Telmisartan is the most effective ARB to increase adiponectin via PPARα in adipocytes

in Journal of Molecular Endocrinology
View More View Less
  • 1 Department of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan
  • | 2 Advanced Medical Care Center, Omi Medical Center, Shiga, Japan

Correspondence should be addressed to N Hattori: hattorin@fc.ritsumei.ac.jp
Restricted access

Telmisartan and irbesartan are angiotensin II receptor blockers (ARBs) and reportedly stimulate adiponectin secretion from adipocytes via partial peroxisome proliferator-activated receptor γ (PPARγ) activation. However, quantitative evaluation among different ARBs has not been performed. Adiponectin exerts strong protection against a number of pathological events by suppressing cell death, inhibiting inflammation, and enhancing cell survival, while leptin promotes inflammation, oxidative stress, atherogenesis, and thrombosis. The aim of this study was to identify the most effective ARB enhancing adiponectin secretion without raising leptin secretion from human white adipocytes (HWAs). Among seven ARBs (azilsartan, candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan), telmisartan was the most effective ARB for the increase of adiponectin secretion and irbesartan was the second, whereas the other ARBs at 1 µM had no effect on adiponectin secretion. GW9662, a PPARγ antagonist, completely blocked pioglitazone (PPARγ agonist)-induced adiponectin secretion and mRNA expression, whereas it unexpectedly blocked neither telmisartan- nor irbesartan-induced adiponectin secretion and mRNA expression but rather increased them. GW6471, PPARα antagonist, and siRNA for PPARα suppressed telmisartan- and irbesartan-induced adiponectin secretion, suggesting that PPARα is the main target of these ARBs to increase adiponectin secretion in HWAs. Leptin secretion was not affected by any ARBs at 1 µM and GW9662 significantly decreased the basal secretion of leptin, suggesting that basal leptin secretion is regulated in a PPARγ-dependent manner. We conclude that telmisartan is the most effective ARB to increase adiponectin secretion via PPARα without raising leptin secretion from HWAs.

 

Society for Endocrinology logo

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 366 366 366
Full Text Views 13 13 13
PDF Downloads 17 17 17
  • Adams PT, McElwee MJ, Ehrenborg E, Gustafsson MC, Palmer CN & McLauchlan J 2005 A PPAR response element regulates transcription of the gene for human adipose differentiation-related protein. Biochimica et Biophysica Acta 1728 95104. (https://doi.org/10.1016/j.bbaexp.2005.01.017)

    • Search Google Scholar
    • Export Citation
  • Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, Qi N, Wang J, Avery MA & Kurtz TW 2004 Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARγ-modulating activity. Hypertension 43 9931002. (https://doi.org/10.1161/01.HYP.0000123072.34629.57)

    • Search Google Scholar
    • Export Citation
  • Brody R, Peleg E, Grossman E & Sharabi Y 2009 Production and secretion of adiponectin from 3T3-L1 adipocytes: comparison of antihypertensive drugs. American Journal of Hypertension 22 11261129. (https://doi.org/10.1038/ajh.2009.171)

    • Search Google Scholar
    • Export Citation
  • Chihara K, Hattori N, Ichikawa N, Matsuda T & Saito T 2020 Re-evaluation of serum leptin and adiponectin concentrations normalized by body fat mass in patients with rheumatoid arthritis. Scientific Reports 10 15932. (https://doi.org/10.1038/s41598-020-73068-2)

    • Search Google Scholar
    • Export Citation
  • Clemenz M, Frost N, Schupp M, Caron S, Ludwig AF, Böhm C, Hartge M, Gust R, Staels B & Unger T et al.2008 Liver-specific peroxisome proliferator-activated receptor alpha target gene regulation by the angiotensin type 1 receptor blocker telmisartan. Diabetes 57 14051413. (https://doi.org/10.2337/db07-0839)

    • Search Google Scholar
    • Export Citation
  • Derosa G, Cicero AFG, Angelo AD, Ragonesi PD, Ciccarelli L, Piccinni MN, Pricolo F, Salvadeo SAT, Ferrari I & Gravina A et al.2006 Telmisartan and irbesartan therapy in type 2 diabetic patients treated with rosiglitazone: effects on insulin-resistance, leptin and tumor necrosis factor-alpha. Hypertension Research 29 849856. (https://doi.org/10.1291/hypres.29.849)

    • Search Google Scholar
    • Export Citation
  • Fujino M, Miura SI, Kiya Y, Tominaga Y, Matsuo Y, Karnik SS & Saku K 2010 A small difference in the molecular structure of angiotensin II receptor blockers induces AT1 receptor-dependent and -independent beneficial effects. Hypertension Research 33 10441052. (https://doi.org/10.1038/hr.2010.135)

    • Search Google Scholar
    • Export Citation
  • Gaudreau KB, Rehfeldt C, Blouin R, Bordignon V, Murphy BD & Palin MF 2010 Adiponectin action from head to toe. Endocrine 37 1132. (https://doi.org/10.1007/s12020-009-9278-8)

    • Search Google Scholar
    • Export Citation
  • Hirose H, Kawai T, Yamamoto Y, Taniyama M, Tomita M, Matsubara K, Okazaki Y, Ishii T, Oguma Y & Takei I et al.2002 Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes. Metabolism: Clinical and Experimental 51 314317. (https://doi.org/10.1053/meta.2002.30506)

    • Search Google Scholar
    • Export Citation
  • Hiuge A, Tenenbaum A, Maeda N, Benderly M, Kumada M, Fisman EZ, Tanne D, Matas Z, Hibuse T & Fujita K et al.2007 Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level. Arteriosclerosis, Thrombosis, and Vascular Biology 27 635641. (https://doi.org/10.1161/01.ATV.0000256469.06782.d5)

    • Search Google Scholar
    • Export Citation
  • Imaizumi S, Miura SI, Yahiro E, Uehara Y, Komuro I & Saku K 2013 Class- and molecule-specific differential effects of angiotensin II type 1 receptor blockers. Current Pharmaceutical Design 19 30023008. (https://doi.org/10.2174/1381612811319170005)

    • Search Google Scholar
    • Export Citation
  • Jakob T, Nordmann AJ, Schandelmaier S, Ferreira-González I & Briel M 2016 Fibrates for primary prevention of cardiovascular disease events. Cochrane Database of Systematic Reviews 11 CD009753. (https://doi.org/10.1002/14651858.CD009753.pub2)

    • Search Google Scholar
    • Export Citation
  • Janke J, Engeli S, Gorzelniak K, Luft FC & Sharma AM 2002 Mature adipocytes inhibit in vitro differentiation of human preadipocytes via angiotensin type 1 receptors. Diabetes 51 16991707. (https://doi.org/10.2337/diabetes.51.6.1699)

    • Search Google Scholar
    • Export Citation
  • Katsiki N, Mikhailidis DP & Banach M 2018 Leptin, cardiovascular diseases and type 2 diabetes mellitus. Acta Pharmacologica Sinica 39 11761188. (https://doi.org/10.1038/aps.2018.40)

    • Search Google Scholar
    • Export Citation
  • Leesnitzer LM, Parks DJ, Bledsoe RK, Cobb JE, Collins JL, Consler TG, Davis RG, Hull-Ryde EA, Lenhard JM & Patel L et al.2002 Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry 41 66406650. (https://doi.org/10.1021/bi0159581)

    • Search Google Scholar
    • Export Citation
  • Liu Y, Leri A, Li B, Wang X, Cheng W, Kajstura J & Anversa P 1998 Angiotensin II stimulation in vitro induces hypertrophy of normal and postinfarcted ventricular myocytes. Circulation Research 82 11451159. (https://doi.org/10.1161/01.res.82.11.1145)

    • Search Google Scholar
    • Export Citation
  • Makita S, Abiko A, Naganuma Y, Moriai Y & Nakamura M 2008 Effects of telmisartan on adiponectin levels and body weight in hypertensive patients with glucose intolerance. Metabolism: Clinical and Experimental 57 14731478. (https://doi.org/10.1016/j.metabol.2008.05.019)

    • Search Google Scholar
    • Export Citation
  • Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, Hamnvik OPR & Koniaris A 2011 Leptin in human physiology and pathophysiology. American Journal of Physiology: Endocrinology and Metabolism 301 E567E584. (https://doi.org/10.1152/ajpendo.00315.2011)

    • Search Google Scholar
    • Export Citation
  • Mori Y, Itoh Y & Tajima N 2007 Telmisartan improves lipid metabolism and adiponectin production but does not affect glycemic control in hypertensive patients with type 2 diabetes. Advances in Therapy 24 146153. (https://doi.org/10.1007/BF02850002)

    • Search Google Scholar
    • Export Citation
  • Moriuchi A, Yamasaki H, Shimamura M, Kita A, Kuwahara H, Fujishima K, Satoh T, Fukushima K, Fukushima T & Hayakawa T et al.2007 Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-gamma activation. Biochemical and Biophysical Research Communications 356 10241030. (https://doi.org/10.1016/j.bbrc.2007.03.084)

    • Search Google Scholar
    • Export Citation
  • Müller-Fielitz H, Hübel N, Mildner M, Vogt FM, Barkhausen J & Raasch W 2014 Chronic blockade of angiotensin AT1 receptors improves cardinal symptoms of metabolic syndrome in diet-induced obesity in rats. British Journal of Pharmacology 171 746760. (https://doi.org/10.1111/bph.12510)

    • Search Google Scholar
    • Export Citation
  • Ogihara T, Minami F, Kanuma H, Asai Y, Okada Y, Fukuyo K, Nakamura Y, Osaka A & Tatami S 2002 Pharmacokinetic evaluation of an angiotensin II AT1 receptor antagonist, BIBR277 (telmisartan) in hypertensive patients. Japanese Pharmacology and Therapeutics 30 (Supplement1) S271S283.

    • Search Google Scholar
    • Export Citation
  • Oparil S, Acelajado MC, Bakris GL, Berlowitz DR, Cífková R, Dominiczak AF, Grassi G, Jordan J, Poulter NR & Rodgers A et al.2018 Hypertension. Nature Reviews: Disease Primers 4 18014. (https://doi.org/10.1038/nrdp.2018.14)

    • Search Google Scholar
    • Export Citation
  • Pawlak M, Lefebvre P & Staels B 2015 Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. Journal of Hepatology 62 720733. (https://doi.org/10.1016/j.jhep.2014.10.039)

    • Search Google Scholar
    • Export Citation
  • Sánchez NM 2020 There and back again: leptin actions in white adipose tissue. International Journal of Molecular Sciences 21 6039. (https://doi.org/10.3390/ijms21176039)

    • Search Google Scholar
    • Export Citation
  • Schupp M, Janke J, Clasen R, Unger T & Kintscher U 2004 Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation 109 20542057. (https://doi.org/10.1161/01.CIR.0000127955.36250.65)

    • Search Google Scholar
    • Export Citation
  • Shehzad A, Iqbal W, Shehzad O & Lee YS 2012 Adiponectin: regulation of its production and its role in human diseases. Hormones 11 820. (https://doi.org/10.1007/BF03401534)

    • Search Google Scholar
    • Export Citation
  • Straub LG & Scherer PE 2019 Metabolic messengers: adiponectin. Nature Metabolism 1 334339. (https://doi.org/10.1038/s42255-019-0041-z)

  • Tagami T, Yamamoto H, Moriyama K, Sawai K, Usui T, Shimatsu A & Naruse M 2009 A selective peroxisome proliferator-activated receptor-gamma modulator, telmisartan, binds to the receptor in a different fashion from thiazolidinediones. Endocrinology 150 862870. (https://doi.org/10.1210/en.2008-0502)

    • Search Google Scholar
    • Export Citation
  • Taguchi I, Toyoda S, Takano K, Arikawa T, Kikuchi M, Ogawa M, Abe S, Node K & Inoue T 2013 Irbesartan, an angiotensin receptor blocker, exhibits metabolic, anti-inflammatory and antioxidative effects in patients with high-risk hypertension. Hypertension Research 36 608613. (https://doi.org/10.1038/hr.2013.3)

    • Search Google Scholar
    • Export Citation
  • Tilg H & Moschen AR 2006 Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Reviews: Immunology 6 772783. (https://doi.org/10.1038/nri1937)

    • Search Google Scholar
    • Export Citation
  • Wang ZV & Scherer PE 2016 Adiponectin, the past two decades. Journal of Molecular Cell Biology 8 93100. (https://doi.org/10.1093/jmcb/mjw011)

  • Yamada S, Ano N, Toda K, Kitaoka A, Shiono K, Inoue G, Atsuda K & Irie J 2008 Telmisartan but not candesartan affects adiponectin expression in vivo and in vitro. Hypertension Research 31 601606. (https://doi.org/10.1291/hypres.31.601)

    • Search Google Scholar
    • Export Citation
  • Zhang QZ, Liu YL, Wang YR, Fu LN, Zhang J, Wang XR & Wang BM 2017 Effects of telmisartan on improving leptin resistance and inhibiting hepatic fibrosis in rats with non-alcoholic fatty liver disease. Experimental and Therapeutic Medicine 14 26892694. (https://doi.org/10.3892/etm.2017.4809)

    • Search Google Scholar
    • Export Citation