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

被引:132
作者
Ye, JM
Iglesias, MA
Watson, DG
Ellis, B
Wood, L
Jensen, PB
Sorensen, RV
Larsen, PJ
Cooney, GJ
Wassermann, K
Kraegen, EW
机构
[1] Garvan Inst Med Res, Diabet & Obes Program, Sydney, NSW 2010, Australia
[2] Rheosci, DK-2100 Copenhagen, Denmark
[3] Novo Nordisk AS, DK-2760 Malov, Denmark
来源
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 2003年 / 284卷 / 03期
关键词
peroxisome proliferator-activated receptor subtypes; adipokines; tissue lipids; insulin resistance;
D O I
10.1152/ajpendo.00299.2002
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma 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 PPARalpha/gamma agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPARalpha agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPARgamma 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 adiponeictin 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 PPARalpha/gamma agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPARgamma ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPARalpha activation, but without hepatomegaly.
引用
收藏
页码:E531 / E540
页数:10
相关论文
共 49 条
[1]   Activators of peroxisome proliferator-activated receptor γ have depot-specific effects on human preadipocyte differentiation [J].
Adams, M ;
Montague, CT ;
Prins, JB ;
Holder, JC ;
Smith, SA ;
Sanders, L ;
Digby, JE ;
Sewter, CP ;
Lazar, MA ;
Chatterjee, VKK ;
O'Rahilly, S .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (12) :3149-3153
[2]   Molecular or pharmacologic perturbation of the link between glucose and lipid metabolism is without effect on glucose-stimulated insulin secretion - A re-evaluation of the long-chain acyl-CoA hypothesis [J].
Antinozzi, PA ;
Segall, L ;
Prentki, M ;
McGarry, JD ;
Newgard, CB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (26) :16146-16154
[3]   Dehydroepiandrosterone suppresses the elevated hepatic glucose-6-phosphatase and fructose-1,6-bisphosphatase activities in C57BL/Ksj-db/db mice -: Comparison with troglitazone [J].
Aoki, K ;
Saito, T ;
Satoh, S ;
Mukasa, K ;
Kaneshiro, M ;
Kawasaki, S ;
Okamura, A ;
Sekihara, H .
DIABETES, 1999, 48 (08) :1579-1585
[4]   Surgical removal of visceral fat reverses hepatic insulin resistance [J].
Barzilai, N ;
She, L ;
Liu, BQ ;
Vuguin, P ;
Cohen, P ;
Wang, JL ;
Rossetti, L .
DIABETES, 1999, 48 (01) :94-98
[5]   The adipocyte-secreted protein Acrp30 enhances hepatic insulin action [J].
Berg, AH ;
Combs, TP ;
Du, XL ;
Brownlee, M ;
Scherer, PE .
NATURE MEDICINE, 2001, 7 (08) :947-953
[6]   Novel peroxisome proliferator-activated receptor (PPAR) γ and PPARδ ligands produce distinct biological effects [J].
Berger, J ;
Leibowitz, MD ;
Doebber, TW ;
Elbrecht, A ;
Zhang, B ;
Zhou, GC ;
Biswas, C ;
Cullinan, CA ;
Hayes, NS ;
Li, Y ;
Tanen, M ;
Ventre, J ;
Wu, MS ;
Berger, GD ;
Mosley, R ;
Marquis, R ;
Santini, C ;
Sahoo, SP ;
Tolman, RL ;
Smith, RG ;
Moller, DE .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (10) :6718-6725
[7]  
BLIGH EG, 1959, CAN J BIOCHEM PHYS, V37, P911
[8]   Abdominal fat and insulin resistance in normal and overweight women - Direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM [J].
Carey, DG ;
Jenkins, AB ;
Campbell, LV ;
Freund, J ;
Chisholm, DJ .
DIABETES, 1996, 45 (05) :633-638
[9]   RAPID METHOD FOR DETERMINATION OF GLYCOGEN CONTENT AND RADIOACTIVITY IN SMALL QUANTITIES OF TISSUE OR ISOLATED HEPATOCYTES [J].
CHAN, TM ;
EXTON, JH .
ANALYTICAL BIOCHEMISTRY, 1976, 71 (01) :96-105
[10]   Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight [J].
Chaput, E ;
Saladin, R ;
Silvestre, M ;
Edgar, AD .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2000, 271 (02) :445-450