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J. Biol. Chem., Vol. 282, Issue 32, 23672-23678, August 10, 2007

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High Circulating Leptin Receptors with Normal Leptin Sensitivity in Liver-specific Insulin Receptor Knock-out (LIRKO) Mice^*

Shmuel E. Cohen¹, Efi Kokkotou¹², Sudha B. Biddinger, Tatsuya Kondo, Rolf Gebhardt^¶, Juergen Kratzsch^||, Christos S. Mantzoros, and C. Ronald Kahn³

From the Joslin Diabetes Center, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, the ^¶Institute of Biochemistry, University of Leipzig, D-04103 Leipzig, Germany, and the ^||Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, University Hospital, D-04103 Leipzig, Germany

Liver-specific insulin receptor knock-out (LIRKO) mice display hyperinsulinemia, abnormal glucose metabolism, and progressive liver dysfunction. In addition, circulating leptin levels appear to be increased more than 10-fold. However, food intake, body weight, and adipose mass are not significantly altered in LIRKO mice compared with wild-type littermates. Using a ligand immunofunctional assay, we found that the apparent increase in circulating leptin in LIRKO mice is because of an 80-fold increased serum level of soluble leptin receptor. Gene expression analysis by microarray and real time PCR reveals the liver as the source of soluble leptin receptor in LIRKO mice, with an increase in expression of the short (Ob-Ra), long (Ob-Rb), and soluble (Ob-Re) forms of the leptin receptor. Direct control of leptin receptor expression by insulin could also be demonstrated in isolated hepatocytes from normal mice. Despite the markedly increased levels of leptin receptor in their circulation, LIRKO mice exhibit normal or even enhanced leptin sensitivity, as assessed by their physiological and molecular responses to exogenous leptin administration and their lower base-line hypothalamic levels of SOCS3 mRNA. Thus, insulin signaling in the liver plays an important role in control of leptin receptor expression and shedding. In the LIRKO mouse, this is lost, leading to markedly increased leptin receptors into the circulation. These high levels of circulating leptin receptor bind leptin and likely alter its clearance, but do not inhibit leptin action and may actually potentiate leptin action. In this manner, insulin signaling in liver plays an important role in leptin homeostasis and fine modulation of leptin action.

Received for publication, May 16, 2007 , and in revised form, June 1, 2007.

^* This work was supported by National Institutes of Health Grants DK31036 and DK33201, the Joslin Diabetes and Endrocrinology Research Center, the Iacocca Foundation (to C. R. K.), and National Institutes of Health Grant NIDDK RO1-58785 (to C. S. M.). 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 Both authors contributed equally to this work.

² Supported by the Harvard Clinical Nutrition Research Center Pilot and Feasibility Project P30-DK040561.

³ To whom correspondence should be addressed: Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Tel.: 617-732-2635; Fax: 617-732-2593; E-mail: c.ronald.kahn{at}joslin.harvard.edu.

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