The RAS is a novel target in the study of diabetes, and clinical trials have indicated that ARBs, such as valsartan, may exert some of their clinical effects through an influence on adipose tissue. We studied the effect of valsartan on adipokine genes resistin (rstn) and fasting-induced adipose factor (fiaf) using obese and diabetic ob/ob mice. In addition to visceral and subcutaneous fat, rstn and fiaf mRNA levels were also measured in several other tissues known to express these adipokines, including the pituitary, cerebral cortex and hypothalamus. The significant findings were that (a) fiaf gene expression was elevated two- to fourfold in visceral and subcutaneous fat from ob/ob mice, compared with lean controls; (b) the increase in fiaf mRNA in subcutaneous, but not visceral, fat from ob/ob mice was returned to lean control levels following 2 weeks of valsartan treatment; (c) fiaf expression was reduced in the hypothalamus, but not in the cortex or pituitary, of ob/ob mice; (d) rstn expression was greatly reduced in visceral fat from ob/ob mice, compared with lean controls, but this was unaffected by valsartan; and (e) rstn expression was unchanged in all other tissues from ob/ob mice, with or without valsartan treatment.
Scheen, A.J. (2004b) Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 2. Overview of physiological and biochemical mechanisms. Diabetes Metab30:498-505.
2.
Scheen, A.J. (2004a) Prevention of type 2 diabetes mellitus through inhibition of the Renin-Angiotensin system. Drugs64:2537-65.
3.
Chu, K.Y. , Leung, P.S. (2009) Angiotensin II in type 2 diabetes mellitus. Curr Protein Pept Sci10(1):75-84.
4.
Shiuchi, T., Iwai, M., Li, H.S., et al. (2004) Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice. Hypertension43:1003-10.
5.
Yusuf, S., Gerstein, H., Hoogwerf, B., et al. (2001) Ramipril and the development of diabetes . JAMA286:1882-5.
6.
Dahlöf, B., Devereux, R.B., Kjeldsen, S.E., et al. (2002) Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet359: 995-1003.
7.
Vermes, E., Ducharme, A., Bourassa, M.G., et al. (2003) Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation107:1291-6.
8.
Yusuf, S., Ostergren, J.B., Gerstein, H.C., et al. (2005) Effects of candesartan on the development of a new diagnosis of diabetes mellitus in patients with heart failure. Circulation112(1):48-53.
9.
Kjeldsen, S.E. , Julius, S., Mancia, G., et al. (2006) Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients: the VALUE trial. J Hypertens24:1405-12.
10.
Elliott, W.J. , Meyer, P.M. (2007) Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet369:201-7.
11.
Abuissa, H. , Bel, D.S., O’Keefe , J.H. Jr. (2005) Strategies to prevent type 2 diabetes. Curr Med Res Opin21:1107-14.
12.
Abuissa, H. , Jones, P.G., Marso, S.P., O’Keefe , J.H. Jr. (2005) Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomised clinical trials. J Am Coll Cardiol46:821-6.
13.
Brown, R.E., Imran, S.A., Wilkinson, M. In: Preedy, V.R. (ed). Handbook of Behaviour, Diet and Nutrition. Springer. In Press.
14.
Fowler, J.D. , Krueth, S.B., Bernlohr, D.A., Katz, S.A.(2009) Renin dynamics in adipose tissue: adipose tissue control of local renin concentrations. Am J Physiol Endocrinol Metab296:E343-50.
15.
Schling, P. , Mallow, H., Trindl, A., Löffler, G. (1999) Evidence for a local renin angiotensin system in primary cultured human preadipocytes. Int J Obes Relat Metab Disord23:336-41.
16.
Mallow, H., Trindl, A., Löffler, G. ( 2000) Production of angiotensin II receptors type one (AT1) and type two (AT2) during the differentiation of 3T3-L1 preadipocytes. Horm Metab Res32:500-3.
17.
Fogari, R., Zoppi, A. ( 2005) Is the effect of antihypertensive drugs on platelet aggregability and fibrinolysis clinically relevant? Am J Cardiovasc Drugs5:211-23.
18.
Kawamura, T., Yoshida, K., Sugawara, A., et al. (2002) Impact of exercise and angiotensin-converting enzyme inhibition on tumor necrosis factor-alpha and leptin in fructose-fed hypertensive rats. Hypertens Res25:919-26.
19.
Umeda, M., Kanda, T., Murakami, M. ( 2003) Effects of angiotensin II receptor antagonists on insulin resistance syndrome and leptin in sucrose-fed spontaneously hypertensive rats . Hypertens Res26:485-92.
20.
Mathai, M.L. , Naik, S., Sinclair, A.J., Weisinger, H.S., Weisinger, R.S. (2008) Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats. Int J Obes (Lond) 32:1576-84.
21.
Nielsen, S. , Lihn, A.S., Stergaard, T., Mogensen, C.E., Schmitz, O. (2004) Increased plasma adiponectin in losartan-treated type 1 diabetic patients. a mediator of improved insulin sensitivity?Horm Metab Res36(3):194-6.
22.
Furuhashi, M., Ura, N., Higashiura, K., et al. (2003) Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension42(1):76-81.
23.
Nomura, S., Shouzu, A., Omoto, S., et al. (2006) Effect of valsartan on monocyte/endothelial cell activation markers and adiponectin in hypertensive patients with type 2 diabetes mellitus. Thromb Res117:385-92.
24.
Trayhurn, P. , Wood, I.S. (2004) Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr92:347-55.
25.
Hauner, H. ( 2005) Secretory factors from human adipose tissue and their functional role. Proc Nutr Soc64(2): 163-9.
26.
Trayhurn, P. (2005) Endocrine and signalling role of adipose tissue: new perspectives on fat. Acta Physiol Scand184:285-93.
27.
Steppan, C.M. , Lazar, M.A. (2004) The current biology of resistin. J Intern Med255:439-47.
Oike, Y., Akao, M., Kubota, Y., Suda, T. ( 2005) Angiopoietin-like proteins: potential new targets for metabolic syndrome therapy. Trends Mol Med11:473-9.
30.
Xu, A., Lam, M.C., Chan, K.W., et al. (2005) Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice. Proc Natl Acad Sci U S A102:6086-91.
31.
Hato, T., Tabata, M., Oike, Y. ( 2008) The role of angiopoietin-like proteins in angiogenesis and metabolism. Trends Cardiovasc Med18(1):6-14.
32.
Morash, B.A. , Ur, E., Wiesner, G., Roy, J., Wilkinson, M. (2004) Pituitary resistin gene expression: effects of age, gender and obesity. Neuroendocrinology79(3):149-56.
33.
Kersten, S. , Mandard, S., Tan, N.S., Escher, P., Metzger, D., Chambon, P. (2000) Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J Biol Chem275:28488-93.
34.
Wiesner, G. , Morash, B.A., Ur, E., Wilkinson, M. (2004) Food restriction regulates adipose-specific cytokines in pituitary gland but not in hypothalamus. J Endocrinol180(3): R1-6.
35.
Wilkinson, M., Brown, R., Imran, S.A., Ur, E. (2007) Adipokine gene expression in brain and pituitary gland. Neuroendocrinology;86(3):191-209.
36.
Tomono, Y., Iwai, M., Inaba, S., Mogi, M., Horiuchi, M. ( 2008) Blockade of AT1 receptor improves adipocyte differentiation in atherosclerotic and diabetic models. Am J Hypertens21(2):206-12.
37.
Wiesner, G. , Brown, R.E., Robertson, G.S., Imran, S.A., Ur, E., Wilkinson, M. (2006) Increased expression of the adipokine genes resistin and fasting-induced adipose factor in hypoxic/ischaemic mouse brain. Neuroreport17:1195-8.
38.
Yoon, J.C., Chickering, T.W., Rosen, E.D., et al. (2000) Peroxisome proliferator-activated receptor gamma target gene encoding a novel angiopoietin-related protein associated with adipose differentiation. Mol Cell Biol20:5343-9.
39.
Ge, H., Cha, J.Y., Gopal, H., et al. (2005) Differential regulation and properties of angiopoietin-like proteins 3 and 4. J Lipid Res46:1484-90.
40.
Brown, R., Imran, S.A., Ur, E., Wilkinson, M. ( 2008) Valproic acid and CEBPalpha-mediated regulation of adipokine gene expression in hypothalamic neurons and 3T3-L1 adipocytes. Neuroendocrinology88(1):25-34.
41.
Dutton, S., Trayhurn, P. ( 2008) Regulation of angiopoietin-like protein 4/fasting-induced adipose factor (Angptl4/FIAF) expression in mouse white adipose tissue and 3T3-L1 adipocytes. Br J Nutr100(1):18-26.
42.
Atzmon, G., Yang, X.M., Muzumdar, R., Ma, X.H., Gabriely, I., Barzilai, N. ( 2002) Differential gene expression between visceral and subcutaneous fat depots. Horm Metab Res34:622-8.
43.
Vidal, H. ( 2001) Gene expression in visceral and subcutaneous adipose tissues . Ann Med33:547-55.
44.
Hong, S.J., Shim, W.J., Choi, J.I., et al. (2007) Comparison of effects of telmisartan and valsartan on late lumen loss and inflammatory markers after sirolimus-eluting stent implantation in hypertensive patients. Am J Cardiol100:1625-9.
45.
Yilmaz, M.I. , Sonmez, A., Caglar, K., et al. (2007) Effect of antihypertensive agents on plasma adiponectin levels in hypertensive patients with metabolic syndrome. Nephrology (Carlton. 12(2):147-53.
46.
Usui, I., Fujisaka, S., Yamazaki, K., et al. (2007) Telmisartan reduced blood pressure and HOMA-IR with increasing plasma leptin level in hypertensive and type 2 diabetic patients . Diabetes Res Clin Pract77(2):210-4.
47.
Sonmez, A., Kisa, U., Uckaya, G., et al. (2001) Effects of losartan treatment on T-cell activities and plasma leptin concentrations in primary hypertension. J Renin Angiotensin Aldosterone Syst2(2):12-6.
48.
Aksnes, T.A., Seljeflot, I., Torjesen, P.A., Höieggen, A., Moan, A., Kjeldsen, S.E. ( 2007) Improved insulin sensitivity by the angiotensin II receptor blocker losartan is not explained by adipokines, inflammatory markers, or whole blood viscosity. Metabolism56:1470-7.
49.
Kim, S., Soltani-Bejnood, M., Quignard-Boulange, A., Massiera, F., Teboul, M., Ailhaud, G. ( 2006) The adipose Renin-Angiotensin system modulates systemic markers of insulin sensitivity and activates the intrarenal Renin-Angiotensin system. J Biomed Biotechnol2006:27012.
50.
Massiéra, F., Bloch-Faure, M., Ceiler, D., Murakami, K., Fukamizu, A., Gasc, J.M. (2001) Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. FASEB J15:2727-9.
51.
Jones, B.H. , Standridge, M.K., Moustaid, N. (1997) Angiotensin II increases lipogenesis in 3T3-L1 and human adipose cells. Endocrinology138:1512-9.
52.
Sugimoto, K. , Qi, N.R., Kazdová , L., Pravenec, M., Ogihara, T., Kurtz, T.W. (2006) Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis. Hypertension47:1003-9.
53.
Crandall, D.L. , Herzlinger, H.E., Saunders, B.D., Armellino, D.C., Kral, J.G. (1994) Distribution of angiotensin II receptors in rat and human adipocytes. J Lipid Res35:1378-85.
54.
Way, J.M. , Görgün , C.Z., Tong, Q., et al. (2001) Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. J Biol Chem276:25651-3.
55.
Rajala, M.W. , Qi, Y., Patel, H.R., Takahashi, N., Banerjee, R., Pajvani, U.B. (2004) Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes53:1671-9.
56.
Krusinová, E., Klementová , M., Kopecký, J., et al. ( 2007) Effect of acute hyperinsulinaemia with and without angiotensin II type 1 receptor blockade on resistin and adiponectin concentrations and expressions in healthy subjects. Eur J Endocrinol157:443-9.
57.
Erbe, D.V., Gartrell, K., Zhang, Y.L., et al. (2006) Molecular activation of PPARgamma by angiotensin II type 1-receptor antagonists. Vascul Pharmacol45(3):154-62.
58.
Ahima, R.S. , Osei, S.Y. (2008) Adipokines in obesity . Front Horm Res36:182-97.
59.
Delporte, M.L. , El Mkadem, S.A., Quisquater, M., Brichard, S.M. (2004) Leptin treatment markedly increased plasma adiponectin but barely decreased plasma resistin of ob/ob mice. Am J Physiol Endocrinol Metab287:E446-53.
