-
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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