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Department of Nutrition (B.H.J., M.S., N.M.) and Physiology Program (B.H.J., N.M.), University of Tennessee, Knoxville, Tennessee 37996-1900
Address all correspondence and requests for reprints to: Naïma Moustaïd, Department of Nutrition and Physiology Program, University of Tennessee, 1215 West Cumberland Avenue, Knoxville, Tennessee 37996-1900. E-mail: nmoustai{at}utk.edu
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, for example, which is synthesized by human and rodent
adipocytes, has been shown to inhibit adipocyte differentiation and
expression of lipogenic genes and may thus play a role in reduction of
adipose mass associated with wasting syndrome (reviewed in Ref.3).
Leptin, recently identified as a satiety factor produced in adipocytes,
has also been shown to regulate body weight through its effects on food
intake (4, 5). The human homologue of the murine agouti gene, the
product of which has been recently shown in our laboratory to increase
lipogenesis in cultured adipocytes (6), is expressed in human adipose
tissue (7). Taken together, these findings suggest that adipocytes have
the potential to autoregulate their metabolism and thus adipose mass
through locally produced hormones and related factors. Adipocytes also synthesize the vasoactive hormone Angiotensin II (Ang II) (8). Interestingly, the developmental pattern of expression of angiotensinogen, the substrate from which Ang II is formed, parallels that of key lipogenic genes, progressing from very low levels in preadipocytes to elevated, sustained expression after differentiation into mature fat cells (9, 10). Although the function of the adipocyte renin-angiotensin system (RAS) has not been identified, peripheral RAS in other tissues such as heart and kidney have been linked to regulation of cellular growth and development (reviewed in Ref.11). Consistent with this concept, recent evidence suggests that Ang II is involved in regulation of adipogenesis and fat pad mass. In vitro, Ang II has been shown to indirectly (via prostacyclin release) induce differentiation of adipocyte precursors into mature fat cells, suggesting a mechanism by which Ang II may increase fat pad size (12). In vivo, rats treated with an oral Ang II receptor antagonist (losartan) displayed decreased fat pad weight and diminished adipocyte size, independent of food intake, relative to control animals (13).
These studies collectively indicate that Ang II plays an important role in adipocyte physiology. However, little is known about either the actions of this hormone in isolated adipose cells or the mechanisms through which it modifies adipose mass. Because the available data indicated a link between Ang II and control of adiposity, we wanted to determine if Ang II directly regulated lipogenesis in adipocytes. To investigate this issue, we analyzed the effects of Ang II on lipid metabolism in 3T3-L1 adipocytes. Because the presence of Ang II receptors had not previously been demonstrated in 3T3-L1 adipocytes, we first conducted radioligand binding assays to characterize Ang II receptors in this adipocyte model. We then analyzed the effects of Ang II on triglyceride storage and on the activities and expression of key lipogenic enzymes, namely fatty acid synthase (FAS) and glycerol-3-phosphate dehydrogenase (GPDH), in both 3T3-L1 adipocytes and in human adipose cells maintained in primary culture. In addition we investigated the effects of Ang II on expression of the ob gene, which has recently been shown to reflect changes in adipose mass (14, 15, 16).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human adipose cells
sc abdominal adipose tissue was taken from 4 Caucasian female
patients, 19–58 yr of age, undergoing elective cosmetic surgery.
Samples were obtained in compliance with a protocol approved by the
Institutional Review Board for Human Subjects and by the Committee for
Research Protocols at the University of Tennessee, Knoxville. All
patients were nondiabetic and nonhypertensive, with no known metabolic
abnormalities. Patients with a body mass index (BMI) greater than 28
were considered obese; four patients (2 nonobese and 2 obese) were
included in this study. Tissue samples to be used for RNA isolation
were frozen immediately until use. Human adipocytes were isolated by
collagenase digestion and filtration of adipose tissue, as we recently
described (18). Mature, lipid-filled adipocytes were separated from
stromal-vascular cells by centrifugation, the latter of which were
discarded. Floating cells (mature adipocytes) were maintained in
primary culture in DMEM supplemented with 1% BSA for 2 weeks.
Viability during culture was confirmed by trypan blue exclusion and by
spectrophotometric assay of glycerol-3-phosphate dehydrogenase activity
(18).
Radioligand binding assays
3T3-L1 adipocytes were grown in 6-well (35 mm) culture dishes as
described above. At day 6 of differentiation, cells were changed to
DMEM supplemented with 1% FBS for 18 h before binding assays.
Following the overnight incubation, cells were washed twice with HBSS.
Adherent cells were then incubated with DMEM supplemented with 2
mM EDTA and 1% BSA containing 125I-labeled Ang
II (DuPont New England Nuclear, Boston, MA). For Scatchard analysis,
cells were incubated with increasing concentrations of
125I-labeled Ang II (2200 Ci/mmol), ranging from 0.01 to
1.8 nM, in the presence (nonspecific) or absence (total
counts) of excess unlabeled Ang II (1 µM). For
displacement assays, cells were incubated in the presence of
125I-labeled Ang II (1.0 nM) with increasing
concentrations of Ang II, losartan (type-1 (AT1) receptor antagonist,
kindly provided by Dr. Ron Smith of DuPont) or P-186 (type-2 (AT2)
receptor antagonist; Research Biochemicals International, Natick, MA).
The concentrations of radiolabeled Ang II that we used were chosen
based on previous reports of the Kd in rat adipocyte plasma membranes
(19). Three wells were used for each treatment point. Cells were then
returned to the cell culture incubator (37 C) for 90 min. Binding was
terminated by placing culture plates on ice and rapidly removing
binding buffer. Unbound 125I-labeled Ang II was further
removed by washing cells three times with ice-cold PBS. Cells were then
harvested by scraping into 200 µl of ice-cold NaOH (0.5
N) and homogenized by sonicating. Aliquots of the
homogenate were counted using a Cobra gamma counter. For Scatchard
analysis, nonspecific counts were subtracted from total counts to yield
specific binding. Results were analyzed using a statistical software
package (GraphPad Prism) adapted for radioligand analysis. Scatchard
analysis was used to calculate the dissociation constant
(Kd; nM) of the receptor and the number of
binding sites (Bmax, fmol/mg protein).
Triglyceride assay
Cellular triglyceride content was measured
spectrophotometrically using an enzyme-based assay kit (Sigma) as we
previously described (6). Cells were washed once with PBS, then scraped
in 0.9% saline. Cell suspensions were homogenized by sonication. Data
were expressed as mg of triglyceride/mg cellular protein.
FAS and GPDH activities
FAS and GPDH activities were assayed spectrophotometrically in
crude cytosolic extracts of 3T3-L1 adipocytes by measuring the
oxidation rate of NADPH or NADH, respectively, as we previously
described (6). Data were expressed as nmol NAD(P)H oxidized/min/mg of
cytosolic protein, which was assayed by the method of Bradford
(20).
RNA analysis
RNA was isolated by the cesium chloride density gradient method.
For RNA extraction from 3T3-L1 adipocytes, individual culture dishes
(100 mm) of cells were used for each RNA sample within treatments, and
three to four samples were included in each treatment group. Increasing
amounts of total RNA (0.4, 0.8, 1.2 µg) for each sample were
transferred to nylon membranes using a dot blot apparatus. Membranes
were hybridized with 32P-labeled complementary DNA (cDNA)
probes for FAS (pFAS7, cloned in Dr. J. W. Porter’s lab and kindly
provided by Dr. A. G. Goodridge), and for ß-actin (pActin, ATCC).
cDNA probes were labeled by the random primer method. Unbound probe was
removed by washing membranes in 2x SSPE for 30 min at 25 C, then in
0.1x SSPE/0.1% SDS for 60 min at 65 C. After washing membranes were
exposed to x-ray film (New England Nuclear, Boston, MA). Autoradiograms
were analyzed by densitometric scanning; FAS expression was calculated
as a ratio of FAS messenger RNA (mRNA)/ß-actin mRNA.
Transcription assay
Transcription rate assays were performed in 3T3-L1 and human
adipocyte nuclei. Nuclei were isolated from 3T3-L1 adipocytes according
to previously described methods (21). Briefly, cells were homogenized
by gentle pipetting in detergent buffer (NP-40), and nuclei were
isolated by differential centrifugation. Human adipocyte nuclei were
isolated using the same protocol, except that a lower concentration of
NP-40 (0.005%) was used during the homogenization step. Nuclear run-on
assays and hybridizations were then conducted as we previously
described for 3T3-L1 adipocytes (21). Labeled RNA was hybridized with
plasmids containing cDNAs encoding FAS (pFas7; or pHFAS, human fatty
acid synthase plasmid kindly provided by Dr. C. F. Semenkovich, St.
Louis, MO); Ob (pOb, kindly provided by Dr. S. Usala,
Greenville, NC) and ß-actin, and with vector alone (pBS). Membranes
were then exposed to film and autoradiogram results were quantitated by
scanning laser densitometry. FAS and Ob transcription rates were
normalized to those of ß-actin. Transcription assays were repeated
twice for 3T3-L1s (24 and 44 h) and for human adipocytes.
Statistics
ANOVA was used to compare overall group means. A significant
overall F test was followed by post-hoc comparisons using the
Bonferroni Multiple Comparisons Procedure (22). All tests were
conducted using a 95% confidence interval.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows
specific binding of 125I-Ang II to 3T3-L1 adipocytes with
increasing concentrations of radiolabeled ligand. At the highest
concentration of labeled Ang II (1.8 nM), nonspecific
binding accounted for approximately 28% of total binding. Binding of
Ang II exhibited saturable kinetics at relatively low Ang II
concentrations. Analysis of three independent experiments revealed a
dissociation constant (Kd) of 0.73 ± 0.26
nM (range = 0.51–0.97 nM), which is
consistent with values of Kd reported in other cell types
(reviewed in Ref.23) and with the Kd value previously
reported for rat adipocyte membranes (0.90 nM; 19). Based
on these analyses, Bmax was estimated as 0.25 ± 0.04
fmol binding sites/ml cells, 1.51 ± 0.49 fmol binding sites/mg
total cellular protein, 1.057 fmol/106 cells, or 636.6
x 106 sites/106 cells. This estimate is lower
than but within the range of the Bmax value (53.7 fmol/mg
protein) previously reported for rat epididymal adipocyte membranes
(19). Therefore, the values for Ang II binding parameters that we have
reported are consistent with the only previous estimates of Ang II
binding parameters in adipose cells. We conducted similar binding
assays in undifferentiated 3T3-L1 preadipocytes but found no evidence
for high affinity Ang II binding sites in these cells (data not
shown).
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Effects of Ang II on cellular triglyceride content
Several reports had previously suggested that Ang II regulated
adiposity (12, 13, 24, 25). Fat mass in adipose cells can be increased
through one of three possible mechanisms: 1) increased adipocyte
number; 2) decreased lipolysis of stored triglycerides; 3) increased
triglyceride synthesis and storage. As a starting point, we
investigated the third possibility by examining the effects of Ang II
on triglyceride content in 3T3-L1 adipocytes. As shown in Fig. 2, ANOVA indicated that Ang II significantly increased
triglyceride levels in 3T3-L1 adipocytes after 48 h of treatment.
Post-hoc comparisons (Bonferroni) revealed a significant effect of both
1.0 nM and 10.0 nM Ang II concentrations
(1.30 ± 0.04, cont; 1.59 ± 0.012, 1.0 nM;
1.68 ± 0.096, 10 nM; P < 0.05). The
slight increase (
10%) observed with 0.1 nM Ang II was
not statistically significant. A 24-h treatment period was not
sufficient to significantly elevate cellular triglyceride content (data
not shown). These data indicate that physiological concentrations of
Ang II induce adipocyte hypertrophy, as indexed by the level of stored
triglycerides in the cells. Both cellular hypertrophy, via increased
protein synthesis, and cellular hyperplasia, through mitogenic actions,
have been reported for Ang II in numerous other cell types (reviewed in
Ref.26). However, hypertrophic actions of Ang II in adipocytes
occurred only through increased triglyceride stores, as neither DNA nor
protein levels were changed by Ang II in 3T3-L1 adipocytes (data not
shown).
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demonstrates the effects of 48 h of
Ang II treatment on FAS activity. ANOVA indicated a significant effect
of Ang II on FAS (P < 0.05). Post-hoc comparisons
(Bonferroni) revealed that Ang II at concentrations of 0.1 and 1.0
nM significantly increased FAS activity in 3T3-L1
adipocytes (4.665 ± 0.47, control; 10.66 ± 2.38, 0.1
nM; 9.49 ± 1.11, 1.0 nM; nmol
NADPH/min/mg protein; P < 0.05). The effects of Ang II
on GPDH activity are shown in Fig. 4. As with FAS, Ang
II at concentrations of 0.1 nM (103.5 ± 5.7, nmol
NADH/min·mg protein) and 1.0 nM (102.3 ± 2.63)
significantly increased GPDH activity over control levels (80.57
± 8.0; P < 0.05) after 48 h. There was no
significant increase in either enzyme in response to Ang II
concentrations greater than 1.0 nM. Analyses of the time
course of Ang II effects on enzyme activities are shown in Fig. 5. Significant effects of Ang II on FAS activity (Fig. 5a) were first apparent after 24 h of treatment with 0.1
nM Ang II, at which point FAS activity increased by
approximately 35% over control levels (5.98 ±
0.85.vs. 9.23 ± 1.10; P < 0.05). GPDH
activity (Fig. 5b) was slightly but not significantly elevated after
24 h of Ang II treatment. Activities of both enzymes in Ang II
treated cells were significantly higher than controls after 48 and
72 h treatment. The effect of Ang II did not increase for
treatment periods longer than 72 h (data not shown).
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, simultaneous blockade of the type 2 Ang
II receptor completely prevented up-regulation of FAS and GPDH in
response to Ang II treatment; there was no effect of antagonist alone.
We conducted similar experiments using the AT1 antagonist losartan,
although our binding studies provided no evidence that high affinity
Ang II binding sites in 3T3-L1 adipocytes were of the AT1 type.
Surprisingly, losartan (100 nM) also attenuated the effects
of Ang II on FAS and GPDH activities; enzyme activities in losartan +
Ang II-treated samples were not significantly different from control
values (data not shown).
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; the data are
expressed as percentage increase over control values from untreated
adipocytes from the same patient, due to the wide range of basal enzyme
activities across the patients studied. Adipose cells from four
different patients were used in this study. Preliminary experiments
with adipocytes from one patient indicated that a treatment period of 3
days was necessary to observe an effect of Ang II on enzyme activities
in human adipocytes (data not shown). As in 3T3-L1 adipocytes, Ang II
(1.0 nM) increased FAS activity in human adipose cells,
although the degree of response varied considerably among patients.
Expressed as percent increase above control values, the rise in FAS
activity ranged from approximately 85% to 205%. GPDH activity
increased modestly in these patients with Ang II treatment, ranging
from 60–120% above control values. These results indicate that Ang II
increases the activities of key lipogenic enzymes in human as well as
3T3-L1 adipocytes.
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shows the results of these analyses. Consistent with
the rise in FAS activity upon Ang II treatment, Ang II (0.1 and 1.0
nM) increased FAS mRNA content by approximately 2-fold in
3T3-L1 adipocytes. We then determined if the changes in FAS mRNA in
response to Ang II treatment were due to changes in the transcriptional
rate of the FAS gene. We conducted these assays with both 3T3-L1 (Fig. 9a) and human (Fig. 9b) adipocytes. In 3T3-L1
adipocytes, Ang II treatment (1.0 nM) increased
transcription of the FAS gene by approximately 2-fold, which is
consistent with the approximately 2-fold increase in FAS mRNA level
shown in Fig. 8. Time course experiments indicated that 24 h but
not 7 h of Ang II treatment was sufficient to up-regulate FAS
transcription. There was no additional increase in transcription rate
after 44 h of treatment. Data obtained from adipocytes taken from
one human patient (Fig. 9b) indicate that FAS transcription also
increased by approximately 2-fold in human adipocytes treated with 1.0
nM Ang II for 48 h.
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) and 3-fold (human; Fig. 9b) over control values. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After we established the presence of saturable, specific, high affinity Ang II binding in 3T3-L1 adipocytes, we investigated the direct actions of Ang II on adipocyte metabolism. In recent years, several lines of evidence cumulatively suggested that Ang II might be involved in control of adipose mass. Weight loss was reported as a side effect of angiotensin converting enzyme inhibitors (24, 25), and rats treated with losartan displayed diminished fat mass and adipocyte size (13). In addition, genetic variation near the ANG locus was recently shown to be associated with increased waist-to-hip ratio in male Hutterites (30). A potential link between Ang II and control of adiposity was made more intriguing by the identification of a functional renin-angiotensin system in adipose cells (8, 9, 10), creating the possibility that Ang II produced by adipose tissue might be involved in control of its own mass. Adipose tissue can undergo net expansion by either an increase in the number of adipocytes (hyperplasia) or by increased lipid storage within existing adipocytes (cellular hypertrophy). Darimont et al. (12) recently reported that Ang II treatment of mature adipose cells in vitro induced differentiation of preadipocytes, thereby providing a potential mechanism for adipose tissue hyperplasia in response to Ang II. We determined that Ang II at relatively low concentrations (10.0 and 1.0 nM) also induced adipocyte hypertrophy, as indicated by an approximately 20% increase in cellular triglyceride content and thus a "fatter" fat cell.
Triglyceride synthesis in adipocytes depends upon supplies of glycerol-3-phosphate (via glycolysis), and FFA provided either from extracellular uptake, intracellular lipolysis, or de novo fatty acid biosynthesis. To investigate the mechanisms underlying increased cellular triglycerides in response to Ang II, we analyzed the activities of two key enzymes in glycerol-3-phosphate provision (GPDH) and de novo fatty acid synthesis (FAS) and found that the activities of both enzymes were increased by Ang II. GPDH and FAS are coordinately regulated in various physiological conditions: activities and mRNA levels of both enzymes are up-regulated by the fed state, insulin, and obesity and suppressed during fasting and in Type 1 diabetes (reviewed in Ref.27). This is the first report, however, that the activities of these enzymes increase in response to Ang II in the adipocyte models studied here.
We were able to prevent the induction of FAS and GPDH activities by simultaneously treating cells with a pharmacological antagonist to the AT2 receptor. However, we also observed that losartan, an antagonist to the AT1 receptor, attenuated the actions of Ang II. Given that we found no evidence of high affinity AT1 receptors in our binding studies or of AT1 expression by Northern blot (data not shown), we attribute this response to nonspecific actions of losartan: nonangiotensin receptor related actions of losartan have recently been reported in glomeruli and mesangial cells, vascular smooth muscle cells, brain, and liver (reviewed in Ref.23). Alternatively, we cannot rule out the possibility that the effects of Ang II on lipogenic enzymes are due to dual actions of both cell surface AT2 receptors and nuclear membrane AT1 receptors, the latter of which was shown to mediate the effects of Ang II on ANG transcription in hepatocyte nuclei (31). The presence of a nuclear receptor in 3T3-L1 adipocytes would have gone undetected in our displacement binding assays because the AT1 antagonist that we used (losartan) does not enter the cell (11). In any regard, our results suggest that AT2 is involved in up-regulation of FAS and GPDH in 3T3-L1 adipose cells.
We also have reported that Ang II increased FAS activity in human adipocytes maintained in primary culture. These data represent the first analysis of any kind regarding the actions of Ang II in human adipose cells. The response to Ang II varied among the four patients included in this study: the rise in FAS activity over control levels ranged from 85–205%, whereas the increases in GPDH activity varied from 60–120%. We interpret this variation to stem from the heterogeneity of the patients from which adipose samples were taken. Nonetheless, human adipocytes responded to Ang II in a manner similar to that of 3T3-L1 adipocytes, namely by increasing the activities of key lipogenic enzymes, although the degree of response varied among patients.
We have determined that increased FAS activity in both human and 3T3-L1 adipocytes was paralleled by similar changes in transcription rates of the human and mouse FAS genes, respectively. The FAS enzyme is not known to be regulated by allosteric modification; FAS mRNA levels are thought to be the primary factor controlling enzyme activity (reviewed in Ref.27). Our results are thus consistent with known mechanisms of FAS regulation.
We also evaluated the effects of Ang II on the transcription rate of the ob gene in 3T3-L1 and human adipocytes. The ob gene encodes the protein leptin, which appears to act as a satiety factor (4, 5). Numerous studies have recently demonstrated that, in rats, mice, and humans, the level of ob expression is positively related to adipose mass (14, 15, 16). Ob expression has thus emerged as a marker of adiposity, and factors such as Ang II that elicit adipocyte hypertrophy and/or hyperplasia can thus be expected to increase expression of the ob gene. Consistent with this concept, we have reported that Ang II increased ob transcription rate in 3T3-L1 and human adipocytes, concomitant with elevated lipogenesis in these models. We used sensitive transcription rate assays to evaluate the effects of Ang II on the ob gene because ob mRNA levels in cultured adipocytes are very difficult to detect by Northern blot analysis (32). It is worth noting that increased transcription rate does not necessarily reflect higher mRNA levels because mRNA stability could simultaneously decrease and thus counteract elevated gene transcription rates. The ob gene was only recently cloned, and it is currently unknown if gene transcription rate and mRNA stability interact to determine net ob mRNA levels. Nonetheless, our results indicate that Ang II increased ob transcription in both adipocyte models that we examined.
Our data demonstrate that Ang II increases fatty acid and triglyceride
synthesis and storage in adipose cells. Coupled with previous evidence
that suggested a link between Ang II and adiposity, these data indicate
that Ang II can positively regulate adipose mass by producing adipocyte
hypertrophy. We cannot rule out alternative or additional mechanisms,
such as decreased lipolysis or enhanced recruitment of preadipocytes
into adipocyte differentiation; future studies will address these
possibilities. These findings constitute a plausible physiological
function for the intraadipose RAS, namely as a paracrine mechanism that
contributes to regulation of adipose energy stores. Similar
autocrine/paracrine regulation of adipocyte metabolism has been
demonstrated for other adipocyte products including TNF (1) and the
agouti protein (6). Local synthesis of Ang II could thus be expected to
change in response to factors known to regulate adipocyte metabolism.
Indeed, adipocyte angiotensinogen content has been shown to be
decreased and restored by fasting and refeeding, respectively (33).
Furthermore, we have recently found that insulin increases and a
ß-adrenergic agonist decreases angiotensinogen mRNA levels in 3T3-L1
adipocytes (unpublished data).
In conclusion, we have demonstrated that adipose cells respond to Ang II by increasing fatty acid and triglyceride synthesis and storage. We have also determined that Ang II positively regulates transcription of the FAS and ob genes in 3T3-L1 and human adipocytes. Collectively, these findings indicate that Ang II may be involved in regulation of adipose mass, which could provide insight into the physiological role of the adipose tissue renin-angiotensin system. Additional studies will be necessary to determine whether similar regulation of lipogenesis by Ang II occurs in vivo.
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Footnotes |
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Received August 21, 1996.
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: a key component of the obesity-diabetes link. Diabetes 43:1271–1278[Abstract]
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