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J. Biol. Chem., Vol. 278, Issue 46, 45638-45650, November 14, 2003

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Adipocyte-selective Reduction of the Leptin Receptors Induced by Antisense RNA Leads to Increased Adiposity, Dyslipidemia, and Insulin Resistance^*

Jing-Ning Huan, Ji Li, Yiping Han, Ke Chen, Nancy Wu, and Allan Z. Zhao¶

From the Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 and the Department of Biochemistry, University of Southern California, Norris Cancer Research Institute, Los Angeles, California 90033

Although recent evidence suggests that leptin can directly regulate a wide spectrum of peripheral functions, including fat metabolism, genetic examples are still needed to illustrate the physiological significance of direct actions of leptin in a given peripheral tissue. To this end, we used a technical knock-out approach to reduce the expression of leptin receptors specifically in white adipose tissue. The evaluation of leptin receptor reduction in adipocytes was based on real time PCR analysis of the mRNA levels, Western blot analysis of the proteins, and biochemical analysis of leptin signaling capability. Despite a normal level of leptin receptors in the hypothalamus and normal food intake, mutant mice developed increased adiposity, decreased body temperature, hyperinsulinemia, hypertriglyceridemia, impaired glucose tolerance and insulin sensitivity, as well as elevated hepatic and skeletal muscle triglyceride levels. In addition, a variety of genes involved in regulating fat and glucose metabolism were dysregulated in white adipose tissue. These include tumor necrosis factor-, adiponectin, leptin, fatty acid synthase, sterol regulatory element-binding protein 1, glycerol kinase, and ₃-adrenergic receptor. Furthermore, the mutant mice are significantly more sensitive to high fat feeding with regard to developing obesity and severe insulin resistance. Thus, we provide a genetic model demonstrating the physiological importance of a peripheral effect of leptin in vivo. Importantly, this suggests the possibility that leptin resistance at the adipocyte level might be a molecular link between obesity and type 2 diabetes.

Received for publication, April 21, 2003 , and in revised form, August 8, 2003.

^* This work was supported by a career development award from the American Diabetes Association, by a pilot and feasibility grant from the Obesity and Nutrition Research Center, and by a competitive medical research fund from the School of Medicine at the University of Pittsburgh. 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Data Figs. 1, 2, 3.

^¶ To whom correspondence should be addressed: Department of Cell Biology and Physiology, University of Pittsburgh, S-326, 3500 Terrace St., Pittsburgh, PA 15261. E-mail: azhao{at}pitt.edu.

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