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J. Biol. Chem., Vol. 278, Issue 36, 34268-34276, September 5, 2003
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Liver Peroxisome Proliferator-activated Receptor 
Contributes to Hepatic Steatosis, Triglyceride Clearance, and Regulation of Body Fat Mass*
||
From the
Diabetes Branch, NIDDK and
¶Laboratory of Metabolism, NCI, National
Institutes of Health, Bethesda, Maryland 20892
Peroxisome proliferator-activated receptor 
(PPAR) is a
nuclear receptor that mediates the antidiabetic effects of thiazolidinediones.
PPAR is present in adipose tissue and becomes elevated in fatty livers,
but the roles of specific tissues in thiazolidinedione actions are unclear. We
studied the function of liver PPAR in both lipoatrophic A-ZIP/F-1
(AZIP) and wild type mice. In AZIP mice, ablation of liver PPAR reduced
the hepatic steatosis but worsened the hyperlipidemia, triglyceride clearance,
and muscle insulin resistance. Inactivation of AZIP liver PPAR also
abolished the hypoglycemic and hypolipidemic effects of rosiglitazone,
demonstrating that, in the absence of adipose tissue, the liver is a primary
and major site of thiazolidinedione action. In contrast, rosiglitazone
remained effective in non-lipoatrophic mice lacking liver PPAR,
suggesting that adipose tissue is the major site of thiazolidinedione action
in typical mice with adipose tissue. Interestingly, mice without liver
PPAR, but with adipose tissue, developed relative fat intolerance,
increased adiposity, hyperlipidemia, and insulin resistance. Thus, liver
PPAR regulates triglyceride homeostasis, contributing to hepatic
steatosis, but protecting other tissues from triglyceride accumulation and
insulin resistance.
Received for publication, January 2, 2003 , and in revised form, April 15, 2003.
* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| Present address: Merck Research Laboratories, Rahway, New Jersey 07065.
To whom correspondence should be addressed: Diabetes Branch, NIDDK, NIH, Bldg.
10, Rm. 8N-250, 10 Center Dr., Bethesda, MD 20892-1770. Tel.: 301-435-5370;
Fax: 301-402-5788; E-mail:
oksanag{at}bdg10.niddk.nih.gov.
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