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PPARα/γ ragaglitazer eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly

journal contribution
posted on 2023-05-17, 13:49 authored by Ye, JM, Miguel IglesiasMiguel Iglesias, Watson, DG, Ellis, B, Wood, L, Jensen, PB, Sorensen, RV, Larsen, PJ, Cooney, GJ, Wassermann, K, Kraegen, EW
Peroxisome proliferator-activated receptor (PPAR)α and PPARγ agonists lower lipid accumulation in muscle and liver by different mechanisms. We investigated whether benefits could be achieved on insulin sensitivity and lipid metabolism by the dual PPARα/γ agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPARα agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPARγ agonist rosiglitazone only slightly lessened liver triglyceride without affecting visceral adiposity. Compared with rosiglitazone or Wy-14643, ragaglitazar showed a much greater effect (79%, P < 0.05) to enhance insulin's suppression of hepatic glucose output. Whereas all three PPAR agonists lowered plasma triglyceride levels and lessened muscle long-chain acyl-CoAs, ragaglitazar and rosiglitazone had greater insulin-sensitizing action in muscle than Wy-14643, associated with a threefold increase in plasma adiponectin levels. There was a significant correlation of lipid content and insulin action in liver and particularly muscle with adiponectin levels (P < 0.01). We conclude that the PPARα/γ agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPARγ ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPARα activation, but without hepatomegaly.

History

Publication title

American Journal of Physiology: Endocrinology and Metabolism

Volume

284

Pagination

E531-540

ISSN

0193-1849

Department/School

School of Health Sciences

Publisher

Amer Physiological Soc

Place of publication

9650 Rockville Pike, Bethesda, USA, Md, 20814

Rights statement

Copyright 2003 the American Physiological Society

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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