1) and in vivo (32) to /3-agonists is accompanied

by a rapid decrease in /3-adrenoceptor number and responsive-

ness. The mechanisms behind desensitization have not been

clarified. It appears, however, that there are no regulatory changes

distal to cyclic AMP accumulation in desensitized fat cells (33).

The uncoupling of i3 adrenoceptors from G, during desensiti-

zation has been described in brown fat cells (34). Heterologous

desensitization of/3 adrenoceptors has also been described in fat

cells (35). The a2 receptor in fat cells appears to be less sensitive

to desensitization. Thus, the exposure of fat cells to natural cat-

echolamines or selective a2-agonist in vitro, in vivo, and in situ

does not alter a2-receptor number or function in fat cells (32,

36-38). As yet, there are no reports on a1-receptor desensitizationin fat cells, although homologous desensitization for this receptor

has been described in other tissues (39).

Regulation of adrenoceptors by hormones and otherendogenous substances

Several hormones and other endogenous substances may alter

the expression and function of adrenoceptors in white fat cells

(Table 3). Some have permissive effects and increase the cate-cholamine sensitivity, whereas others inhibit catecholamine re-

ceptor function.

The permissive effect of thyroid hormones on catecholamine

sensitivity is well established, but the mechanisms are unclear.

It has been stated in a review (10) that thyroid hormones do notalter 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 differencesin thyroid hormone action, since the in vivo administration of

these hormones to humans is accompanied by an increased

number of /3 adrenoceptors in adipocytes (42).

Estrogens reduce the lipolytic action of catecholamines in fat

cells. This cannot be attributed to changes in the number of /3or a2 receptors (43). Instead, estrogens inhibit the catalytic com-

ponent of adenylate cyclase (44). Androgens have permissive

effects and increase the lipolytic sensitivity of catecholamines.

The latter may to some extent be due to an increase in the

number of /3 adrenoceptors in fat cells (45), although andogens

may also alter a2-receptor function in adipocytes, at least when

testosterone is administered in vivo (46).

Glucocorticoids also produce catecholamine-permissive effects

on lipolysis in fat cells. The mechanisms behind this 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 (47). In addition, the effect ofglucocorticoids on

/3 adrenoceptors may be subtype specific. In 3T3-Ll adipocytes,

glucocorticoids promote the expression of/32 adrenoceptors and

reduce the expression of/31 adrenoceptors (48). This may involve

ADRENOCEPTORS IN FAT CELLS 23 lS

glucocorticoid effects on /3-adrenoceptor gene activity, although

steroid hormone effects on the differentiation of 3T3-Ll cells

per se may also be of importance (49, 50).

Apart from catecholamines, insulin is the major regulatory

hormone for fat cell metabolism. It is well established that cat-

echolamines, through /3 adrenoceptors, inhibit insulin action in

fat cells and thereby cause insulin resistance (5 1 ). However, re-

cent data suggest that insulin-/3-adrenoceptor interactions also

occur in fat cells. Insulin can acutely reduce cell surface 13-ad-

renoceptor number in fat cells through a translocation mecha-

nism that reduces catecholamine sensitivity; this may be an im-

portant mechanism for the antilipolytic effect of insulin (52). It

is noteworthy that lactate can also stimulate /3-adrenoceptor in-

ternalization in fat cells, which is accompanied by a decrease in

the lipolytic sensitivity of catecholamines (53).

It has recently been shown that hormones and parahormones

that inhibit lipolysis through G may produce their antilipolytic

action partly through interactions with the /3adrenoceptor. Thus,the stimulation ofhuman fat cells with prostaglandin E, nicotimc

acid, or adenosine is accompanied by a decrease in /3-adreno-

ceptor affinity and a concomitant decrease in lipolytic sensitivity

of/3-agonist (54). This is reversed by pertussis toxin, which sug-

gests a G-mediated effect (54).

Physiological adaptation of adrenoceptor function

There is increasing evidence that adrenoceptor function in

white fat cells is subject to physiological regulation and leads to

adaptive changes in catecholamine-induced lipolysis (Table 4).In fasting and in connection with exercise, when there is an

increased need for free fatty acid as a fuel, catecholamine-induced

lipolysis is increased. In addition, the sex ofthe subject influences

the lipolytic action of catecholamines. There are also marked

developmental changes in the latter action of the hormones.

Fasting increases markedly the in vivo lipolytic sensitivity of

norepinephrine (55) and epinephrine (56). This may in part cx-plain the increased lipolytic activity that occurs in fasting hu-

mans, since there is only a moderate increase in the circulating

catecholamine concentration during caloric deprivation (55, 56).

Fasting presumably has multiple effects on the chain of events

that mediate catecholamine-induced lipolysis. The observed in-

crease in /3-adrenoceptor number and the decrease in a2-adre-

noceptor number in fat cells may contribute to the enhanced

lipolytic sensitivity to catecholamines during fasting (57, 58).

On the other hand, overfeeding with high-carbohydrate or high-

fat diets does not alter adrenoceptor function in fat cells of nor-

mal subjects (59, 60).It is well established that physical exercise is accompanied by

adaptive changes in the regulation oflipolysis in human fat cells,

including an increased lipolytic action of catecholamines. This

is observed in male and female subjects (6 1, 62). The effect of

training is rapid and occurs within 30 mm of physical exercise

(63). The mechanism is probably due to increased effectiveness

ofhormone-sensitive lipase; there seems to be little or no change

in the stoichiometric properties of adrenoceptors during exercise

(61-64).

Developmental aspects of adrenoceptor function have been

investigated in detail in humans (Fig 2). Shortly after birth, cat-

echolamines have almost no lipolytic effect in vitro because of

increased a2-receptor responsiveness (65). The latter may be due

to a combination ofan increase in the number and the coupling

TABLE 4Physiological adaption ofcatecholamine function in white fat cells

Catecholamine-inducedFactor lipolysis rate Major mechanism

Fasting Increased Increased fl-adrenoceptornumber and decreased

a-receptor numberExercise Increased Increased hormone sensitive

lipase activityInfancy Decreased Increased cs2-receptor number

and couplingHigh age Decreased Decreased hormone sensitive

lipase

Sex Increased in women Different fl-a2 receptor balancebetween the sexes

efficacy of a2 receptors (66, 67). During early infancy, thyroid-

stimulating hormone appears to be the major regulatory hor-

mone 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

lipolytic effect of catecholamines until the subjects are -50 y

ofage. This effect ofthe hormone then decreases gradually owing

to a reduction in the activity of hormone-sensitive lipase (68).

A similar post-adrenoceptor decrease in catecholamine-induced

lipolysis has been observed in aging rat fat cells (69).

Fat cell adrenoceptor function seems to differ between the

sexes. There is indirect evidence of increased catecholamine-

induced lipolysis in women (29). This may be due to a difference

in the balance between /3 and a2 adrenoceptors in males as com-

pared with females (70, 7 1). However, it is difficult to determine

the influence ofsex on adrenoceptor function because there are

marked regional variations in adrenoceptor activity that are also

influenced by sex, as discussed below.

Regional variations in adrenoceptors

Human adipose tissue is a heterologous metabolic organ; re-

gional variations in the activity of several metabolic pathways

have been described since this tissue began to be investigated

.-30 y ago. As noted in a review, the effect of catecholamines

on lipolysis differs markedly between and within human fat de-

pots (72). Visceral fat cells are more responsive than abdominal

subcutaneous fat cells, which are much more responsive than

peripheral (ie, gluteal or femoral) subcutaneous fat cells. These

variations have important applications to clinical medicine. Since

triglycerides constitute > 95% ofthe total fat cell volume, small

regional variations in synthesis and breakdown (through lipolysis)

of this lipid may be involved in the regulation of the total fat

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

increase in the delivery offree fatty acids to the liver from visceral

fat cells may cause hypertriglyceridemia and glucose intolerance.Recently, the mechanisms underlying intersite variations in

catecholamine sensitivity have been partly elucidated. In men

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. Regional

100

0.5 5 50

2325 ARNER

:

4

IL

0

(/)

>-

AGE (YEARS), LOG SCALE

FIG 2. Developmental changes in catecholamine-induced lipolysis in human fat cells. a2 R = a2 adrenoceptor.HSL = hormone-sensitive lipase.

variations in /3-adrenoceptor function have also been described

in vivo recently (29). In women, there are also regional variations

in a2-receptor activity within the subcutaneous fat depot (71,

75). There is a higher a2-receptor affinity in peripheral than in

abdominal subcutaneous fat cells, which may explain why the

regional variation in catecholamine-induced lipolysis within the

subcutaneous adipose tissue is more pronounced in women than

in men (29, 75). It is note worthy that site variations in a2- and

13-adrenoceptor distribution have also been observed in the adi-

pose tissue ofdogs (77).

There may be several mechanisms responsible for regional

variations in j3-adrenoceptor expression in human adipose tissue,

including circulatory, paraendocrine, and stromal factors. It is

also possible that fat cells in different regions are derived from

separate precursor cells. Marked regional variations in the activity

of regulatory genes have recently been described within the sub-

cutaneous fat depots. An increase in the transcription activity

ofthe genes encoding for $ and 132 adrenoceptors in abdominalas compared with gluteal fat cells has recently been described,

which corresponds to the increase in the total number of /3 ad-

renoceptors in the former cells (78). The transcriptional activity

of the glucocorticoid receptor gene and the mRNA expression

ofthe gene encoding for lipoprotein lipase also differ in the sub-

cutaneous fat depots (79, 80). These data may suggest that fat

cells from different regions represent separate cell populations,

where metabolism is regulated differently at the level of gene

expression.

Adrenoceptors in obesity

The attractive hypothesis that there is a lipolysis defect in

obesity has been tested frequently. A few obese patients with a

postadrenoceptor block in catecholamine-induced lipolysis have

been described, in whom the lipolysis defect may be involved

in the development ofoverweight (8 1). A blunted lipolytic effeci

of catecholamines in obese rats has been reported frequently.

As mentioned, however, old obese rats have been compared

with young lean littermates, so that it is not possible to distinguish

between changes due to age and those due to obesity (82).In genetically obese mice, stimulation oflipolysis by /3-agonists

is impaired (83). This may be due to a decrease in the number

of 13 adrenoceptors and an excess of the /3 subunit of the G

protein (84, 85). The latter impairs the interaction between /i

adrenoceptors, G and adenylate cyclase. However, it is difficult

to extrapolate from the monogenic obese mouse model to themultifactorial obese human state.

The findings in obese dogs are conflicting (86, 87). There seem

to be an increased number ofa2 receptors and a decreased num-

ber of /3 adrenoceptors in the fat cells of these animals. This iscounterbalanced by an increase in f3-adrenoceptor affinity inobese dog adipocytes. Moreover, the possible influence of age

on the findings in obese dogs has not been elucidated.

Surprisingly few studies have been published concerning cat-

echolamine action on obese human fat cells. A normal lipolytic

sensitivity of catecholamines in vitro has been demonstrated

(88). The a2- and /3-adrenoceptor-mediated actions of cate-

cholamines on lipolysis in vivo are reported to be normal in

obese humans (89). The fat cells of obese subjects are usually

larger than those of nonobese subjects. There is a relationship

between fat cell size and adrenoceptor function in humans. Largefat cells have an increased /3-adrenoceptor activity (90) and a

decreased a2-receptor activity (9 1). The latter findings indicatethat catecholamines have, ifanything, an increased lipolytic ac-

tion in human obesity.

When the findings in humans and laboratory animals are

considered together there is no evidence of a major alteration

ADRENOCEPTORS IN FAT CELLS 233S

TABLE 5

Catecholamine-induced lipolysis in clinica 1 disorders

Condition Lipolytic effect of catecholamines Major mechanism

ObesityPheochromocytomaCushing syndromeHyperthyroidism

Hypothyroidism

Type I diabetes mellitusAutonomic diabetes neuropathy

Chronic /3 blockade

Normal (?)DecreasedDecreasedIncreased

Decreased

Increased

Increased

Increased

-

UnknownUnknownIncreased 13-adrenoceptor number and decreased

phosphodiesterase activity

Decreased 13-adrenoceptor number and increased

phosphodiesterase activityIncreased coupling between 13-adrenoceptor and G5

Increased fl-adrenoceptor numberIncreased fl-adrenoceptor number

of adipocyte adrenoceptor function in obesity. However, this

does exclude a possible role ofthese receptors in the development

of obesity in certain individuals. For example, an altered phys-

iological adaptation of adipocytes to exercise, diets, fasting, or

hormones may be associated with small alterations in adreno-

ceptor function, which are not possible to detect during short-

term observations but have an impact on the adipose mass over

a long period of time. For example, overfeeding is associated

with marked inhibition of/3-adrenoceptor-mediated lipolysis in

obese Pima Indians (92), which is in contrast to the findings in

non-obese subjects discussed above. Pathological developmental

changes in adrenoceptors during infancy may be involved in

childhood obesity. The decrease in hormone-sensitive-lipase ac-

tivity in elderly people may be ofimportance for the development

of obesity during this period of life. The regional variation in

adrenoceptors within the subcutaneous fat depots may be in-

volved in the female (gynoid) type of obesity. As mentioned in

one review (72), there are also regional variations in fat cell

adaptation during therapeutic fasting in obese subjects. Fasting

is associated with a decrease in catecholamine-induced lipolysis

rate in peripheral, but not abdominal, subcutaneous adipose

tissue. This may further promote the development of gynoid

obesity.

Adrenoceptors in disorders not related to obesity

Catecholamine action in fat cells is altered in several common

disorders (Table 5). Catecholamine-induced lipolysis is decreased

in patients with pheocromocytoma or Cushings syndrome; the

mechanisms behind these alterations have not been elucidated

(93, 94).

The lipolytic effect of catecholamines is increased in hyper-

thyroidism and decreased in hypothyroidism. This is attributed

to an increase and a decrease, respectively, in /3-adrenoceptor

number (95, 96), although postadrenoceptor changes (ie, at the

level ofphosphodiesterase) are also involved (97). There appears

to be no change in a2-receptor function in hyper- and hypothy-

roidism (95, 96).It is well known that type I diabetes is associated with increased

sympathetic nervous activity. In fat cells from type I diabetic

patients there is increased /3-adrenoceptor sensitivity owing to

an enhanced coupling between these receptors and G (98). The

total amounts ofG and adenylate cyclase activity are not altered

in type I diabetes (98, 99). In type I diabetics with autonomic

neuropathy there is a further increase in /3 adrenoceptor sensi-

tivity, which reflects an additional increase in the number of /3

adrenoceptors (100).

A prolonged administration ofbeta-blocking agents is followed

by the up-regulation of /3 adrenoceptors; this may cause the

sympathetic rebound phenomenon after withdrawal of beta

blockers. Long-term treatment ofhypertensive patients with beta-

blocking agents is accompanied by an increase in the number

of /3 adrenoceptors in fat cells and an increase in /3-receptorresponsiveness (101). This may partly explain why there is little

or no weight gain during the /3-adrenoceptor blockade.

Conclusions

Adrenoceptors play a major role in the regulation of fat cell

metabolism. Adipocytes are unique because they express all the

classical adrenoceptor subtypes, although there are important

species differences in this respect. The effects of catecholamines

on fat cell metabolism can be modulated in fat cells at the level

of adrenoceptor molecules. Beta adrenoceptors are particularly

sensitive to physiological and pathophysiological adaptation.

Hormones, nutritional factors, beta-blocking treatment, thyroiddisorders, and diabetes influence the expression and function of

/3 adrenoceptors. Alpha receptors are less adaptable, except dur-ing infancy when a2 receptors undergo marked developmentalchanges in expression and function.

There is no evidence of an overall change in adrenoceptor

function in obesity. On the other hand, site variations occur in

/3-receptor expression and a-receptor affinity, which may be in-

volved in the development of regional forms of obesity.

The importance of subclasses within /3 adrenoceptors and a2adrenoceptors for fat cell metabolism remains unclear. However,

it may be feasible to develop drugs with super-selectivity towards

these adrenoceptor subtypes in the treatment ofobesity. In par-

ticular, 133-agonists and a2-antagonists may be useful. #{163}3

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