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J. Biol. Chem., Vol. 281, Issue 5, 2654-2660, February 3, 2006
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Mice Lacking Adiponectin Show Decreased Hepatic Insulin Sensitivity and Reduced Responsiveness to Peroxisome Proliferator-activated Receptor 
Agonists*
11
**3
From the
Departments of Cell Biology, ||Molecular Pharmacology, **Medicine, Division of Endocrinology, and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, the Department of Medicine, Physiology, and Biophysics and the Diabetes Unit, Boston University Medical Center, Boston, Massachusetts 02118, and ¶Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey 07065
The adipose tissue-derived hormone adiponectin improves insulin sensitivity and its circulating levels are decreased in obesity-induced insulin resistance. Here, we report the generation of a mouse line with a genomic disruption of the adiponectin locus. We aimed to identify whether these mice develop insulin resistance and which are the primary target tissues affected in this model. Using euglycemic/insulin clamp studies, we demonstrate that these mice display severe hepatic but not peripheral insulin resistance. Furthermore, we wanted to test whether the lack of adiponectin magnifies the impairments of glucose homeostasis in the context of a dietary challenge. When exposed to high fat diet, adiponectin null mice rapidly develop glucose intolerance. Specific PPAR
agonists such as thiazolidinediones (TZDs) improve insulin sensitivity by mechanisms largely unknown. Circulating adiponectin levels are significantly up-regulated in vivo upon activation of PPAR. Both TZDs and adiponectin have been shown to activate AMP-activated protein kinase (AMPK) in the same target tissues. We wanted to address whether the ability of TZDs to improve glucose tolerance is dependent on adiponectin and whether this improvement involved AMPK activation. We demonstrate that the ability of PPAR agonists to improve glucose tolerance in ob/ob mice lacking adiponectin is diminished. Adiponectin is required for the activation of AMPK upon TZD administration in both liver and muscle. In summary, adiponectin is an important contributor to PPAR-mediated improvements in glucose tolerance through mechanisms that involve the activation of the AMPK pathway.
Received for publication, May 16, 2005 , and in revised form, October 26, 2005.
* This work was supported in part by National Institutes of Health (NIH) Medical Scientist Training Grant T32-GM07288 (to M. W. R. and U. B. P.), postdoctoral fellowships from the Swiss National Science Foundation and the American Heart Association (to A. R. N.), and NIH Grants R01-HL073163-01 (to Maureen J. Charron), DK 19514, 49147, and HL68758 (to N. R.), and R01-DK55758 (to P. E. S.). 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.
1 These two authors contributed equally to this work.
2 Present address: Sanofi-Aventis, Bridgewater, NJ 08807.
3 To whom correspondence should be addressed: Dept. of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-2928; Fax: 718-430-8574; E-mail: scherer{at}aecom.yu.edu.
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