Institut National de la Santé et de la Recherche Médicale U 465, Centre Biomédical des Cordeliers, Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, 75270 Paris, France
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We investigated angiotensinogen (AGT) expression in adipose tissue and liver of Zucker rats during the onset of obesity. The developmental pattern of AGT expression (protein and mRNA) in liver was similar in both genotypes. In inguinal adipose tissue, AGT cell content was similar in suckling and weaned pups in lean rats, whereas it continuously increased with age in obese rats. AGT amount in adipocytes was unaffected by the genotype until weaning. Thereafter, adipocytes from obese rats displayed a significant increase in AGT content that was strengthened with age. Compared with the cell content, the amount of secreted AGT over 24 h was higher, and a genotype effect was observed as early as 14 days of age. Using fat cell populations differing by size, we showed that this AGT oversecretion was not solely related to adipocyte hypertrophy. Our results demonstrate that the fa genotype exerts a control on the production of AGT in a tissue-specific manner, suggesting a local role of AGT in the overdevelopment of adipose tissue.
adipocyte; leptin; liver; renin; obesity-induced hypertension
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
THE VIEW THAT THE ADIPOCYTE ACTS only as a passive storage site for energy in the form of triacylglycerols is now obsolete after the discovery that adipose cells secrete a variety of active factors. Among them, angiotensinogen (AGT), in addition to its role in the regulation of systemic blood pressure, appears to be involved in preadipocyte differentiation processes (34, 35). According to previous studies, the link between AGT production and the control of adipose mass involves angiotensin II (ANG II), which has been implicated in the differentiation of adipose precursors by a paracrine/autocrine mechanism (12). The role of a local production of ANG II in adipose growth and development has been described (38). Using an ANG II receptor antagonist, Crandall et al. (11) reported a reduction in adiposity due mainly to a reduced adipocyte size. Moreover, developmental studies in the components of renin-angiotensin system (RAS) in retroperitoneal adipose tissue have shown that the production of AGT was higher in young, rapidly growing rats compared with older rats (20). This indicates that the level of AGT production in adipocytes was increased during the early phase of adipose tissue growth. Accordingly, the local production of ANG II has been linked to control of adipocyte number and size, suggesting an important role of AGT production by adipose cells in adipose tissue development.
In rodents, results from different models of obesity are divergent, showing an increased AGT production by adipose cells from genetically obese (ob/ob) mice, whereas AGT gene expression is reduced in adipose tissue from fa/fa rats and the viable yellow (Avy) mouse (17, 23). However, all of these studies were performed in adult animals, which displayed an established hyperplasia of adipose tissue. The obesity in the Zucker rat is an autosomal and recessive inheritance and is caused by a leptin receptor missense mutation resulting in a failure of leptin signaling in fa/fa rats (9). This rat develops a syndrome with multiple metabolic and hormonal disorders that shares many features with human obesity. Hyperphagia, hyperinsulinemia, hypertriglyceridemia, hypertrophy, and hyperplasia of fat cells, as well as insulin resistance, renal complications, and hypertension are features common to both species (5). In contrast to the complex syndrome exhibited by the adult obese Zucker rat, we have previously demonstrated that, early in life, the obese fa/fa rat presents an overdevelopment of fat deposits, which is related to only a moderate adipocyte hypertrophy (3). After weaning, the enlargement of adipocytes is accelerated, and the later emergence of hyperplasia exacerbates fat accretion (31). The fact that all of the previous observations in obese models were performed when hyperplasia was already present did not allow a real evaluation of the potential influence of RAS in the onset of obesity. Moreover, although AGT appears to be secreted only constitutively by the liver, it is unclear whether the ability of adipose cells to secrete the protein is entirely related to its gene expression. A lack of relationship between gene expression and protein secretion has been previously demonstrated for the emergence of AGT during the adipocyte differentiation process of Ob1771 cells (33). All of these observations prompted us to evaluate AGT production and gene expression by adipocytes during the developmental changes that led to adipocyte hyperplasia. Interestingly, a linkage between intra-abdominal fat accumulation and hypertension has been found in obese Japanese women independently of age or body mass index, suggesting a possible site-specific variation in adipose tissue AGT secretion (24). Furthermore, we investigated whether levels of AGT production were comparable in subcutaneous and visceral fat deposits. Then we compared the developmental pattern of AGT expression in adipose tissue and in liver to estimate the relative importance that these tissues play in the control of circulating AGT at different phases of obesity.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animals. Lean (Fa/fa) and obese (fa/fa) Zucker rat littermates were obtained in our animal house by breeding heterozygous lean females and homozygous obese males. Pups were weaned at 28 days of age on a regular chow diet (UAR, Epinay-sur-Orge, France). Before weaning, obese and lean pups were identified on the basis of ob receptor mutation as previously described (30). All animals were housed in a temperature-controlled condition with a 12:12-h light-dark period (0700-1900) and free access to regular food and tap water. Experiments were undertaken according to the Guidelines for Care and Use of Experimental Animals. After animal decapitation, blood was collected for serum determinations. The inguinal, epididymal, and retroperitoneal adipose tissues and liver were removed and used for further determinations or directly frozen in liquid N2 for total RNA extraction.
Adipose cell culture. To evaluate the AGT secretion, a portion of adipose tissue from suckling and weaned rats was digested with collagenase, and isolation of mature adipocytes and preadipocytes was performed as previously described (6). Mature adipocytes were maintained for 24 h in DMEM supplemented with 1% FCS, 2% BSA, antibiotics, and 15 nM insulin. In a preliminary experiment, we verified that the amount of AGT secreted in the medium was linear during a 24-h incubation (data not shown). To study the effect of adipocyte size on its ability to secrete AGT, we isolated different cell populations according to their size. After isolation and dilution, mature adipocytes issued from one fat pad were separated by successive filtration through one or three nylon meshes (from 190- to 30-µm meshes). By this procedure, we obtained three or four cell populations of different mean size. Cells from each population (2-4 × 105) were suspended in standard medium and incubated for 24 h to estimate their AGT protein production.
Adipose tissue cellularity. Size and number of adipocytes were determined as previously described (6). Fat cell size was determined by a procedure derived from a microphotometric method (26). Briefly, images of isolated cells were acquired from a light microscope fitted with a camera, and the measurement of cell diameters was performed using a computer equipped with an analyzing program (Perfect-Image, Numeris, Nanterre, France). The mean fat cell volume was calculated as previously described (26), and the mean fat cell weight was determined by calculation of triolein density (0.92). Fat cell number was estimated on an aliquot of adipocyte suspension or a portion of adipose tissue by dividing the lipid content by average fat cell weight.
Measurement of AGT protein. In whole adipose tissue or in primary cultures, the AGT protein content was measured in a cellular extract. Briefly, adipose tissue or cells were homogenized in a lysis buffer containing 250 mM Tris-acetate, pH 7, 5 mM EDTA, 3% BSA, 100 µM captopril, and 50 µM protease inhibitor [4-(2-aminoethyl)benzenesulfonyl fluoride], centrifuged at 4°C for 15 min at 3,000 g, and used for AGT determination. AGT concentration in whole tissues, isolated cells, and the culture medium was determined by incubating the samples with an excess of porcine renin (50 µU) for 90 min at 37°C and measuring the generated ANG I by RIA (REN-CT2, Cis-Bio International, Gif-sur-Yvette, France). For each sample, we verified that there was no detectable ANG I in the incubation medium without addition of exogenous renin. Results were expressed as nanograms of ANG I liberated by 106 cells.
Western blotting. Aliquots of proteins from medium and adipose cell homogenate were electrophoresed on a 12% SDS-polyacrylamide gel and electroblotted overnight onto a nitrocellulose membrane at room temperature. The membrane was further incubated at room temperature for 1 h with a 1:5,000 dilution of anti-AGT antibody [rabbit antibody against rat AGT (2), a kind gift from Prof. P. Corvol]. The blot was washed and exposed for 1 h to horseradish peroxidase-conjugated anti-rabbit IgG. The immune complex was detected by luminescent visualization (ECL, Amersham Pharmacia Biotech, Orsay, France). Molecular weight standards were obtained from Bio-Rad (Richmond, CA).
Biochemical assays. Plasma renin activity was measured by RIA (28). Briefly, 4 µl of plasma were incubated for 90 min at 37°C and used for ANG I assay. For measurement of plasma AGT concentration, 100 µl of plasma were incubated for 90 min at 37°C in the presence of renin as described, and the generated ANG I was assayed by RIA. To estimate the level of leptin secretion by the adipocytes, leptin concentration was measured in the culture medium by RIA (Linco Research, St. Charles, MO).
RNA extraction and Northern blot analysis.
Total RNA from cultured adipocytes or frozen tissues (liver and
adipose) was extracted according to Chomczynski and Sacchi (8). Equal amounts of total RNA were electrophoresed on
1% agarose gels containing 2.2 M formaldehyde and transferred by capillarity onto nylon membranes (Membranes N+- Eurobio,
Les Ulis, France). Hybridization was performed at 65°C overnight with the 32P-labeled complementary RNA probe from
plasmid containing rat AGT cDNA (pGEM4Z/AGT from American Type Culture
Collection). Blots were autoradiographed at 70°C for 6-8 h.
Each Northern blot was hybridized with a ribosomal 18S probe to verify
that equivalent amounts of total RNA were loaded in each lane. The
relative amount of AGT mRNA was quantified by densitometry and
normalized to the 18S rRNA level.
Data analysis. Data are expressed as means ± SE. All data from developmental studies were compared using a one-way analysis of variance, followed by Tukey's and Fisher's tests. Comparison of adipose sites data was performed using Student's t-test.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
There was no difference between lean and obese rats in body weight
and liver weight throughout this developmental period (Table 1). In agreement with the well-known
genotype effect on adipose tissue, we observed that inguinal adipose
tissue weight increased in fa/fa rats more rapidly than in
the Fa/fa rats. This overdevelopment of adipose tissue is
mainly due to an adipocyte hypertrophy, which occurs as soon as 7 days
of age. During the suckling period, adipose cell size continuously
increased in fa/fa rats, whereas it remained unchanged in
Fa/fa rats, and there was no difference in cell number between genotypes. During the weaning period, the enlargement of
adipocytes was manifested in both genotypes but with a greater extent
in obese than in lean rats (+80 vs. +200% in Fa/fa and fa/fa rats, respectively), and cell number was 28% lower in
fa/fa than in lean rats at 28 days of age. By contrast,
adipocyte hyperplasia was evident in 56-day-old fa/fa rats.
This is in agreement with the primary obesity effect of fa
genotype (3) and gives evidence of a late onset of
adipocyte hyperplasia. We also evaluated the RAS in the serum and, as
shown in Table 1, plasma renin activity and plasma AGT in obese rats
were comparable to values in age-matched lean rats.
|
Developmental changes in AGT protein and mRNA in liver and adipose
tissue.
Figure 1A depicts AGT protein
levels in the liver of lean and obese growing Zucker rats. The
developmental pattern was quite similar in both genotypes, increasing
until weaning and decreasing thereafter. Northern blot analysis of
liver AGT mRNA revealed that AGT gene expression tended to be decreased
with age and that no significant differences in AGT mRNA levels between
lean and obese Zucker rats were detected at all ages studied (Fig.
1B).
|
|
|
AGT secretion by adipose cells.
To determine whether increased levels of AGT content exhibited by the
adipocytes from fa/fa rats were concomitant with an increased rate of AGT secretion, we measured AGT protein content in
culture medium of mature adipocytes. Figure
4 shows that the amount of secreted
protein per day was 30-60 times higher than the cellular content,
regardless of the genotype. In lean rats, we found similar secretion
rates of AGT by adipocytes from suckling (14 days) or weaned (28 days)
rats. In contrast, we observed an age-related increase (40%) in AGT
secretion in adipocytes from obese rats. Moreover, adipocytes from
14-day-old obese rats, despite the lack of genotype effect on the AGT
expression (mRNA and protein content; see Fig. 2), displayed a clear
twofold increase in the amount of secreted protein compared with that
of lean rats. These data suggested that the secretion level is a better
index to evaluate the AGT production by adipocytes than mRNA or protein
concentrations.
|
Effect of adipose tissue site on secretion capacity.
Because some site-specific variations in the storage and release of
lipids from adipose tissue have been described, we investigated the AGT
secretion by adipocytes of 56-day-old rats from three different sites:
subcutaneous (inguinal) and visceral (epididymal and retroperitoneal)
adipose tissues. Table 2 shows that
different sites of fat depots from lean rats exhibited a similar
capacity to produce and secrete AGT. By contrast, obese rats exhibited significant intersite differences in AGT content, since retroperitoneal adipose tissue displayed a twofold increase in intracellular AGT compared with the other sites. This site effect was also obvious when
the secretion rates were compared, showing a specific effect of the
retroperitoneal localization. The greater potency to secrete AGT
exhibited by adipose cells from the retroperitoneal site was also
observed for leptin secretion (Table 2). Thus adipocytes from obese
rats exhibit a higher capacity to secrete different factors, and this
capacity is largely related to the localization. The influence of the
site in the amplification of the genotype effect was also observed at
the mRNA levels (Table 2).
|
Effect of the adipose cell size on angiotensinogen secretion.
To assess whether the genotype-related effect on AGT secretion by
adipose cells could be related to the cell hypertrophy per se, we
examined the production of AGT by adipocytes according to their size.
In obese rats, we observed that adipocytes from the retroperitoneal
site exhibited higher levels of AGT production than from other sites,
whereas no change in adipocyte size could be detected (Table 2). We
further estimated the AGT secretion by three to four populations of
adipocytes, which differed in their cell diameter distribution. Using a
successive filtration procedure, we were able to isolate within the
same tissue (inguinal) three or four populations on the basis of the
fat cell size distribution, as presented in Fig.
5A. In each population, AGT
secretion was measured, and the results show that there was a negative
relationship between AGT secretion and cell size in both
Fa/fa and fa/fa genotypes (Fig. 5B).
Moreover, when we compared the secretion rates by adipocytes of the
same size (14-16 ng) but issued from different genotypes, there
was a fivefold increase in the AGT secretion rate (6 ± 2.5 and
30 ± 12 for lean and obese genotypes, respectively;
n = 3). These findings led us to exclude an important
role of cell hypertrophy in the overproduction of AGT by adipocytes
from fa/fa rats.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Because the secretion of AGT by adipose tissue has been involved in the differentiation of adipose tissue through a paracrine effect, we have explored in a genetic model of obesity whether adipose tissue AGT expression and secretion differ during the early onset of obesity. Previous studies have yielded conflicting results regarding the effect of obesity on AGT expression in adipose tissue. Both increased and decreased AGT expression in adipose tissue has been reported in ob/ob mice or fa/fa rats, respectively (17, 23). We document here an early and clear-cut increase in the content and secretion of AGT by obese fa/fa rat adipocytes. Conversely, AGT content in the liver is not affected, showing the tissue-specific character of this increase. These findings are at variance with those of Jones et al. (23), reporting a decreased expression of AGT in adipose tissue from obese adult Zucker rats. Such different findings could be explained by the age of the animals studied. In adults, in which hormonal and metabolic abnormalities are more pronounced, confounding factors such as hyperinsulinemia could be present, since insulin downregulated the AGT expression in cultured adipose cells (1).
The fa genotype effect was visible as early as 14 days of age, in contrast to changes seen with mRNA level or protein content. Such a discrepancy has already been observed in the ob cell line, where AGT secretion was dramatically increased during the adipocyte differentiation process, whereas the cellular content remained stable during the same period (33). It could be postulated that this difference was due to the use of an indirect method of AGT assay. The presence of a potent proteolytic system in the tissue extract may provoke a degradation of ANG I during the renin incubation, as previously demonstrated in the liver (10). However, the difference between the intracellular pool and the secretion level of AGT persisted when the protein was detected by immunoblotting, suggesting that the quantification by RIA of secreted AGT by intact adipose cells is reliable. Thus these results also suggest that the measurement of AGT mRNA amount is not sufficient to estimate accurately the AGT production by the adipose tissue.
In adipocytes from obese rodents (fa/fa, ob/ob), the
capacity of adipocytes to secrete different proteins, leptin, tumor
necrosis factor-, lipoprotein lipase, and AGT (present study) is
enhanced, suggesting a potential relationship between cell hypertrophy
and secretion capacity (4, 21, 27). In fact, our results
do not support such a hypothesis, because in both lean and obese rat
adipocytes, a negative relationship between cell size and secretion was
found, and at comparable sizes, adipocytes of the fa
genotype clearly secrete more AGT than those of the control one. The
reasons why the production of AGT is specifically increased in adipose
tissue of obese Zucker rats remain unclear. To our knowledge, AGT is
secreted constitutively and is not stored in secretory vesicles
(13). This implies that AGT production is controlled
mostly at the transcriptional level (36). We have previously demonstrated that adipocytes from obese Zucker rats display
a marked increase in the transcription of a subset of genes related to
the lipid storage pathway (15, 19). The present data
support the hypothesis that, in obese rat adipocytes, the AGT gene
could also be a target of the fa mutation. Whether defective leptin signaling is implicated in this feature remains to be
determined. The lack of effect of exogenous leptin (100 ng/ml) on AGT
release in lean rat adipose cells (data not shown) argues against a
direct effect of this cytokine.
Adipose tissue is now well established as being heterogeneous in its metabolic activity, and regional variation in storage and mobilization capacities has been previously described in humans and rodents (18, 25, 29, 32). We found that adipocytes from retroperitoneal tissue of fa/fa rats displayed an increase in AGT expression and secretion rate. Such a site-related difference is consistent with a higher level of AGT mRNA in visceral than in subcutaneous fat found in obese subjects (16). The overproduction of both AGT and leptin found in retroperitoneal adipocytes from obese Zucker rats appears to be a part of a generalized increase in the adipocyte function of this localization as previously described (4, 18). Further studies are necessary to learn the underlying mechanism of this regional difference in AGT production in adipose tissue of obese fa/fa rats.
The present study raises questions about the potential impact of increased adipocyte AGT production. On the one hand, an excess of local production of ANG II by triggering adipocyte differentiation and lipid storage capacity may contribute to the onset of both hypertrophy and hyperplasia of adipose tissue in obese rats (11, 12, 22). On the other hand, we can speculate that, in obese rats, AGT overproduction by adipose tissue is increasing with its development and could contribute to promoting a later onset of hypertension when the mass of adipose tissue represents an important part of the body weight (37).
In conclusion, the data presented here demonstrate that during the onset of obesity, there is an adipose tissue-specific increase in the production of AGT, which is concomitant with the overexpression of genes of lipid storage-related enzymes. These results raise the possibility that AGT, besides its role in vascular tone, may also play a complex role in the physiology and/or pathology of the adipose tissue itself.
![]() |
ACKNOWLEDGEMENTS |
---|
This work was supported by the Institut National de la Santé et de la Recherche Médicale and by a research contract from the Groupe Lipides et Nutrition.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: A. Quignard-Boulangé, INSERM U 465, 15 rue de l'Ecole de Médecine, 75270 Paris Cedex 06, France (E-mail: quignard{at}bhdc.jussieu.fr).
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.
Received 27 February 2001; accepted in final form 31 August 2001.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Aubert, J,
Safonova I,
Negrel R,
and
Ailhaud G.
Insulin down-regulates angiotensinogen gene expression and angiotensinogen secretion in cultured adipose cells.
Biochem Biophys Res Commun
250:
77-82,
1998[ISI][Medline].
2.
Bouhnik, J,
Clauser E,
Gardes J,
Corvol P,
and
Menard J.
Direct radioimmunoassay of rat angiotensinogen and its application to rats in various endocrine states.
Clin Sci (Colch)
62:
355-360,
1982[ISI][Medline].
3.
Boulangé, A,
Planche E,
and
de Gasquet P.
Onset of genetic obesity in the absence of hyperphagia during the first week of life in the Zucker rat (fa/fa).
J Lipid Res
20:
857-864,
1979[Abstract].
4.
Boulangé, A,
Planche E,
and
de Gasquet P.
Onset and development of hypertriglyceridemia in the Zucker rat (fa/fa).
Metabolism
30:
1045-1052,
1981[ISI][Medline].
5.
Bray, GA,
and
York DA.
Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis.
Physiol Rev
59:
719-809,
1979
6.
Briquet-Laugier, V,
Dugail I,
Ardouin B,
Le Liepvre X,
Lavau M,
and
Quignard-Boulangé A.
Evidence for a sustained genetic effect on fat storage capacity in cultured adipose cells from Zucker rats.
Am J Physiol Endocrinol Metab
267:
E439-E446,
1994
7.
Campbell, DJ,
Bouhnik J,
Coezy E,
Pinet F,
Clauser E,
Menard J,
and
Corvol P.
Characterization of precursor and secreted forms of rat angiotensinogen.
Endocrinology
114:
776-785,
1984[Abstract].
8.
Chomczynski, P,
and
Sacchi N.
Single step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction.
Anal Biochem
162:
156-159,
1987[ISI][Medline].
9.
Chua, SC,
Chung WK,
Wu-Peng S,
Zhang YY,
Liu S,
Tartaglia LA,
and
Leibel RL.
Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor.
Science
271:
994-996,
1996[Abstract].
10.
Clauser, E,
Bouhnik J,
Coezy E,
Corvol P,
and
Menard J.
Synthesis and release of immunoreactive angiotensinogen by rat liver slices.
Endocrinology
112:
1188-1193,
1983[Abstract].
11.
Crandall, DL,
Herzlinger HE,
Saunders BD,
and
Kral JG.
Developmental aspects of the adipose tissue renin-angiotensin system: therapeutic implications.
Drug Dev Res
32:
117-125,
1994[ISI].
12.
Darimont, C,
Vassaux G,
Ailhaud G,
and
Negrel R.
Differentiation of preadipose cells: role of prostacyclin upon stimulation of adipose cells by angiotensin-II.
Endocrinology
135:
2030-2036,
1994[Abstract].
13.
Deschepper, CF,
and
Reudelhuber TL.
Rat angiotensinogen is secreted only constitutively when transfected into AtT-20 cells.
Hypertension
16:
147-153,
1990[Abstract].
14.
Dugail, I,
Quignard-Boulangé A,
Bazin R,
Le Liepvre X,
and
Lavau M.
Adipose-tissue-specific increase in glyceraldehyde-3-phosphate dehydrogenase activity and mRNA amounts in suckling pre-obese Zucker rats. Effect of weaning.
Biochem J
254:
483-487,
1988[ISI][Medline].
15.
Dugail, I,
Quignard-Boulangé A,
Le Liepvre X,
Ardouin B,
and
Lavau M.
Gene expression of lipid-storage-related enzymes in adipose tissue of the gentically obese Zucker rats.
Biochem J
281:
607-611,
1992[ISI][Medline].
16.
Dusserre, E,
Moulin P,
and
Vidal H.
Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues.
Biochim Biophys Acta
1500:
88-96,
2000[ISI][Medline].
17.
Frederich, RC,
Kahn BB,
Peach MJ,
and
Flier JS.
Tissue-specific nutritional regulation of angiotensinogen in adipose tissue.
Hypertension
19:
339-344,
1992[Abstract].
18.
Fried, SK,
Lavau M,
and
Pi-Sunyer FX.
Variations of glucose metabolism by fat cells from three adipose depots of the rat.
Metabolism
31:
876-883,
1982[ISI][Medline].
19.
Hainault, I,
Hajduch E,
and
Lavau M.
Fatty genotype-induced increase in GLUT4 promoter activity in transfected adipocytes: delineation of two fa-responsive regions and glucose effect.
Biochem Biophys Res Commun
209:
1053-1061,
1995[ISI][Medline].
20.
Harp, JB,
and
DiGirolamo M.
Components of the renin-angiotensin system in adipose tissue: changes with maturation and adipose mass enlargement.
J Gerontol
50A:
B270-B276,
1995[ISI].
21.
Hotamisligil, GS,
Shargill NS,
and
Spiegelman BM.
Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.
Science
259:
87-91,
1993[ISI][Medline].
22.
Jones, BH,
Standridge MK,
and
Moustaid N.
Angiotensin II increases lipogenesis in 3T3-L1 and human adipose cells.
Endocrinology
138:
1512-1519,
1997
23.
Jones, BH,
Standridge MK,
Taylor JW,
and
Moustaid N.
Angiotensinogen gene expression in adipose tissue; analysis of obese models and hormonal and nutritional control.
Am J Physiol Regulatory Integrative Comp Physiol
273:
R236-R242,
1997
24.
Kanai, H,
Matsuzawa Y,
Kotani K,
Keno Y,
Kobatake K,
Nagai Y,
Fujioka S,
Tokunaga K,
and
Tarui S.
Close correlation of intra-abdominal fat accumulation to hypertension in obese women.
Hypertension
16:
484-490,
1990[Abstract].
25.
Lacasa, D,
Agli B,
Pecquery R,
and
Giudicelli Y.
Influence of ovariectomy and regional fat distribution on the membranous transducing system controlling lipolysis in rat fat cells.
Endocrinology
128:
747-753,
1991[Abstract].
26.
Lavau, M,
Susini C,
Knittle J,
Blanchet-Hirst S,
and
Greenwood MR.
A reliable photomicrographic method to determining fat cell size and number: application to dietary obesity.
Proc Soc Exp Biol Med
156:
251-256,
1977.
27.
Masuzaki, H,
Hosoda K,
Ogawa Y,
Shigemoto M,
Satoh N,
Mori K,
Tamura N,
Nishi S,
Yoshimasa Y,
Yamori Y,
and
Nakao K.
Augmented expression of obese (ob) gene during the process of obesity in genetically obese-hyperglycemic Wistar fatty (fa/fa) rats.
FEBS Lett
378:
267-271,
1996[ISI][Medline].
28.
Menard, J,
and
Catt KJ.
Measurement of renin activity, concentration and substrate in rat plasma by radioimmunoassay of angiotensin I.
Endocrinology
90:
422-430,
1972[ISI][Medline].
29.
Ostman, J,
Arner P,
Engfeldt P,
and
Kager L.
Regional differences in the control of lipolysis in human adipose tissue.
Metabolism
28:
1198-1205,
1979[ISI][Medline].
30.
Phillips, M,
Liu GQ,
Hammond H,
Dugan V,
Hey PJ,
Caskey CT,
and
Hess J.
Leptin receptor missense mutation in the fatty Zucker rat.
Nat Genet
13:
18-19,
1996[ISI][Medline].
31.
Quignard-Boulangé, A,
Dugail I,
and
Brigant L.
Contribution of adipocyte precursors to the onset of adipose tissue hyperplasia in the Zucker rat.
Int J Obes
9, Suppl 1:
4,
1985.
32.
Rebuffe-Scrive, M,
Lönnroth P,
Marin P,
Wesslau C,
Bjorntorp P,
and
Smith U.
Regional adipose tissue metabolism in men and postmenopausal women.
Int J Obes
11:
347-355,
1987[ISI][Medline].
33.
Safonova, I,
Aubert J,
Negrel R,
and
Ailhaud G.
Regulation by fatty acids of angiotensinogen gene expression in preadipose cells.
Biochem J
322:
235-239,
1997[ISI][Medline].
34.
Saye, JA,
Cassis LA,
Sturgill TW,
Lynch KR,
and
Peach MJ.
Angiotensingen gene expression in 3T3-L1 cells.
Am J Physiol Cell Physiol
256:
C448-C451,
1989
35.
Saye, JA,
Lynch KR,
and
Peach MJ.
Changes in angiotensinogen messenger RNA in differentiating 3T3-F442A adipocytes.
Hypertension
15:
867-871,
1990[Abstract].
36.
Tamura, K,
Umemura S,
Iwamoto K,
Yamaguchi S,
Kobayashi S,
Takeda K,
Tokita Y,
Takagi N,
Murakami K,
Fukamizu A,
and
Ishii M.
Molecular mechanism of adipogenic activation of the angiotensinogen gene.
Hypertension
23:
364-368,
1994[Abstract].
37.
Turner, NC,
Guillaume JL,
and
Toseland N.
Effects of genetic hyperinsulinaemia on vascular reactivity, blood pressure, and renal structure in the Zucker rat.
J Cardiovasc Pharmacol
26:
714-720,
1995[ISI][Medline].
38.
Zorad, S,
Fickova M,
Zelezna B,
Macho L,
and
Kral JG.
The role of angiotensin II and its receptors in regulation of adipose tissue metabolism and cellularity.
Gen Physiol Biophys
14:
383-391,
1995[ISI][Medline].