Candesartan cilexetil prevents diet‑induced insulin resistance via peroxisome proliferator‑activated receptor‑γ activation in an obese rat model

Yan,Wen‑Hua; Pan,Chang‑Yu; Dou,Jing‑Tao; Meng,Jun‑Hua; Wang,Bao‑An; Mu,Yi‑Ming

doi:10.3892/etm.2016.3297

Candesartan cilexetil prevents diet‑induced insulin resistance via peroxisome proliferator‑activated receptor‑γ activation in an obese rat model

Authors:
- Wen‑Hua Yan
- Chang‑Yu Pan
- Jing‑Tao Dou
- Jun‑Hua Meng
- Bao‑An Wang
- Yi‑Ming Mu
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Affiliations: Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
Published online on: April 27, 2016 https://doi.org/10.3892/etm.2016.3297
Pages: 272-278
Copyright: © Yan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Angiotensin II type 1 receptor (AT1R) blockers (ARBs) have been shown to reduce the incidence of type 2 diabetes mellitus; however, the underlying molecular mechanism is unknown. Peroxisome proliferator‑activated receptor γ (PPARγ) is the central regulator of insulin and glucose metabolism, which improves insulin sensitivity. Whether candesartan cilexetil, as a prodrug of the AT1R blocker candesartan, has PPARγ‑activating properties remains to be elucidated. The aim of the present study was to investigate the effects of oral administration of candesartan cilexetil on glucose tolerance and the actions of PPARγ on liver and adipose tissue in the insulin‑resistant obese rat induced by high‑fat diet. Animals treated with candesartan cilexetil showed an improved glucose tolerance after oral glucose challenge. Whole‑body insulin sensitivity was evaluated using the hyperinsulinemic‑euglycemic clamp technique. During high‑fat feeding in high‑fat diet (HF) rats, the glucose infusion rate (GIR) was 52.3% lower than that in normal chow (NC) rats. However, the GIR was significantly enhanced following candesartan cilexetil treatment. Angiotensin II receptor antagonism also resulted in significant increases in PPARγ protein expression in adipose and liver tissue. These results indicate that PPARγ activation by candesartan cilexetil may provide novel therapeutic options in the treatment of patients with metabolic syndrome.

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1.	Neutel JM: Choosing among renin-angiotensin system blockers for the management of hypertension: From pharmacology to clinical efficacy. Curr Med Res Opin. 26:213–222. 2010. View Article : Google Scholar : PubMed/NCBI
2.	Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, et al: LIFE Study Group: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet. 359:995–1003. 2002. View Article : Google Scholar : PubMed/NCBI
3.	Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, et al: VALUE Study Group: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomised trial. Lancet. 363:2022–2231. 2004. View Article : Google Scholar : PubMed/NCBI
4.	Lindholm LH, Ibsen H, Borch-Johnsen K, Olsen MH, Wachtell K, Dahlöf B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, et al: LIFE Study Group: Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens. 20:1879–1886. 2002. View Article : Google Scholar : PubMed/NCBI
5.	Clasen R, Schupp M, Foryst-Ludwig A, Sprang C, Clemenz M, Krikov M, Thöne-Reineke C, Unger T and Kintscher U: PPARgamma-activating angiotensin type-1 receptor blockers induce adiponectin. Hypertension. 46:137–143. 2005. View Article : Google Scholar : PubMed/NCBI
6.	Higgins LS and Depaoli AM: Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulation as a strategy for safer therapeutic PPARgamma activation. Am J Clin Nutr. 91:267S–272S. 2010. View Article : Google Scholar : PubMed/NCBI
7.	Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, Qi N, Wang J, Avery MA and Kurtz TW: Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension. 43:993–1002. 2004. View Article : Google Scholar : PubMed/NCBI
8.	Schupp M, Janke J, Clasen R, Unger T and Kintscher U: Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation. 109:2054–2057. 2004. View Article : Google Scholar : PubMed/NCBI
9.	Henriksen EJ, Jacob S, Kinnick TR, Teachey MK and Krekler M: Selective angiotensin II receptor antagonism reduces insulin resistance in obese Zucker rats. Hypertension. 38:884–890. 2001. View Article : Google Scholar : PubMed/NCBI
10.	Li GW and Pan XR: A new insulin-sensitivity index for the population-based study. Zhonghua Nei Ke Za Zhi. 32:656–660. 1993.(In Chinese). PubMed/NCBI
11.	Sridhar MG, Vinayagamoorthi R, Arul Suyambunathan V, Bobby Z and Selvaraj N: Bitter gourd (Momordica charantia) improves insulin sensitivity by increasing skeletal muscle insulin-stimulated IRS-1 tyrosine phosphorylation in high-fat-fed rats. Br J Nutr. 99:806–812. 2008. View Article : Google Scholar : PubMed/NCBI
12.	Allison DB, Paultre F, Maggio C, Mezzitis N and Pi-Sunyer FX: The use of areas under curves in diabetes research. Diabetes Care. 18:245–250. 1995. View Article : Google Scholar : PubMed/NCBI
13.	Cheung A and Bryer-Ash M: Modified method for the performance of glucose insulin clamp studies in conscious rats. J Pharmacol Toxicol Methods. 31:215–220. 1994. View Article : Google Scholar : PubMed/NCBI
14.	Kump DS and Booth FW: Sustained rise in triacylglycerol synthesis and increased epididymal fat mass when rats cease voluntary wheel running. J Physiol. 565:911–925. 2005. View Article : Google Scholar : PubMed/NCBI
15.	Matsuda M and DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing: Comparison with the euglycemic insulin clamp. Diabetes Care. 22:1462–1470. 1999. View Article : Google Scholar : PubMed/NCBI
16.	Burnier M and Brunner HR: Angiotensin II receptor antagonists. Lancet. 355:637–645. 2000. View Article : Google Scholar : PubMed/NCBI
17.	Tuncer I, Ozbek H, Ugras S and Bayram I: Anti-fibrogenic effects of captopril and candesartan cilexetil on the hepatic fibrosis development in rat. The effect of AT1-R blocker on the hepatic fibrosis. Exp Toxicol Pathol. 55:159–166. 2003. View Article : Google Scholar : PubMed/NCBI
18.	Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B and Ostergren J: CHARM Investigators and Committees: Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved trial. Lancet. 362:777–781. 2003. View Article : Google Scholar : PubMed/NCBI
19.	Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA and Swedberg K: CHARM Investigators and Committees: Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet. 362:772–776. 2003. View Article : Google Scholar : PubMed/NCBI
20.	McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S and Pfeffer MA: CHARM Investigators and Committees: Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: The CHARM-Added trial. Lancet. 362:767–771. 2003. View Article : Google Scholar : PubMed/NCBI
21.	Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P and Zanchetti A: SCOPE Study Group: The Study on cognition and prognosis in the elderly (SCOPE): Principal results of a randomized double-blind intervention trial. J Hypertens. 21:875–886. 2003. View Article : Google Scholar : PubMed/NCBI
22.	Grassi G, Seravalle G, Dell'Oro R, Trevano FQ, Bombelli M, Scopelliti F, Facchini A and Mancia G: CROSS Study: Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity and sympathetic drive in obese hypertensive individuals: Results of the CROSS study. J Hypertens. 21:1761–1769. 2003. View Article : Google Scholar : PubMed/NCBI
23.	Lindholm LH, Persson M, Alaupovic P, Carlberg B, Svensson A and Samuelsson O: Metabolic outcome during 1 year in newly detected hypertensives: Results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy evaluation (ALPINE study). J Hypertens. 21:1563–1574. 2003. View Article : Google Scholar : PubMed/NCBI
24.	Kinnick TR, Youngblood EB, O'Keefe MP, Saengsirisuwan V, Teachey MK and Henriksen EJ: Modulation of insulin resistance and hypertension by voluntary exercise training in the TG(mREN2)27 rat. J Appl Physiol (1985). 93:805–812; discussion 797. 2002. View Article : Google Scholar : PubMed/NCBI
25.	Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, O'Rahilly S, et al: International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol Rev. 58:726–741. 2006. View Article : Google Scholar : PubMed/NCBI
26.	Balakumar P, Rose M and Singh M: PPAR ligands: Are they potential agents for cardiovascular disorders? Pharmacology. 80:1–10. 2007. View Article : Google Scholar : PubMed/NCBI
27.	Kersten S, Desvergne B and Wahli W: Roles of PPARs in health and disease. Nature. 405:421–424. 2000. View Article : Google Scholar : PubMed/NCBI
28.	Spiegelman BM: PPAR-gamma: Adipogenic regulator and thiazolidinedione receptor. Diabetes. 47:507–514. 1998. View Article : Google Scholar : PubMed/NCBI
29.	Kurtz TW: Treating the metabolic syndrome: Telmisartan as a peroxisome proliferator-activated receptor-gamma activator. Acta Diabetol. 42(Suppl 1): S9–S16. 2005. View Article : Google Scholar : PubMed/NCBI
30.	Morsing P, Adler G, Brandt-Eliasson U, Karp L, Ohlson K, Renberg L, Sjöquist PO and Abrahamsson T: Mechanistic differences of various AT1-receptor blockers in isolated vessels of different origin. Hypertension. 33:1406–1413. 1999. View Article : Google Scholar : PubMed/NCBI
31.	Koh KK, Quon MJ, Han SH, Chung WJ, Lee Y and Shin EK: Anti-inflammatory and metabolic effects of candesartan in hypertensive patients. Int J Cardiol. 108:96–100. 2006. View Article : Google Scholar : PubMed/NCBI
32.	Frühbeck G, Gómez-Ambrosi J, Muruzábal FJ and Burrell MA: The adipocyte: A model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab. 280:E827–E847. 2001.PubMed/NCBI
33.	Banerjee RR and Lazar MA: Resistin: Molecular history and prognosis. J Mol Med (Berl). 81:218–226. 2003.PubMed/NCBI
34.	Goossens GH, Blaak EE and van Baak MA: Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders. Obes Rev. 4:43–55. 2003. View Article : Google Scholar : PubMed/NCBI
35.	Engeli S, Böhnke J, Gorzelniak K, Janke J, Schling P, Bader M, Luft FC and Sharma AM: Weight loss and the renin-angiotensin-aldosterone system. Hypertension. 45:356–362. 2005. View Article : Google Scholar : PubMed/NCBI
36.	Motley ED, Eguchi K, Gardner C, Hicks AL, Reynolds CM, Frank GD, Mifune M, Ohba M and Eguchi S: Insulin-induced Akt activation is inhibited by angiotensin II in the vasculature through protein kinase C-alpha. Hypertension. 41:775–780. 2003. View Article : Google Scholar : PubMed/NCBI
37.	Furuhashi M, Ura N, Takizawa H, Yoshida D, Moniwa N, Murakami H, Higashiura K and Shimamoto K: Blockade of the renin-angiotensin system decreases adipocyte size with improvement in insulin sensitivity. J Hypertens. 22:1977–1982. 2004. View Article : Google Scholar : PubMed/NCBI
38.	de Gasparo M, Catt KJ, Inagami T, Wright JW and Unger T: International Union of Pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev. 52:415–472. 2000.PubMed/NCBI
39.	Hao GH, Niu XL, Gao DF, Wei J and Wang NP: Agonists at PPAR-gamma suppress angiotensin II-induced production of plasminogen activator inhibitor-1 and extracellular matrix in rat cardiac fibroblasts. Br J Pharmacol. 153:1409–1419. 2008. View Article : Google Scholar : PubMed/NCBI
40.	Sugawara A, Takeuchi K, Uruno A, Ikeda Y, Arima S, Kudo M, Sato K, Taniyama Y and Ito S: Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptor-gamma in vascular smooth muscle cells. Endocrinology. 142:3125–3134. 2001. View Article : Google Scholar : PubMed/NCBI