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From the
Received for publication, June 15, 2000, and in revised form, July 24, 2000
Catecholamines play an important role in
controlling white adipose tissue function and development. The contribution of catecholamines to the control of metabolic
events occurring in mature adipocytes such as lipolysis has been well
documented. Human adipocytes express significant levels of Murine adipocytes differ from human adipocytes in that they express
many To assess the importance of Transgenic Mice--
All genetically modified animals were
created and maintained on an FVB/n inbred background and were
genetically identical except for the specified genetic alterations.
Creation of Radioligand Binding Assays--
Specific binding of the
Lipolysis--
The in vitro lipolytic response of
isolated white fat cells to epinephrine without or with 10 µM selective mRNA Analyses--
Total RNA was isolated using a Brinkman
homogenizer and RNA STAT-60 solution (Tel-Test "B," Inc.,
Friendswood, TX). Oxygen Consumption--
Oxygen consumption was measured in
10 Assessment of Fat Stores--
The measurement of total
body lipid content was performed as described previously (17, 18). Fat
cell size and fat cell number per fat depot were determined in
perigonadal fat samples using the Hirsch and Gallian method (19) of
lipid extraction, osmium tetroxide fixation, and Coulter Counter
analysis. Histological determinations were performed as described
previously (microscopic assessment of fat cell size; 600 cells per
depot quantified in paraffin-embedded, inguinal fat pad sections from
female mice) (20, 21).
Circulating Blood Metabolites and Hormones--
Whole blood was
collected and analyzed for blood glucose levels (One Touch blood
glucose meter, Lifescan Inc., Milpitas, CA). Serum was isolated and
assayed for non-esterified fatty acids (NEFA C kit, Wako Pure Chemical
Industries, Ltd.), insulin, and leptin (mouse insulin or leptin kit,
Linco Research Inc., St. Louis, MO).
To evaluate the physiologic significance of adipocyte In the present study, we assessed the importance of Epinephrine, an agonist for both
Expression of Human
2-Adrenergic Receptors in Adipose Tissue
of 
3-Adrenergic Receptor-deficient Mice Promotes Diet-induced
Obesity*
§¶,¶,,,
,
,,¶¶
Beth Israel Deaconess Medical Center and
Harvard Medical School, Boston, Massachusetts 02215, the
§ INSERM U317, Institut Louis Bugnard,
Université Paul Sabatier, CHR Rangueil, 31403 Toulouse Cedex 4, France, the Institute of Normal Human Morphology, University of
Ancona, 60020 Ancona, Italy, the ** Department of Microbiology and
Cancer Center, University of Pennsylvania, Philadelphia,
Pennsylvania 19104, and the §§ Section of
Gastroenterology, Department of Medicine, University of Chicago,
Chicago, Illinois 60637
ABSTRACT
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
- and
2-adrenergic receptors (ARs) couple positively and negatively,
respectively, to adenylyl cyclase and are co-expressed in human
adipocytes. Previous studies have demonstrated increased adipocyte
2/-AR balance in obesity, and it has been proposed that increased
2-ARs in adipose tissue with or without decreased -ARs may
contribute mechanistically to the development of increased fat mass. To
critically test this hypothesis, adipocyte 2/-AR balance was
genetically manipulated in mice. Human 2A-ARs were transgenically
expressed in the adipose tissue of mice that were either homozygous
(
/) or heterozygous (+/) for a disrupted
3-AR allele. Mice expressing 2-ARs in fat, in
the absence of 3-ARs (3-AR / background), developed high fat
diet-induced obesity. Strikingly, this effect was due entirely to
adipocyte hyperplasia and required the presence of 2-ARs, the
absence of 3-ARs, and a high fat diet. Of note, obese 2-transgenic, 3 / mice failed to develop insulin resistance, which may reflect the fact that expanded fat mass was due to adipocyte hyperplasia and not adipocyte hypertrophy. In summary, we have demonstrated that increased 2/-AR balance in adipocytes promotes obesity by stimulating adipocyte hyperplasia. This study also demonstrates one way in which two genes (2 and
3-AR) and diet interact to influence fat mass.
INTRODUCTION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
1-,
2-, and 2-adrenergic receptors
(ARs),1 which couple
positively (1 and 2) and negatively (2) to adenylyl cyclase
(1). Endogenous ligands, epinephrine and norepinephrine, activate both
classes of receptors (1, 2), suggesting an important role for
2/-AR balance in regulating lipolysis and energy balance (1, 3,
4). Adipocytes from obese humans have increased 2-ARs, 2/-AR
ratios, and 2-AR-mediated responses (3-9). In addition,
longitudinal studies in animal models have shown that 2-ARs are
increased with fat cell hypertrophy and that increased 2/-AR
balance is correlated with obesity (5, 10, 11). Thus, it has been
proposed that 2/-AR balance affects adipose tissue development.
3-ARs, in addition to 1- and 2-ARs, and very few 2-ARs
(1, 12). 3-ARs, like 1- and 2-ARs, couple positively to
adenylate cyclase. In mice, 3-ARs are expressed predominantly in
white and brown adipocytes, where they are thought to play an important
role in regulating lipolysis and thermogenesis (1). Surprisingly,
3-AR gene knockout mice have little or no increase in body weight and only a slight increase in body fat (13, 14). The
absence of greater effects of 3-AR deficiency on fat stores could be
due to the fact that murine adipocytes, unlike human adipocytes,
express very few 2-ARs (12), which if present would antagonize
actions mediated by residual 1- and 2-ARs and even initiate some
additional effects.
2/-AR balance in adipocytes in
vivo, we have combined gene targeting and transgenic approaches to
create mice with increased 2/-AR balance in adipose tissue. Specifically, the aP2 promoter (15) was used to drive
adipocyte-specific expression of 2-ARs in mice that were either
homozygous (/) or heterozygous (+/) for a disrupted
3-AR allele. Mice with genetically altered
2/-AR balance were then assessed for sensitivity to high fat
diet-induced obesity. Of note, mice with increased 2/-AR balance
developed diet-induced obesity secondary to adipocyte hyperplasia.
These results strongly suggest that 2/-AR balance plays an
important role in regulating fat mass.
MATERIALS AND METHODS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
3 / mice, homozygous for the
Ardb3tm1Lowl allele, has previously been
described (13). The aP2-2A-AR transgene (see Fig. 1a) was
constructed by fusing mouse aP2 fatty acid-binding protein 5'-flanking
regulatory sequence (16), 5.4 kb (EcoRI) to +21 base
pairs (PstI), to 1.4 kb (NcoI to
HindIII) of human genomic DNA containing the human
2C10 gene (16) and the
splice/polyadenylation site of SV40. Comparisons between mice with
Tg(ADRA2A)Lowl and without the 2-AR transgene were all performed on
littermates. Animals were group-housed at 24 °C, had free access to
food and water, and were handled in accordance with the principles and
guidelines established by the National Institutes of Health. Where
indicated, mice were weaned at the age of 3 weeks onto low fat
(#D12450) or high fat (#D12451) diets (Research Diets, New Brunswick,
NJ). Diets were matched for protein content and had the following
composition (as a % of total calories): low fat diet (10% fat, 70%
carbohydrate, and 20% protein); high fat diet (45% fat, 35%
carbohydrate, and 20% protein).
2-adrenergic receptor antagonist (3H)RX-821002 to
fat cell membranes was determined after 30 min of incubation at
25 °C without (total binding) or with (nonspecific binding) 10 µM epinephrine (12). The maximal number of 2-AR binding sites (Bmax) and equilibrium
dissociation constants (KD) were calculated using
Scatchard analysis of saturation binding data.
2-adrenergic receptor antagonist
RX-821002 was measured. Adipocytes were isolated, and lipolysis
was measured as described previously (12). The in vivo
lipolytic response of conscious overnight-fasted mice was measured 10 min after a 0.1 mg/kg epinephrine intraperitoneal injection by
non-esterified fatty acid blood levels.
2-AR transgene mRNA was analyzed by Northern
blotting using either a specific 1.5-kb SV40 probe or 1.2-kb 2C10
probe. UCP1 mRNA levels were analyzed by Northern blotting using a
specific mouse 0.3-kb UCP1 cDNA probe.
week-old mice using the OXYMAX system 4.93 (Colombus Instruments,
Colombus, OH), with a settling time of 100 s, a measuring time of
50 s, and with the reference as room air. The animals were placed
in four 0.3-liter chambers at thermal neutrality (30 °C).
RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
2-ARs, we
had previously generated and studied transgenic mice, on a wild-type
3-AR (+/+) background, which express human 2A-ARs in white and
brown fat (22) (transgene shown in Fig.
1a). Despite the presence of
abundant 2-AR binding sites, transgenic mice had normal body weight
and fat content (data not shown). We hypothesized that the absence of
an effect of 2-ARs on fat stores was due to the presence of abundant
3-ARs, which along with 1- and 2-ARs override the inhibitory
actions of transgenically expressed 2-ARs.
View larger version (39K):
[in a new window]
Fig. 1.
a, schematic representation of the
aP2- 2A-AR transgene. aP2 fatty acid-binding protein 5'-flanking
regulatory sequence (15), 5.4 kb (EcoRI) to +21 base pairs
(PstI), was fused to 1.4 kb of human genomic DNA containing
the human 2C10 gene and the
splice/polyadenylation site of SV40. b, fat-specific
expression of 2-AR transgene mRNA in mouse tissues and isolated
fat cells. Total RNA was isolated from tissues (left) or
isolated cells from white adipose tissue (right) and was
analyzed by Northern blotting using a specific 1.5-kb SV40 probe.
c, specific binding of (3H)RX-821002 to fat cell
membranes incubated for 30 min at 25 °C without (total binding) or
with (nonspecific binding) 10 µM epinephrine (24). The
maximal number of sites (Bmax) and equilibrium
dissociation constant (KD) were calculated using
Scatchard analysis of binding data from control (3 /) and
transgenic (2-trans, 3 /) samples (n = 2).
2/-AR balance
in adipocytes by creating 2-AR transgenic mice (Tg(ADRA2A)1Lowl) on
a 3-AR / and +/ background (mice / or +/ for the
Ardb3tm1Lowl allele) (13). The transgene
employed was the aP2-promoter/human 2A-AR construct mentioned above
(shown in Fig. 1a). As expected, mRNA encoding human
2A-AR was expressed in white and brown adipocytes, but not in liver,
kidney, skeletal muscle, brain, intestine, heart, or non-adipocyte
cells resident within adipose tissue (stroma-vascular fraction) (Fig.
1b). Using the 2-AR-selective radioligand,
(3H)RX-821002, few 2-AR binding sites were found in
membranes isolated from white adipocytes and brown adipose tissue of
3 / mice, confirming that murine adipocytes express very few
2-ARs (Fig. 1c). In contrast, abundant binding sites were
observed in membranes isolated from 2-trans, 3 / mice (Fig.
1c). It is important to note that the number of
1/2-ARs (91.6 ± 4.0 fmol/mg of protein; n = 5) observed in adipocytes of 2-trans, 3 / mice was not different from that found in adipocytes of 3 / mice (102.7 ± 7.5 fmol/mg of protein; n = 3) and was within the
range of -AR binding sites typically observed in human fat cells
(23). Moreover, the number of 2-AR binding sites detected in 2-AR
transgenic mice is comparable with that seen in human adipocytes and
lower than that sometimes observed in obese human adipocytes (4, 5,
7).
- and 2-ARs, stimulates
lipolysis in white adipocytes by increasing cAMP levels (1). As
predicted, the human-like 2/-AR balance obtained in 2-trans, 3 / mice shifted the epinephrine concentration-response curve for stimulation of lipolysis to the right (Fig.
2a, left panel). This effect was lost when the 2-AR-selective antagonist, RX-821002, was present (Fig. 2a, right panel). In addition,
the 2-AR agonist, UK14304, inhibited lipolysis in a
concentration-dependent fashion (data not shown). Finally,
displacement of (3H)RX-821002 binding by epinephrine in
2-trans, 3 / fat cell membranes (data not shown) gave the
expected shallow competition curve with high and low affinity
components (KiH, 0.81 nM;
KiL, 30 nM) as
classically described in human fat cells (7). These results demonstrate
that 2-ARs in transgenic adipocytes are coupled to Gi protein. As
expected, the in vivo circulating free fatty acid response
to a single injection of epinephrine was blunted in 2-trans, 3
/ mice (Fig. 2b). These in vitro and in
vivo studies demonstrate that 2-ARs in white adipocytes of
2-trans, 3 / mice functionally antagonize epinephrine-induced stimulation of lipolysis (similar to what has been observed using isolated human white adipocytes) (6).
View larger version (47K):
[in a new window]
Fig. 2.
a, in vitro lipolytic
response of isolated white fat cells to epinephrine without
(left) or with (right) 10 µM
selective 2-adrenergic receptor antagonist RX-821002. Adipocytes
were isolated, and lipolysis was measured as described previously (24).
Values are the mean ± S.E. from six experiments. b,
In vivo lipolytic response of control (3 /) or
transgenic (2-trans, 3 /) overnight-fasted mice 10 min after
a 0.1 mg/kg epinephrine intraperitoneal injection. Basal values were
1.11 ± 0.13 and 1.12 ± 0.11 mM, respectively;
*, p < 0.05 when compared with basal
(n = 6). c, time course of UCP1 mRNA
levels (left) and body temperature (right)
adaptation during a 4 °C exposure in wild type, control (3
/), or transgenic (2-trans, 3 /) fed mice. UCP1 mRNA
levels were analyzed by Northern blotting using a specific mouse 0.3-kb
UCP1 cDNA probe and expressed as a percent of time zero. *,
p < 0.05 when compared with basal (n = 6). d, effect of 0.1 mg/kg intraperitoneal
epinephrine on O2 consumption measured 10 min after
injection in control (3 /) or transgenic (2-trans, 3
/) fed mice. Basal values were 39.9 ± 2.3 and 38.3 ± 2.4 ml/kg/min, respectively; *, p < 0.05 (unpaired,
2-tailed t test) when compared with basal (n = 6). All results are expressed as the mean ± S.E.
The effects of 2-AR expression on brown fat function were assessed.
Cold exposure induces sympathetic nervous stimulation of
UCP1 gene expression and thermogenesis in brown
adipocytes, and this response plays an important role in maintaining
the body temperature of mice (25-27). Compared with wild-type mice,
3 / mice had impaired induction of UCP1 mRNA and decreased
body temperature following acute cold exposure (Fig. 2c).
These responses were not inhibited further by expression of 2-ARs in
brown fat (2-trans, 3 / mice) (Fig. 2c). In
addition, a single injection of epinephrine stimulated energy
expenditure to a similar degree in 3 / mice and 2-trans, 3
/ mice (Fig. 2d). These studies suggest that brown
adipocyte function, in contrast to white adipocyte function, is not
impaired by transgenic expression of 2-ARs.
To assess effects of 2/-AR balance on body weight and total body
lipid content, 3 / mice and 2-trans, 3 / mice were fed
high fat and low fat diets from age 3 weeks to 20 weeks. When fed a low
fat diet, body weights were similar in 3 / mice and 2-trans,
3 / mice (Fig. 3a). In
contrast, when fed a high fat diet, body weights were markedly greater
in 2-trans, 3 / mice compared with 3 / mice (Fig.
3b). Of interest, the effect of 2-AR expression on body
weight was greater in female mice. A second line of 2-AR transgenic
mice was created which, compared with the first line, expressed 50%
lower levels of human 2-AR mRNA transcripts in white and brown
fat (data not shown). Despite this lower level of expression, high fat
diet-induced obesity was also observed in the second line of 2-AR
transgenic mice on a 3-AR / background (Fig. 3c).
|
To assess the contribution of 3-AR deficiency in mediating the
positive effect of 2-AR expression on high fat diet-induced obesity,
2-trans, 3 / mice (line 1) were crossed with wild-type mice
(+/+ for the 3-AR allele). All offspring were ± for
the 3-AR allele, whereas approximately 50% of offspring
were positive for the 2-AR transgene. As above, mice were fed a high
fat diet from age 3 weeks to 20 weeks. In contrast to studies performed using 3-AR / mice, 2-AR expression failed to promote high fat
diet-induced obesity in 3-AR +/ mice (Fig. 3d). Thus,
development of high fat diet-induced obesity required both the presence
of 2-ARs in fat and the absence of 3-ARs.
Further study of 3 / mice and 2-trans, 3 / mice fed a
high fat diet demonstrated that female mice expressing 2-ARs had a
2.7-fold increase in total body lipid content and 2.4- and 3.4-fold
increases in perigonadal and inguinal fat pad weights, respectively
(Fig. 4a). Male mice
expressing 2-ARs had a 1.5-fold increase in total body lipid content
and 1.5- and 1.7-fold increases in perigonadal and inguinal fat pad
weights, respectively (Fig. 4b). These results demonstrate
that increased body weight in high fat diet-fed 2-AR-expressing 3
/ mice is due to an expansion of total body fat mass.
|
To assess the contribution of adipocyte hyperplasia versus
hypertrophy to increased adipose tissue mass, the Hirsch and Gallian method (19) of lipid extraction and osmium tetroxide fixation were used
to determine fat cell size and number in the perigonadal depots of high
fat diet-fed mice. Fat cell size was decreased in 2-trans,
3 / mice by 25% in females (not statistically significant) and
by 32% in males. Fat cell number, on the other hand, was markedly
increased in 2-trans, 3 / mice 3.5-fold in females and
1.7-fold in males. These findings indicate that expansion of adipose
tissue mass in 20-week-old high fat diet-fed 2-trans, 3
/ mice is due to adipocyte hyperplasia and not to an increase in
fat cell size. This observation was confirmed using an alternative
method of fat cell size determination (20, 21) (microscopic assessment
of fat cell size; 600 cells per depot quantified in paraffin-embedded,
inguinal fat pad sections from female mice) (data not shown).
Obesity is usually associated with elevated blood levels of glucose,
insulin, free fatty acids, and leptin. It has been proposed that these
features of obesity are due to the presence of enlarged adipocytes (28,
29). However, as shown in Fig. 4c, obese 2-trans, 3
/ mice, have normal blood glucose and insulin levels and reduced
fatty acid levels, which is in agreement with hyperplasia without
changes in adipocyte size observed in these mice. The weak but
significant rise in blood leptin levels is not associated with
increased leptin mRNA expression in adipose tissue (data not shown)
but probably with the higher number of adipocytes.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
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In the present study we have used genetic engineering in mice to
test the hypothesis that 2/-AR balance in adipocytes is an
important determinant of total body fat stores. By creating mice that
have a "human-like" pattern of AR expression in fat (predominance
of 2- over 1- and 2-ARs and absence of 3-ARs), we have
demonstrated that increased 2/-AR balance promotes high fat
diet-induced obesity in mice. Notably, the development of obesity
requires the presence of 2-ARs on adipocytes, the absence of
3-ARs, and a high fat diet, suggesting an important interaction between two genes (2 and
3-AR) and diet on the regulation of total body
fat stores.
The present study clearly indicates that increased 2/-AR balance
in adipocytes promotes high fat diet-induced obesity. However, the
mechanism for this effect has yet to be established. Three possibilities are worthy of further discussion. Firstly, impaired sympathetic activation of lipolysis in white adipocytes could lead to
increased accumulation of triglyceride. Secondly, impaired sympathetic
activation of thermogenesis in brown adipose tissue could cause
decreased energy expenditure and, consequently, positive energy
balance. Thirdly, impaired sympathetic activation of white adipocytes
could cause, via mechanisms to be discussed below, hyperplasia of white
adipose tissue. Detailed analysis of 2-trans, 3 / mice
indicates that the first and second possibilities are less likely to be
true. Obesity due to either impaired lipolysis or decreased energy
expenditure would be expected to cause adipocyte enlargement, a feature
common to nearly all models of obesity (30, 31). In the case of
2-trans, 3 / mice, obesity was due entirely to adipocyte
hyperplasia. In addition, brown fat function appeared not to be
impaired in 2-trans, 3 / mice. Thus, the fact that enlarged
fat mass in 2-trans, 3 / mice is due entirely to the
proliferation of small adipocytes strongly suggests that high
2/-AR balance promotes adipocyte hyperplasia.
The form of obesity observed in high fat diet-fed 2-trans,
3 / mice is atypical because it is due entirely to adipocyte hyperplasia. In this regard, these animals do not represent murine models of "typical" human obesity (31). Obesity in humans as well
as rodents is nearly always associated with adipocyte hypertrophy and
hyperplasia. Typically, adipocyte hypertrophy occurs early during the
development of obesity. It has been speculated that adipocytes, upon
reaching a "critical fat cell size," release a factor that promotes
adipocyte hyperplasia; however, the identity of this hypothetical
factor is unknown. The present study indicates that 2-trans, 3
/ mice have a primary disturbance in adipocyte hyperplasia, and on
that basis these animals provide a novel means to explore pathways
controlling adipocyte hyperplasia. One candidate signal for stimulating
adipocyte hyperplasia in 2-trans, 3 / mice is
lysophosphatidic acid, a bio-active phospholipid. It has previously
been shown that stimulation of 2-ARs causes release of
lysophosphatidic acid leading to proliferation of preadipocytes (34). Further studies will be required to determine whether lysophosphatidic acid is the mediator of this effect.
Obese 2-trans, 3 / mice, on the other hand, have an increased
number of small adipocytes, normal blood glucose and insulin levels,
reduced free fatty acid levels, and minimally elevated leptin levels
(Fig. 4c). In this regard, 2-trans, 3 / mice resemble rodents treated with thiazolidinediones (32, 33), agonists of peroxisome proliferator-activated receptor-
. Based upon
this similarity, it is possible that increased 2/-AR balance in
adipocytes somehow leads to activation of peroxisome
proliferator-activated receptor-, possibly through generation of
PPAR ligands.
High fat diet-fed 2-trans, 3 / mice develop an obesity
that is characterized by an increase in both adipocyte number and lipid
storage without any increase in fat cell size. The findings suggest
that, when fed a high fat diet, 2-trans, 3 / mice develop
obesity through two mechanisms: (i) an increase in fat cell number due
to increased preadipocyte recruitment and (ii) an increase in the
ability to store lipids due to impaired epinephrine-stimulated lipolytic activity. If increased lipid storage was not present, then
average adipocyte size would have been decreased by an amount reciprocal to the increase in fat cell number. Because this was not the
case, it must be assumed that lipid storage was also increased, an
effect presumably mediated by 2-AR-induced antilipolytic activity, potentiated by the absence of 3-ARs. Thus, the increased fat mass in 2-trans, 3 / mice appears to be due to both
preadipocyte recruitment and increased lipid storage in the newly
recruited adipocytes.
Brown adipocyte function appears not to have been impaired by
transgenic expression of 2-ARs in 3 / mice. This assessment is based upon the observation that cold exposure-induced changes in
UCP1 mRNA in brown fat and body temperature as well as
epinephrine-induced effects on whole body oxygen consumption were not
impaired in 2-trans, 3 / mice compared with 3 /
control mice. This raises the possibility that 2-ARs in brown
adipocytes were not negatively coupled to adenylate cyclase. The reason
for such failure of coupling in brown adipocytes, but not white
adipocytes, is presently unknown.
In summary, the present study clearly demonstrates that increased
2/-AR balance in adipose tissue promotes diet induced obesity.
These findings suggest that increased 2/-AR balance, which is
frequently observed in human obesity (3-9), has physiologic significance in the generation of adipocyte hyperplasia and the obese
state. Identification of the biochemical mechanism by which 2/-AR
balance and high fat diet promote adipocyte hyperplasia will focus on
the possible roles of lysophosphatidic acid and peroxisome
proliferator-activated receptor-. 2-trans, 3 / mice
should provide a unique opportunity to explore the mechanisms by which
expansion of adipose tissue mass is regulated.
| |
ACKNOWLEDGEMENTS |
|---|
We thank Barbara Kahn and Ed Hadro for advice on determination of fat cell size and number and Jeffrey Flier, Bruce Spiegelman, Barbara Kahn, Gemma Solanes, and Chen-Yu Zhang for helpful discussions.
| |
FOOTNOTES |
|---|
* This work was supported by the National Institutes of Health, the Boston/Obesity Nutrition Research Center Transgenic Core, and Eli Lilly.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
¶ Both authors contributed equally to this work.
Present Address: Dept. of Biochemistry, Molecular Biology, and
Cell Biology, Northwestern University, Evanston, IL 60201.
¶¶ To whom correspondence should be addressed: Beth Israel Deaconess Medical Center and Harvard Medical School, RN-325, Div. of Endocrinology, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-5954; Fax: 617-667-2927; E-mail: blowell@caregroup.harvard.edu.
Published, JBC Papers in Press, August 17, 2000, DOI 10.1074/jbc.M005210200
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ABBREVIATIONS |
|---|
The abbreviations used are: AR, adrenergic receptor; kb, kilobase(s); trans, transgenic.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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