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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online October 15, 2001 as doi:10.1096/fj.01-0457fje. |
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* CNRS UMR 6543, Institute of Signaling, Development and Cancer, Nice, France;
INSERM U367 Paris, France;
University of Tsukuba, Tsukuba, Japan;
Collège de France, INSERM U36, Paris, France;
INSERM U 465, Paris, France; and
¶ Department of Physiology, Faculty of Medicine, Geneva, Switzerland
2Correspondence: CNRS UMR 6543, Institute of Signaling, Development and Cancer. Faculté des Sciences, Parc Valrose, 06108, Nice cedex 2, France. E-mail: teboulm{at}unice.fr
SPECIFIC AIMS
White adipose tissue is an important production site of angiotensinogen (AGT) consistent with a local role played by adipose AGT. Because plasma AGT levels have been reported to correlate with blood pressure and to be associated with body mass index, we investigated whether adipose AGT is released locally and into the circulation, and thus could be involved in fat mass development and blood pressure regulation.
PRINCIPAL FINDINGS
1. Generation of mice with targeted AGT expression in adipose tissue
To gain insight into the relationships between adipose AGT, fat mass, and blood pressure, we generated transgenic mice that either overexpress adipose AGT (termed Tg-WT mice) or in which AGT expression is restricted to adipose tissue (termed Tg-KO mice). We showed that the product of the transgene accumulated after secretion into the culture medium and was cleavable by mouse renin. As expected, AGT secretion was undetectable in angiotensinogen-deficient mice. Epididymal fat pad explants of Tg-WT mice exhibited increased AGT levels in the culture medium compared with those of WT mice (29.8±4 vs. 7.5±2.9 pmol/g of tissue, n=8). Levels of AGT were also higher in the culture medium from fat pad explants of Tg-KO mice (60.6±9 pmol/g of tissue, n=8) when compared with fat pad explants of Tg-WT mice. From these data it would appear that the accumulation levels are not a direct reflection of synthesis rate. Consistent with previous data obtained in WAT and adipocytes from humans, the RAS components are present in mouse explants as angiotensin II (AngII) could be detected in the culture medium. The values were found to be 0.4 ± 0.1, 0.5 ± 0.1, and 1.4 ± 0.2 pmol/g of tissue (n=8) from WAT explants of wild-type, Tg-KO, and Tg-WT mice, respectively.
2. Adipose AGT expression enhances fat mass development and adipocyte hypertrophy
A trophic role of AngII in adipose tissue development has been suggested from several in vitro and ex vivo studies. To test whether adipose AGT could play a local role, adipose tissue development in Tg-KO and Tg-WT mice was compared with that of control littermates, i.e., AGT-deficient and WT mice, respectively. The four groups of mice were fed a chow diet from weaning to 42 wk of age. At any age, AGT-deficient mice exhibited a lower body weight than WT mice whereas Tg-KO and Tg-WT mice exhibited a significantly greater body weight than their control littermates. When examined at 20 wk of age, differences in body weight were mainly due to differences in total fat mass. Total fat mass, epididymal fat pad weight, and adiposity index were lower in AGT-deficient mice than in WT mice. These values were restored to those of WT mice in Tg-KO mice and increased dramatically in Tg-WT mice. Notably, total fat-free mass was lower in AGT-deficient and Tg-KO mice compared with WT and Tg-WT mice, but leanness indices were similar in the four genotypes .
To investigate further the positive effect of targeted AGT reexpression or overexpression on adipose tissue mass, studies of WAT cellularity were performed during mouse development, i.e., at 6 wk of age. We showed that weight differences were due to adipocyte hypertrophy when comparing AGT-deficient and Tg-KO mice as well as comparing WT and Tg-WT mice (Table 1
). Surprisingly, this hypertrophic phenomenon was accompanied by hypoplasia. To gain insight into the metabolic pathways leading to triglyceride accumulation in adipocytes, fatty acid synthase activities were determined in cytosolic extracts of epididymal fat pads. Compared with each control genotype, fatty acid synthase activities were significantly increased (
twofold) in Tg-KO and Tg-WT mice compared respectively to AGT-deficient and WT mice, consistent with the angiotensin II-stimulated lipogenesis.
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3. Targeting adipose AGT expression leads to secretion into the bloodstream and increases blood pressure
To test whether adipose AGT could also play an endocrine role after secretion into the bloodstream, pAGT levels were determined. As expected AGT was undetectable in the plasma of AGT-deficient mice whereas pAGT levels in Tg-KO mice were 20–30% of those observed in WT mice. Moreover, the data show that pAGT levels increased (from 22 to 44%) in Tg-WT mice compared with WT mice. Altogether, our data show that adipose AGT is a source of pAGT although it is clear that adipose AGT is not the main source of pAGT, which is in accordance with other reports establishing the liver as the main source.
Systolic blood pressure was measured by the tail cuff method to investigate whether secreted adipose AGT plays a role in blood pressure regulation and to which extent adipose AGT reexpression can rescue the phenotype of hypotensive AGT-deficient mice. The results showed that both Tg-KO and Tg-WT mice exhibited higher blood pressure than their controls. Compared with AGT-deficient mice, reexpression of adipose AGT increased fat mass by 1.5-fold and was sufficient, with pAGT levels at 20% of those of WT mice, to normalize systolic blood pressure. Overexpression of adipose AGT increased fat mass by twofold, pAGT levels by 22%, and systolic blood pressure by 16% vs. WT mice. The curve of Fig. 1
defines the equation that relates total fat mass and blood pressure in the four groups of mice at 16–20 wk of age.
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4. Adipose AGT rescues renal morphology and function in AGT-deficient mice
Previous studies have shown that AGT-deficient mice exhibit a marked renal phenotype, including increased renin production and increased urine output associated with histological abnormalities of the papilla. We indeed found that juxtaglomerular complexes appeared much more numerous in AGT-deficient mice than in WT mice In addition, we confirmed the presence of inner medullary disorganization and papilla atrophy in AGT-deficient mice. The expression of adipose AGT completely reversed the morphological abnormalities of the medulla and papilla and the hypertrophy and hyperplasia of the juxtaglomerular complexes. Renin mRNA and protein levels detectable in the kidneys were even lower than those observed in WT mice. In accordance with the renin production by kidney and the well-known regulation of its activity by AngII, the values of plasma renin activity were higher in AGT-deficient mice than WT mice (3779±372 vs. 1768 ng of AngI generated/ml/h; n=6; P<0.005). Renin activity values were decreased in Tg-KO mice to 634 ± 24 ng of AngI generated/ml/h (n=6, P<0.05 compared with AGT-deficient mice) and in Tg-WT mice to 1287 ± 115 ng of AngI generated/ml/h (n=6, P<0.05 compared with WT mice).
To investigate renal function in Tg-KO mice, 24 h water intake and urine production were evaluated in 12-wk-old mice housed in individual metabolic cages. When provided free access to water, AGT-deficient mice showed increased water intake and urine output, as described previously. In contrast, after AGT reexpression, water intake, and urine output were normalized. Measurements of ion excretion and food intake showed no difference between AGT-deficient, WT, and Tg-KO mice. These data show that secreted adipose AGT can correct renal morphological alterations and dysfunction observed in AGT-deficient mice.
CONCLUSIONS
To investigate the role of adipose AGT, transgenic mice with targeted adipose AGT expression were generated. Our results demonstrate, for the first time, that adipose AGT is secreted into the circulation. Although the exact proportion of plasma AGT derived from adipose tissue cannot be determined with certainty in WT mice, our data indicate that in addition to the liver, adipose tissue represents a circulating source of AGT and AngII in plasma. Based on our findings in transgenic mice in which adipose tissue is the only source of AGT, significant circulating levels are found vs. those of WT mice. When total fat mass was increased twofold in Tg-WT mice compared with WT mice, pAGT levels were increased by 22%. In obese patients, fat mass is known to be increased up to three- to fourfold compared with lean subjects. Moreover AGT mRNA has been recently reported to be enhanced in adipose tissue of obese patients, likely due to adipocyte hypertrophy. Therefore, it is assumed that the contribution of adipose tissue to pAGT levels may become significant in the obese state.
Our results show that once released into the circulation, adipose AGT is involved in blood pressure regulation. In Tg-WT mice, increased pAGT levels are associated with an increase in systolic blood pressure ( 23 mm Hg), which rendered these animals hypertensive. In Tg-KO mice, the partial recovery of pAGT levels (20% of WT levels) is sufficient to fully restore normal blood pressure and renal function whereas reexpressing pAGT levels at 30% of WT levels leads to a slight hypertension.
The dramatic stimulatory effect of locally produced adipose AGT on adipose tissue development, associated with adipocyte hypertrophy, is in accordance with the stimulatory effect of AngII on lipogenesis and triglyceride accumulation in WAT. AGT expression is known to be up-regulated in mouse adipose cells by glucocorticoids, and insulin resistance leads to increased AGT expression. Thus, both in animal models of obesity and obese patients, it cannot be excluded that transient or chronic AGT overexpression in WAT may lead to a vicious circle whereby its own development is further increased by enhanced AGT secretion.
Our data summarized in the schematic diagram (Fig. 2
) clearly show that targeted expression of AGT in adipose tissue leads to a series of consequences: 1) adipocyte hypertrophy, 2) fat mass enlargement, 3) enhanced AGT levels from secretory fat tissue explants and enhanced AGT levels in blood, and 4) increased blood pressure. Overall, these observations directly implicate adipose tissue mass in the regulation of blood pressure. When compared with lean subjects with body mass index (BMI) 
25, plasma AGT levels and blood pressure in humans were respectively increased by 22% and 15% in obese patients with BMI 40 (35). Thus it is proposed that the contribution of adipose AGT in pAGT levels may become significant in the obese state.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.01-0457fje; to cite this article, use FASEB J. (October 15, 2001) 10.1096/fj.01-0457fje 
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