Role of adipose tissue renin–angiotensin system in metabolic and inflammatory diseases associated with obesity
2010; Elsevier BV; Volume: 79; Issue: 2 Linguagem: Inglês
10.1038/ki.2010.391
ISSN1523-1755
AutoresLaurent Yvan‐Charvet, Annie Quignard‐Boulangé,
Tópico(s)Adipose Tissue and Metabolism
ResumoObesity is a leading cause of death worldwide because of its associated inflammatory disorders such as hypertension, cardiovascular and kidney diseases, dyslipidemia, glucose intolerance, and certain types of cancer. Adipose tissue expresses all components of the renin–angiotensin system necessary to generate angiotensin (Ang) peptides for local function. The angiotensin type 1 (AT1) and type 2 (AT2) receptors mediate the effect of Ang II and recent studies have shown that both receptors may modulate fat mass expansion through upregulation of adipose tissue lipogenesis (AT2) and downregulation of lipolysis (AT1). Thus, both receptors may have synergistic and additive effects to promote the storage of lipid in adipose tissue in response to the nutrient environment. The production of angiotensinogen (AGT) by adipose tissue in rodents also contributes to one third of the circulating AGT levels. Increased adipose tissue AGT production in the obese state may be responsible in part for the metabolic and inflammatory disorders associated with obesity. This supports the notion that besides the traditional role of Ang II produced by the liver in the control of blood pressure, Ang II produced by the adipose tissue may more accurately reflect the role of this hormone in the regulation of fat mass and associated disorders. Obesity is a leading cause of death worldwide because of its associated inflammatory disorders such as hypertension, cardiovascular and kidney diseases, dyslipidemia, glucose intolerance, and certain types of cancer. Adipose tissue expresses all components of the renin–angiotensin system necessary to generate angiotensin (Ang) peptides for local function. The angiotensin type 1 (AT1) and type 2 (AT2) receptors mediate the effect of Ang II and recent studies have shown that both receptors may modulate fat mass expansion through upregulation of adipose tissue lipogenesis (AT2) and downregulation of lipolysis (AT1). Thus, both receptors may have synergistic and additive effects to promote the storage of lipid in adipose tissue in response to the nutrient environment. The production of angiotensinogen (AGT) by adipose tissue in rodents also contributes to one third of the circulating AGT levels. Increased adipose tissue AGT production in the obese state may be responsible in part for the metabolic and inflammatory disorders associated with obesity. This supports the notion that besides the traditional role of Ang II produced by the liver in the control of blood pressure, Ang II produced by the adipose tissue may more accurately reflect the role of this hormone in the regulation of fat mass and associated disorders. Angiotensinogen (AGT), the precursor of the renin–angiotensin system (RAS) is converted through an enzymatic cascade to angiotensin I and angiotensin II (Ang II) by the actions of renin and angiotensin-converting enzyme (ACE), respectively. Ang(1–7) is formed from Ang I and Ang II by ACE2 (Figure 1). The production of Ang II is linked to hypertension and several inflammatory diseases including cardiovascular and kidney diseases, dyslipidemia and glucose intolerance (also known as the metabolic syndrome). AGT is highly expressed in adipose tissue and is constitutively secreted by mature adipocytes from separate adipose depots in animal models and in humans.1.Engeli S. Schling P. Gorzelniak K. et al.The adipose-tissue renin–angiotensin–aldosterone system: role in the metabolic syndrome?.Int J Biochem Cell Biol. 2003; 35: 807-825Crossref PubMed Scopus (326) Google Scholar In rodents, this production may contribute as much as 30% of circulating AGT levels in vivo,2.Massiera F. Bloch-Faure M. Ceiler D. et al.Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation.FASEB J. 2001; 15: 2727-2729Crossref PubMed Scopus (398) Google Scholar arguing for a paracrine role of adipose AGT and consistent with the new view of adipose tissue as an endocrine organ. Adipose AGT may also have autocrine effects given that adipose tissue expresses all the components of the RAS, including renin, ACE, and ACE2. This permits local production of Ang II and other angiotensin peptides in adipose tissue.3.Darimont C. Vassaux G. Ailhaud G. et al.Differentiation of preadipose cells: role of prostacyclin upon stimulation of adipose cells by angiotensin-II.Endocrinology. 1994; 135: 2030-2036Crossref PubMed Scopus (181) Google Scholar, 4.Crandall D.L. Armellino D.C. Busler D.E. et al.Angiotensin II receptors in human preadipocytes: role in cell cycle regulation.Endocrinology. 1999; 140: 154-158Crossref PubMed Scopus (81) Google Scholar Both adipocytes and preadipocytes express angiotensin receptors including Ang II receptors type 1 (AT1) and type 2 (AT2) as well as Ang IV and Ang(1–7) receptors (MasR).5.Weiland F. Verspohl E.J. Variety of angiotensin receptors in 3T3-L1 preadipose cells and differentiated adipocytes.Horm Metab Res. 2008; 40: 760-766Crossref PubMed Scopus (17) Google Scholar This review will summarize the autocrine role of the adipose RAS (aRAS) as well as the critical paracrine role of this system in regulating lipid and glucose homeostasis with consequences on metabolic and inflammatory diseases. Increased local formation of Ang II in adipose tissue has been originally observed in genetically or diet-induced obese rodents and in humans,6.Frederich R.C. Kahn B.B. Peach M.J. et al.Tissue-specific nutritional regulation of angiotensinogen in adipose tissue.Hypertension. 1992; 19: 339-344Crossref PubMed Scopus (237) Google Scholar, 7.Hainault I. Nebout G. Turban S. et al.Adipose tissue-specific increase in angiotensinogen expression and secretion in the obese (fa/fa) Zucker rat.Am J Physiol Endocrinol Metab. 2002; 282: E59-E66PubMed Google Scholar, 8.Van Harmelen V. Ariapart P. Hoffstedt J. et al.Increased adipose angiotensinogen gene expression in human obesity.Obes Res. 2000; 8: 337-341Crossref PubMed Scopus (137) Google Scholar and generation of transgenic mice overexpressing AGT in adipose tissue leads to the development of obesity.2.Massiera F. Bloch-Faure M. Ceiler D. et al.Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation.FASEB J. 2001; 15: 2727-2729Crossref PubMed Scopus (398) Google Scholar This last observation has been a major contributing factor in favor of Ang II as an endocrine effector in obesity in vivo. Our group has also identified that mice lacking AGT or AT2 were protected from high-fat-diet-induced obesity and featured adipose tissue hypotrophy.9.Massiera F. Seydoux J. Geloen A. et al.Angiotensinogen-deficient mice exhibit impairment of diet-induced weight gain with alteration in adipose tissue development and increased locomotor activity.Endocrinology. 2001; 142: 5220-5225Crossref PubMed Scopus (135) Google Scholar, 10.Yvan-Charvet L. Even P. Bloch-Faure M. et al.Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance.Diabetes. 2005; 54: 991-999Crossref PubMed Scopus (160) Google Scholar Reports by Kouyama et al.,11.Kouyama R. Suganami T. Nishida J. et al.Attenuation of diet-induced weight gain and adiposity through increased energy expenditure in mice lacking angiotensin II type 1a receptor.Endocrinology. 2005; 146: 3481-3489Crossref PubMed Scopus (130) Google Scholar subsequently revealed that mice lacking AT1 were also protected from diet-induced obesity, revealing a synergistic contribution of AT1 and AT2 in mediating the in vivo effect of Ang II on adipose tissue development. In contrast to AT1 and AT2 knockout mice, mice lacking the Mas receptor exhibited increased abdominal fat mass associated with higher adipose tissue AGT expression, thereby suggesting a tight regulation of Ang II production by Ang(1–7) in adipose tissue.12.Santos S.H. Fernandes L.R. Mario E.G. et al.Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism.Diabetes. 2008; 57: 340-347Crossref PubMed Scopus (190) Google Scholar Recently, studies using knockout mice for renin (with reduction of both Ang II and Ang(1–7) formation) or ACE confirmed that blocking Ang II production in turn prevented fat mass enlargement.13.Takahashi N. Li F. Hua K. et al.Increased energy expenditure, dietary fat wasting, and resistance to diet-induced obesity in mice lacking renin.Cell Metab. 2007; 6: 506-512Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 14.Jayasooriya A.P. Mathai M.L. Walker L.L. et al.Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance.Proc Natl Acad Sci USA. 2008; 105: 6531-6536Crossref PubMed Scopus (146) Google Scholar Similar findings were observed through the use of RAS blockade.15.Mathai M.L. Naik S. Sinclair A.J. et al.Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats.Int J Obes. 2008; 32: 1576-1584Crossref PubMed Scopus (50) Google Scholar, 16.de Kloet A.D. Krause E.G. Kim D.H. et al.The effect of angiotensin-converting enzyme inhibition using captopril on energy balance and glucose homeostasis.Endocrinology. 2009; 150: 4114-4123Crossref PubMed Scopus (57) Google Scholar, 17.Lee M.H. Song H.K. Ko G.J. et al.Angiotensin receptor blockers improve insulin resistance in type 2 diabetic rats by modulating adipose tissue.Kidney Int. 2008; 74: 890-900Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Together these findings showed an important role for Ang II in the pathogenesis of obesity in rodents. The reduced fat mass in the aforementioned RAS knockout mouse models was not associated with overall changes in food intake.9.Massiera F. Seydoux J. Geloen A. et al.Angiotensinogen-deficient mice exhibit impairment of diet-induced weight gain with alteration in adipose tissue development and increased locomotor activity.Endocrinology. 2001; 142: 5220-5225Crossref PubMed Scopus (135) Google Scholar, 10.Yvan-Charvet L. Even P. Bloch-Faure M. et al.Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance.Diabetes. 2005; 54: 991-999Crossref PubMed Scopus (160) Google Scholar, 11.Kouyama R. Suganami T. Nishida J. et al.Attenuation of diet-induced weight gain and adiposity through increased energy expenditure in mice lacking angiotensin II type 1a receptor.Endocrinology. 2005; 146: 3481-3489Crossref PubMed Scopus (130) Google Scholar, 12.Santos S.H. Fernandes L.R. Mario E.G. et al.Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism.Diabetes. 2008; 57: 340-347Crossref PubMed Scopus (190) Google Scholar, 13.Takahashi N. Li F. Hua K. et al.Increased energy expenditure, dietary fat wasting, and resistance to diet-induced obesity in mice lacking renin.Cell Metab. 2007; 6: 506-512Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 14.Jayasooriya A.P. Mathai M.L. Walker L.L. et al.Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance.Proc Natl Acad Sci USA. 2008; 105: 6531-6536Crossref PubMed Scopus (146) Google Scholar Attempts have been made to establish a link between fat mass and intestinal lipid absorption among the different RAS models. Although Takahashi et al. showed that renin-deficient mice exhibited elevated gastrointestinal loss of dietary fat,13.Takahashi N. Li F. Hua K. et al.Increased energy expenditure, dietary fat wasting, and resistance to diet-induced obesity in mice lacking renin.Cell Metab. 2007; 6: 506-512Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar we and others were not able to find any difference in lipid absorption in AGT or ACE knockout mice.9.Massiera F. Seydoux J. Geloen A. et al.Angiotensinogen-deficient mice exhibit impairment of diet-induced weight gain with alteration in adipose tissue development and increased locomotor activity.Endocrinology. 2001; 142: 5220-5225Crossref PubMed Scopus (135) Google Scholar, 14.Jayasooriya A.P. Mathai M.L. Walker L.L. et al.Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance.Proc Natl Acad Sci USA. 2008; 105: 6531-6536Crossref PubMed Scopus (146) Google Scholar By contrast, it is clear that all RAS knockout mouse models tested to date show a higher metabolic rate.9.Massiera F. Seydoux J. Geloen A. et al.Angiotensinogen-deficient mice exhibit impairment of diet-induced weight gain with alteration in adipose tissue development and increased locomotor activity.Endocrinology. 2001; 142: 5220-5225Crossref PubMed Scopus (135) Google Scholar, 10.Yvan-Charvet L. Even P. Bloch-Faure M. et al.Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance.Diabetes. 2005; 54: 991-999Crossref PubMed Scopus (160) Google Scholar, 11.Kouyama R. Suganami T. Nishida J. et al.Attenuation of diet-induced weight gain and adiposity through increased energy expenditure in mice lacking angiotensin II type 1a receptor.Endocrinology. 2005; 146: 3481-3489Crossref PubMed Scopus (130) Google Scholar, 12.Santos S.H. Fernandes L.R. Mario E.G. et al.Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism.Diabetes. 2008; 57: 340-347Crossref PubMed Scopus (190) Google Scholar, 13.Takahashi N. Li F. Hua K. et al.Increased energy expenditure, dietary fat wasting, and resistance to diet-induced obesity in mice lacking renin.Cell Metab. 2007; 6: 506-512Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 14.Jayasooriya A.P. Mathai M.L. Walker L.L. et al.Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance.Proc Natl Acad Sci USA. 2008; 105: 6531-6536Crossref PubMed Scopus (146) Google Scholar We previously reported that this increased energy expenditure was the consequence of an increased locomotor activity and whole-body lipid oxidation in AGT- and AT2-deficient mice.9.Massiera F. Seydoux J. Geloen A. et al.Angiotensinogen-deficient mice exhibit impairment of diet-induced weight gain with alteration in adipose tissue development and increased locomotor activity.Endocrinology. 2001; 142: 5220-5225Crossref PubMed Scopus (135) Google Scholar, 10.Yvan-Charvet L. Even P. Bloch-Faure M. et al.Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance.Diabetes. 2005; 54: 991-999Crossref PubMed Scopus (160) Google Scholar These findings could be related in part to the regulatory effect of Ang II on adiponectin secretion, which controls muscle fatty acid oxidation capacity.18.Furuhashi M. Ura N. Higashiura K. et al.Blockade of the renin–angiotensin system increases adiponectin concentrations in patients with essential hypertension.Hypertension. 2003; 42: 76-81Crossref PubMed Scopus (429) Google Scholar, 19.Clasen R. Schupp M. Foryst-Ludwig A. et al.PPARγ-activating angiotensin type-1 receptor blockers induce adiponectin.Hypertension. 2005; 46: 137-143Crossref PubMed Scopus (245) Google Scholar Together, these studies suggest that reduced Ang II signaling protects fat mass enlargement in mice by increasing peripheral energy expenditure and whole-body lipid oxidation. Conflicting data exist about the role of Ang II in preadipocyte differentiation in vitro,3.Darimont C. Vassaux G. Ailhaud G. et al.Differentiation of preadipose cells: role of prostacyclin upon stimulation of adipose cells by angiotensin-II.Endocrinology. 1994; 135: 2030-2036Crossref PubMed Scopus (181) Google Scholar, 20.Janke J. Engeli S. Gorzelniak K. et al.Mature adipocytes inhibit in vitro differentiation of human preadipocytes via angiotensin type 1 receptors.Diabetes. 2002; 51: 1699-1707Crossref PubMed Scopus (286) Google Scholar, 21.Brucher R. Cifuentes M. Acuna M.J. et al.Larger anti-adipogenic effect of angiotensin II on omental preadipose cells of obese humans.Obesity. 2007; 15: 1643-1646Crossref PubMed Scopus (26) Google Scholar, 22.Tomono Y. Iwai M. 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We recently showed that overexpression of AGT in mice led to a slight decrease in adipose cell number revealing an inhibitory effect of Ang II on preadipocyte differentiation in vivo.25.Yvan-Charvet L. Massiera F. Lamande N. et al.Deficiency of angiotensin type 2 receptor rescues obesity but not hypertension induced by overexpression of angiotensinogen in adipose tissue.Endocrinology. 2009; 150: 1421-1428Crossref PubMed Scopus (57) Google Scholar This effect may be explained by a direct action of Ang II on the proliferation and differentiation of adipose tissue precursors,4.Crandall D.L. Armellino D.C. Busler D.E. et al.Angiotensin II receptors in human preadipocytes: role in cell cycle regulation.Endocrinology. 1999; 140: 154-158Crossref PubMed Scopus (81) Google Scholar, 26.Matsushita K. Wu Y. 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Angiotensin II increases lipogenesis in 3T3-L1 and human adipose cells.Endocrinology. 1997; 138: 1512-1519Crossref PubMed Scopus (227) Google Scholar Mice lacking AT2 revealed lower glucose uptake in their adipose tissue following Ang II or insulin stimulation (Figure 1).10.Yvan-Charvet L. Even P. Bloch-Faure M. et al.Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance.Diabetes. 2005; 54: 991-999Crossref PubMed Scopus (160) Google Scholar, 28.Shiuchi T. Iwai M. Li H.S. et al.Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice.Hypertension. 2004; 43: 1003-1010Crossref PubMed Scopus (181) Google Scholar We also reported that Ang II increased the storage of cholesterol in murine adipocytes through a PI3K-dependent translocation of scavenger receptor type BI-mediated cholesterol uptake.29.Tondu A.L. Robichon C. 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Pagler T.A. et al.Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signaling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions.Circulation. 2008; 118: 1837-1847Crossref PubMed Scopus (297) Google Scholar AGT mRNA abundance in adipose tissue may represent 60% of that in liver,51.Lu H. Boustany-Kari C.M. Daugherty A. et al.Angiotensin II increases adipose angiotensinogen expression.Am J Physiol Endocrinol Metab. 2007; 292: E1280-E1287Crossref PubMed Scopus (61) Google Scholar and contribute to approximately 30% of circulating AGT levels in rodents.2.Massiera F. Bloch-Faure M. Ceiler D. et al.Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation.FASEB J. 2001; 15: 2727-2729Crossref PubMed Scopus (398) Google Scholar Under genetic or diet-induced obesity conditions, adipocytes show increased aRAS activity, an effect that is not observed in liver.6.Frederich R.C. Kahn B.B. Peach M.J. et al.Tissue-specific nutritional regulation of angiotensinogen in adipose tissue.Hypertension. 1992; 19: 339-344Crossref PubMed Scopus (237) Google Scholar, 7.Hainault I. Nebout G. Turban S. et al.Adipose tissue-specific increase in angiotensinogen expression and secretion in the obese (fa/fa) Zucker rat.Am J Physiol Endocrinol Metab. 2002; 282: E59-E66PubMed Google Scholar Enhanced AGT mRNA expression is also observed in visceral and subcutaneous adipose tissue of obese patients.8.Van Harmelen V. Ariapart P. Hoffstedt J. et al.Increased adipose angiotensinogen gene expression in human obesity.Obes Res. 2000; 8: 337-341Crossref PubMed Scopus (137) Google Scholar, 52.Dusserre E. Moulin P. Vidal H. Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues.Biochim Biophys Acta. 2000; 1500: 88-96Crossref PubMed Scopus (270) Google Scholar This suggests that under pathophysiological conditions, enhanced adipose tissue AGT secretion may contribute to metabolic disorders associated with obesity (Figure 2). Early reports rev
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