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Department of Microbiology/Cancer Center (V.S.,
S.R.R.) University of Pennsylvania Philadelphia, Pennsylvania
19104
Department of Biochemistry (V.S.) Department of
Physiology and Biophysics (M.M.R.) University of Illinois School of
Medicine Chicago, Illinois 60612
Department of Medicine
(R.A.G.) University of Chicago Medical School Chicago, Illinois
60637
Dana Farber Cancer Institute and Department of Cell
Biology (B.M.S.) Harvard Medical School Boston, Massachusetts
02115
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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- to ß-receptors is thought to
regulate the lipolytic index of adipose depots. To determine whether
increasing the activity of the ß1-adrenergic
receptor (AR) in adipose tissue would affect the lipolytic rate or the
development of this tissue, we used the enhancer-promoter region of the
adipocyte lipid-binding protein (aP2) gene to direct expression of the
human ß1AR cDNA to adipose tissue. Expression
of the transgene was seen only in brown and white adipose tissue.
Adipocytes from transgenic mice were more responsive to ßAR agonists
than were adipocytes from nontransgenic mice, both in terms of cAMP
production and lipolytic rates. Transgenic animals were partially
resistant to diet-induced obesity. They had smaller adipose tissue
depots than their nontransgenic littermates, reflecting decreased lipid
accumulation in their adipocytes. In addition to increasing the
lipolytic rate, overexpression of the ß1AR
induced the abundant appearance of brown fat cells in subcutaneous
white adipose tissue. These results demonstrate that the
ß1AR is involved in both stimulation of
lipolysis and the proliferation of brown fat cells in the context of
the whole organism. Moreover, it appears that it is the overall ßAR
activity, rather than the particular subtype, that controls these
phenomena. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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and ß. Stimulation of the ßARs in white
adipocytes leads to increased lipolysis, primarily through the
production of cAMP and the activation of hormone-sensitive lipase and
other pathways, whereas stimulation of the 2AR leads to
increased lipid storage, through the inhibition of cAMP production
(reviewed in Ref.1). There is a large body of evidence that indicates
that the ratio of 2/ß ARs in different adipose tissue
depots affects the lipolytic rate, with depots containing higher levels
of 2ARs more prone to lipogenesis. Thus, the ratio of
functional 2- and ß-receptors present in adipose
tissue may determine whether fat storage or release is activated by
catecholamines. In addition to differences in receptor numbers, the presence of particular ß-receptor subtypes is thought to affect lipolytic rates in adipose tissue. There are three pharmacologically distinct subtypes of ßARs (ß1, ß2, and ß3) found in adipocytes. While the ß1- and ß2-receptors are found in a number of tissues, the atypical ß3AR is predominantly in fat (2, 3, 4). The ratio of ß1/ß2/ß3 mRNA in mouse adipose tissue is approximately 3:1:150 (5). Because of its high level of expression, it has been proposed that the ß3AR is the major regulator of lipolysis in mouse adipose tissue. However, mice with targeted mutagenesis of the ß3AR gene show only a modest tendency to become obese relative to normal mice, a somewhat surprising finding if the ß3AR was the major regulator of lipolysis (6). Thus, it is possible that the ß1- or ß2-receptors also regulate lipolysis in mice. Moreover, other species, including humans, have higher levels of ß1 and ß2 in adipose tissue (1).
Activation of ß1ARs affects fat cell proliferation as well as adipose tissue metabolism. Specifically, it has been shown in ex vivo explants that ß1-agonists can stimulate the proliferation of brown fat cells (7). Thermogenesis in brown adipose tissue (BAT) functions to dissipate energy in the form of heat through the action of a unique mitochondrial proton transporter, the uncoupling protein (UCP). UCP expression is stimulated by catecholamines released by the sympathetic nervous system, and agonist activation of the ß3AR in BAT leads to thermogenesis (8, 9, 10). In most mammals, BAT is highly localized, with the largest BAT depot found in the interscapular region. However, small numbers of brown fat cells can occasionally be found in white adipose tissue (WAT) depots, especially in cold-exposed rodents (11).
To determine directly whether shifting the balance between the - and
ß-subtypes in vivo would affect the metabolism or anatomy
of adipose tissue, we produced transgenic mice that expressed the human
ß1AR in adipose tissue. White adipocytes from these
transgenic mice were highly sensitive to the ß1-selective
agonist dobutamine and had higher rates of lipolysis than those from
control mice. Moreover, transgenic mice overexpressing the
ß1AR gained weight more slowly and had smaller white
adipose depots than their nontransgenic littermates, especially in
response to a high fat diet. Finally, UCP-expressing brown adipocytes
appeared in the subcutaneous white adipose depots of transgenic males.
These results indicate that shifting the ratio between different ARs
has profound effects on adipose tissue metabolism and morphology,
resulting in altered physiological responses to high fat diets.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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) but not in other tissues
of this mouse strain (Fig. 1B). Transgene RNA levels were lower in the
gonadal fat pad than in other depots, which may be due to transgene
integration site effects, the metabolic state of this fat pad, or to
the transgene sequences; we previously showed that some ap2
promoter-driven transgenes showed variable expression in different
adipose depots (14). Expression of the endogenous mouse
ß1AR gene was detectable in the depots at about 50-fold
lower levels (not shown), as has been previously reported for adult
mice (5). Moreover, the ß1AR transgene had no apparent
effect on the endogenous ß3AR RNA levels (Fig. 9). Under
similar conditions of hybridization and exposure, no ß2AR
RNA was detected (not shown); as described above, the RNA levels of
this receptor are about 1/150th that of the ß3AR in mouse
adipose tissue (5). Assuming that the hybridization efficiencies for
the different probes are the same, the ß1AR transgene RNA
levels were similar to (in gonadal fat) or higher than (in subcutaneous
and brown fat) the ß3AR levels (Figs. 1 and 9). Thus, the
total level of ß-receptors in the adipose tissues was increased at
minimum 2-fold, at least at the RNA level.
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shows the results from such an experiment. As
can be seen, adipocytes from both transgenic and nontransgenic mice
produced cAMP in response to increasing concentrations of the agonist.
However, there was increased ß-adrenergic responsiveness in the
ß1AR transgenic adipocytes; the potency of the response
with transgenic adipocytes was about 20% higher at doses of
isoproterenol between 10-7 M and
10-6 M. Thus, the transgenic animals had more
functional ß-receptors than their nontransgenic littermates.
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, adipocytes isolated from the transgenic mice had
higher lipolytic activity in response to isoproterenol, and there was a
striking shift in the EC50 of this response for both males
(7.5 nM vs. 300 nM for transgenic
and nontransgenic males, respectively) and females (1 nM
vs. 15 nM for transgenic and nontransgenic
females, respectively). The EC50 of the response to
dobutamine was also decreased for the transgenic adipocytes (7
nM for males, 9 nM for females) compared with
nontransgenic adipocytes (200 nM for males, 400
nM for females), showing that the altered lipolytic
response was specific to the ß1AR produced by the
transgene (Fig. 3B). Adipocytes from nontransgenic females had higher
lipolytic rates and lower EC50 values on average than those
from nontransgenic males, especially when stimulated with isoproterenol
(Fig. 3A).
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. These
results showed that there was a small decrease in the total body weight
and a statistically significant difference in the WAT (as a percentage
of total body weight) between transgenic and nontransgenic mice of the
same sex (Fig. 4B). Moreover, the average size of the adipocytes in the
transgenic mice was significantly smaller than that of the
nontransgenic mice (Table 1).
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As shown in Fig. 5, the transgenic males on the high-fat
diet gained weight more slowly than their nontransgenic littermates. In
contrast, smaller differences in body weight gain were seen with the
transgenic and nontransgenic female mice. In general, the female mice
showed a much greater variability in body weight than did male mice,
which may account for the smaller statistical differences.
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, the gonadal and subcutaneous fat pad weights of both
the transgenic males and females were significantly decreased relative
to their nontransgenic littermates. Again, both the gonadal and
subcutaneous adipocytes isolated from the transgenic mice were smaller
in size than those from the nontransgenic mice (Table 1
), suggesting
that there was decreased lipid accumulation resulting from increased
ß1AR responsiveness.
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). As was seen in mice fed normal chow, nontransgenic
females had higher lipolytic activity in their gonadal fat pads than
did nontransgenic males.
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, A and B, respectively). The unilocular adipocytes in
the transgenic WAT depots appeared smaller in size (Fig. 8, C and D),
confirming the data presented in Table 1. In addition to the unilocular
adipocytes, the gonadal adipose tissue from both males (Fig. 8C) and
females (not shown) contained readily visible adipocytes with
multilocular lipid droplets. Moreover, the subcutaneous fat of both
sexes had many large loci of these multilocular adipocytes (Fig. 8D for
males; not shown for females). There were no apparent differences in
the interscapular BAT morphology between the transgenic (Fig. 8E) and
nontransgenic mice (not shown).
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and not shown). UCP RNA was also found at very low
levels in the gonadal fat of transgenic, but not nontransgenic, males
(Fig. 9). In contrast, both transgenic and nontransgenic periovarian
WAT had UCP RNA, although there was 2- to 3 times more in the
transgenic tissue (not shown). There was no effect on UCP expression in
the interscapular BAT of either males (Fig. 9) or females (not shown).
The relative levels of UCP expression paralleled the appearance of
multilocular cells in the WAT depots of the mice, indicating that the
ß1AR transgene induced the appearance of brown adipocytes
in WAT depots. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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That 77% of the maximally stimulated adenylyl cyclase activity in mouse adipose tissue is due to activation of the ß3AR is consistent with this suggestion (5). However, mice that lack ß3ARs due to targeted mutagenesis of the gene encoding this receptor are only mildly obese relative to wild type mice (6). Our results show that increased expression of a functional ß1AR in the presence of ß3ARs results in mice with increased adipose cell lipolytic activity. This increased activity caused less lipid storage in adipose tissue, especially in response to a high-fat diet. Thus, our data support the notion that it may be the overall amount of ßAR in adipose tissue that determines its lipolytic rate. Indeed, in the ß3AR-knockout mice, there was a 2-fold increase in the level of ß1AR transcripts, and activation of these receptors may have prevented excessive adiposity.
The adipose tissue of the ß1AR-transgenic mice was more lipolytic both in vivo and in vitro, indicating that ligand is not limiting in the animal. There was an even more striking decrease in the EC50 of the lipolytic response in vitro to both isoproterenol and dobutamine by the transgenic adipocytes. That the sensitivity of the response was affected more than the maximal response itself is consistent with the notion that there are spare receptors; that is, there was a saturation of the response to ligand even when the additional receptors were not fully occupied. However, in the transgenic mice, activation of lipolysis would occur at lower ligand concentrations than in nontransgenic mice and thus, the adipocytes of the former would be more lipolytic. In support of this, unlike what was observed with transgenic mice on a high-fat diet, we found that the ß1AR transgene did not protect mice from monosodium glutamate-induced obesity (V. Sololeva, unpublished); because monosodium glutamate is thought to decrease adrenergic signaling (17), the additional receptors provided by the ß1AR transgene most likely could not be activated and, therefore, no effects on lipid accumulation were seen.
Female mice were less affected by the expression of the ß1AR transgene than were male mice. This is in contrast to what was observed with the ß3AR knockout mice, where females had, on average, higher fat stores than males (6). We also observed that adipocytes from nontransgenic females were more responsive to ß-stimulated lipolysis in vitro than were those isolated from nontransgenic males. These results indicate that adipose tissue from female mice are naturally more responsive to ß-adrenergic stimulation, perhaps due to higher levels of ß3AR. Hence, addition of more ß1ARs could have a smaller effect than it does in males because the response to ligand may be already saturated, as discussed above. Conversely, if the ß3AR receptors were more active in female mice than in males, their absence would have a greater effect, as was seen in the knockout mice.
Human adipose tissue differs from that of mice in that the ß3AR is present at much lower levels while the levels of ß1AR and ß2AR are higher (1, 23). Moreover, ß3AR levels in guinea pig adipose tissue are also low, and ß1-agonists are effective inducers of lipolysis in this species (24). However, it has been shown that ß3-specific agonists can stimulate lipolysis in human adipocytes isolated from the omental depot (25). In addition, mutations in the gene for this receptor were found to be associated with a lower resting metabolic rate, greater weight gain, and an earlier onset of non-insulin-dependent diabetes mellitus (26, 27, 28). In some cases the correlation between the phenotype and the presence of the mutated gene was of borderline statistical significance, and there was little or no evidence that the mutation was present more frequently in obese than lean individuals. That the ß1AR can also have an effect on the total lipolytic activity of adipose tissue, as shown here, indicates that there may be compensatory increases in the activity of this receptor (or the ß2AR) in humans bearing the ß3AR mutation. This could explain, at least in part, why there is not a stronger correlation between increased adiposity and the mutant ß3AR gene in humans.
The increased ß1AR activity also caused the appearance of brown adipocytes in WAT depots. It is not known whether brown and white adipocytes develop from the same or different stem cells. Brown and white adipocytes are very similar at the level of gene expression. Although there are quantitative differences in the levels of a number of genes that are expressed in WAT and BAT, only UCP has been found to be uniquely expressed in the latter (reviewed in Ref.29). It has been suggested that there is a pool of intraconvertible cells that can differentiate to either cell type in vivo after cold induction, although it is not known what determines the ultimate differentiation fate (11, 30). In the mice studied here, the ß1AR transgene was under the control of the aP2 promoter, which only functions in adipocytes and not in stem cells (reviewed in Ref.29). The increase in brown adipocytes in WAT depots could be due to a catecholamine-triggered proliferation of brown adipocytes or to interconversion between the two cell types, perhaps at an early stage in adipocyte differentiation. Further experiments are needed to address this issue; however, the ß1AR transgenic mice should provide a useful model for the study of this phenomenon, given the larger pool of brown fat cells in their WAT depots.
There are a number of reasons why the ß1AR transgenic mice have decreased adipose stores. The increased lipolytic activity of their adipocytes in general, coupled with the greater number of brown adipocytes, may lead to increased energy expenditure through heat production by BAT (18). Alternatively, increased energy expenditure in other organs, such as liver or skeletal muscle, may occur. Whether expression of the ß1AR transgene in brown or white adipocytes is most important for preventing obesity induced by a high fat diet can be tested by creating transgenic mice that overexpress the ß1AR only in BAT, using the UCP-regulatory region (19).
Because only one line of transgenic mice was studied, it is formally possible that the in vivo phenotypic effects described herein were due to the transgene insertion. However, the in vitro studies showing that there was more ß1AR activity in the adipose tissue indicate that the decreased lipid stores in vivo are the direct result of increased receptor expression. It is also unlikely that the phenotypic changes were the result of the transgene insertion because all of the studies were carried out in mice heterozygous for the transgene; any insertion would have to cause a dominant mutation that only affected adipose tissue.
In conclusion, we have developed transgenic mice that were used to study ß-adrenergic activation of lipolysis in adipocytes and the differentiation of the two types of adipose tissue, BAT and WAT. This genetic approach allowed us to study the role of the ß1AR specifically in adipose tissue, without treating animals with pharmacological agents that may have pleiotropic effects on many tissues. We showed that it is the total ßAR activity of adipose tissue, rather than the particular subtype, that may determine its overall lipolytic state. These and similarly genetically engineered mice should be useful in the study of pharmacological treatment of obesity.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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DNA was injected as previously described (12). Swiss Webster mice (males and females) were purchased from the National Institute of Health Frederick Cancer Research Facility (Frederick, MD). Transgenic mice were identified by PCR and Southern blot analysis, as previously described (14) (not shown).
Transgenic and nontransgenic littermates of the same sex were housed together, four animals per cage, with food and water ad libitum. Except where noted, animals were fed standard mouse chow (Purina 5008, Ralston-Purina, St. Louis, MO). For the high-fat diet experiments, groups of transgenic and nontransgenic littermates were fed powdered chow containing40% fat (3.2 kcal/g) (BioServe Biotechnologies, Laurel, MD) for either 90 days (males) or 120 days (females).
RNA Analysis
RNAs from different tissues and fat pads were purified by
guanidine thiocyanate extraction and CsCI gradient centrifugation (32).
Northern blot analysis (33) was carried out, and the following probes
were used for hybridizations: rat UCP cDNA (34), mouse ß-actin cDNA
(P. Denberg, unpublished), mouse ß3AR cDNA (2), mouse aP2
cDNA (35), and SV40 donor/acceptor splice site (12). Hybridization to
mouse ß-actin and aP2 probes were done as controls for RNA loading
and integrity.
Body and Tissue Weights
Body weights were performed on a regular basis (usually every 10
days) in all experiments. Three- or 4-month-old mice were used to
measure fat pad weight. After the mice were killed, three fat pads were
analyzed: gonadal (GF), subcutaneous inguinal (ScF), and subcutaneous
intrascapular brown (BF) fat. For the GF and ScF measurements, the
bilateral fat pads from each animal were combined and weighed.
Adipocyte Purification
Adipocytes were isolated from gonadal fat pads using collagenase
digestion according to Rodbell (36) with minor modifications (37).
Briefly, the gonadal adipose tissues from several animals (six to eight
mice on the normal diet and three mice on the high-fat diet) were
pooled and minced in Krebs-Ringer bicarbonate buffer (pH 7.5) with 3%
BSA, 2.5 mM glucose, and 1 mg/ml collagenase type II
(C-6885, Sigma Chemical Co., St. Louis, MO). The tissues were incubated
for 30–40 min at 37 C in a 5% CO2 incubator. After
complete collagenase digestion, the adipocytes were separated from the
stromal-vascular fraction and undigested tissue pieces by filtration
through a 250-µm mesh tissue sieve (E-C Apparatus Corp., St.
Petersburg, FL) and centrifugation at 400 x g for 1
min. The fat cake was washed three times with the same buffer without
collagenase. The purified adipocytes were used for adenylyl cyclase and
lipolysis assays.
Adipocyte Size
Adipocytes from whole tissue were fixed in osmium tetroxide, and
the size of the cells was determined by light microscopy using a
reticule. The number of cells was calculated for each 8-µm increment,
and the average size was determined as the arithmetical mean of the
population. The cell size in nanometers was converted to the nanogram
amount of lipid per cell according to the formula developed by Hirsch
and Gallian (38).
Adenylyl Cyclase Assays
For analysis of adenylyl cyclase activity, membranes were
obtained from purified peritoneal adipocytes in cell lysis buffer [2
mMTris-HCI, pH 7.5, 2.5 mM MgCI2,
0.1 mM EGTA, 1 mM dithiothreitol and protease
inhibitors (0.5 mM phenylmethylsulfonyl fluoride, 1 µg/ml
leupeptin, aprotinin, and pepstatin A)] at +4 C. After Dounce
homogenization (five strokes with a type B pestle), sucrose was added
to 0.25 M. The homogenate was centrifuged at 1100 x
g for 3 min. The supernatant was saved and the pellet was
rehomogenized in buffer and spun down a second time. The supernatants
were combined and spun at 39,000 x g for 10 min. The
pellet was washed in the same buffer with 0.25 M sucrose
and repelleted. The crude membrane pellet was resuspended in buffer
containing 20 mM HEPES, pH 7.4, 1 mM
MgCI2, 1 mM dithiothreitol, and 0.3
mM phenylmethylsulfonyl fluoride and frozen in liquid
nitrogen. The crude membranes were assayed for adenylyl cyclase
activity in the presence of 200 µM ATP and varying
concentrations of the ßAR agonist isoproterenol (Sigma) (Ref. 39, as
modified by Ref.40). Protein concentrations were determined using the
Bio-Rad protein assay (Bio-Rad, Inc., Richmond, CA).
Lipolysis Assays
An aliquot of the purified adipocytes was fixed in 2%
osmium tetroxide and counted (38). Aliquots of isolated gonadal
adipocytes were incubated in a total volume of 1 ml Krebs-Ringer
bicarbonate buffer at 37 C, 5% CO2, for 1 h in the
presence of adenosine deaminase type VIII (1 µg/ml) (Sigma).
Different concentrations of either isoproterenol or the
ß1AR-selective agonist, dobutamine (Research Biochemicals
International, Natick, MA) were added to the reactions, as described in
the figures. The release of glycerol was measured in aliquots of the
infranatant according to the manufacturer’s directions (Triglyceride
kit 320-UV, Sigma).
Statistics
All statistical analyses were performed using the one-tailed
Student’s t test.
Experimental Animals
All animal studies were conducted in accord with the principles
and procedures outlined in the "Guidelines for Care and Use of
Experimental Animals."
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Supported by grants from the American Heart Association (to S.R.R), NIMH (to M.M.R.), Tobacco Research Council (to M.M.R.) and NIDDK (to B.M.S.).
Received for publication May 22, 1996. Revision received October 3, 1996. Accepted for publication October 7, 1996.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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D.-W. Gong, Y. He, M. Karas, and M. Reitman Uncoupling Protein-3 Is a Mediator of Thermogenesis Regulated by Thyroid Hormone, beta 3-Adrenergic Agonists, and Leptin J. Biol. Chem., September 26, 1997; 272(39): 24129 - 24132. [Abstract] [Full Text] [PDF]
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