Adiponectin Concentrations Increase during Acute FFA Elevation in Humans Treated with Rosiglitazone

Abstract

The adipocytokine adiponectin is released by adipocytes upon activation of the peroxisome proliferator-activated receptor γ (PPARγ). PPARγ has binding sites for thiazolidinediones and free fatty acids (FFAs). To evaluate if adiponectin serum concentrations are synergistically regulated by FFAs and thiazolidinediones in vivo plasma FFAs were acutely elevated in healthy subjects pre-treated with rosiglitazone or placebo. Sixteen healthy male subjects (23-37 years) were included in this double-blind, randomized, placebo-controlled parallel-group study. Rosiglitazone 8 mg or placebo was administered daily for 21 days. On the last day plasma FFA concentrations were increased by an intravenous triglyceride/heparin infusion. Blood for determination of adiponectin, C-reactive protein (CRP), leptin, resistin, FFAs, glucose, and insulin was drawn at baseline and on day 21 before and after 5 hours of triglyceride/heparin infusion. Adiponectin concentrations increased and FFA levels decreased in subjects receiving rosiglitazone (all p<0.05 vs. baseline). Lipid infusion significantly increased FFA plasma concentrations, with an attenuated elevation in rosiglitazone-treated subjects. However, adiponectin concentrations were only increased in subjects on rosiglitazone (p=0.018 vs. before lipid infusion), but not in controls. Leptin increased during lipid infusion in subjects receiving placebo but not in those on rosiglitazone. CRP and resistin were not affected by rosiglitazone or FFAs. The acute increase in circulating adiponectin concentrations during acutely elevated FFA depends on PPARγ activation in healthy subjects.

Key words

adiponectin - free fatty acids - peroxisome proliferator-activated receptor γ - CRP - resistin - leptin

References

• 1 Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes.  J Biol Chem. 1995;  270 26746-26749
• 2 Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.  J Clin Endocrinol Metab. 2001;  86 1930-1935
• 3 Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, Chen CL, Tai TY, Chuang LM. Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin.  J Clin Endocrinol Metab. 2001;  86 3815-3819
• 4 Yu JG, Javorschi S, Hevener AL, Kruszynska YT, Norman RA, Sinha M, Olefsky JM. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects.  Diabetes. 2002;  51 2968-2974
• 5 Lihn AS, Pedersen SB, Richelsen B. Adiponectin: action, regulation and association to insulin sensitivity.  Obes Rev. 2005;  6 13-21
• 6 Boden G. Effects of free fatty acids (FFA) on glucose metabolism: significance for insulin resistance and type 2 diabetes.  Exp Clin Endocrinol Diabetes. 2003;  111 121-124
• 7 Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.  Proc Natl Acad Sci USA. 2001;  98 2005-2010
• 8 Bernstein EL, Koutkia P, Ljungquist K, Breu J, Canavan B, Grinspoon S. Acute regulation of adiponectin by free fatty acids.  Metabolism. 2004;  53 790-793
• 9 Staiger H, Tschritter O, Kausch C, Lammers R, Stumvoll M, Haring HU. Human serum adiponectin levels are not under short-term nega-tive control by free fatty acids in vivo.  Horm Metab Res. 2002;  34 601-603
• 10 Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein.  Diabetes. 2001;  50 2094-2099
• 11 Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, Devchand P, Wahli W, Willson TM, Lenhard JM, Lehmann JM. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma.  Proc Natl Acad Sci USA. 1997;  94 4318-4323
• 12 Diagnosis Classification of Diabetes Mellitus.  Diabetes Care. 2004;  27 5S-10S
• 13 Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A, Bayazeed B, Baron AD. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation.  J Clin Invest. 1997;  100 1230-1239
• 14 Boden G, Jadali F, White J, Liang Y, Mozzoli M, Chen X, Coleman E, Smith C. Effects of fat on insulin-stimulated carbohydrate metabolism in normal men.  J Clin Invest. 1991;  88 960-966
• 15 Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans.  J Clin Invest. 1996;  97 2859-2865
• 16 Roden M, Stingl H, Chandramouli V, Schumann WC, Hofer A, Landau BR, Nowotny P, Waldhäusl W, Shulman GI. Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans.  Diabetes. 2000;  49 701-707
• 17 Brame LA, Considine RV, Yamauchi M, Baron AD, Mather KJ. Insulin and endothelin in the acute regulation of adiponectin in vivo in humans.  Obes Res. 2005;  13 582-588
• 18 Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, Dandona P. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects.  Diabetes. 2003;  52 2882-2887
• 19 Dhindsa S, Tripathy D, Sanalkumar N, Ravishankar S, Ghanim H, Aljada A, Dandona P. Free fatty acid-induced insulin resistance in the obese is not prevented by rosiglitazone treatment.  J Clin Endocrinol Metab. 2005;  90 5058-5063
• 20 Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.  Nat Med. 2002;  8 731-737
• 21 Delporte ML, El Mkadem SA, Quisquater M, Brichard SM. Leptin treatment markedly increased plasma adiponectin but barely decreased plasma resistin of ob/ob mice.  Am J Physiol Endocrinol Metab. 2004;  287 E446-E453
• 22 Samaha FF, Szapary PO, Iqbal N, Williams MM, Bloedon LT, Kochar A, Wolfe ML, Rader DJ. Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome.  Arterioscler Thromb Vasc Biol. 2006;  26 624-630
• 23 Ghanim H, Dhindsa S, Aljada A, Chaudhuri A, Viswanathan P, Dandona P. Low-dose rosiglitazone exerts an anti-inflammatory effect with an increase in adiponectin independently of free fatty acid fall and insulin sensitization in obese type 2 diabetics.  J Clin Endocrinol Metab. 2006;  91 3553-3558
• 24 Kim SG, Ryu OH, Kim HY, Lee KW, Seo JA, Kim NH, Choi KM, Lee J, Baik SH, Choi DS. Effect of rosiglitazone on plasma adiponectin levels and arterial stiffness in subjects with prediabetes or non-diabetic metabolic syndrome.  Eur J Endocrinol. 2006;  154 433-440
• 25 Hetzel J, Balletshofer B, Rittig K, Walcher D, Kratzer W, Hombach V, Haring HU, Koenig W, Marx N. Rapid effects of rosiglitazone treatment on endothelial function and inflammatory biomarkers.  Arterioscler Thromb Vasc Biol. 2005;  25 1804-1809

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