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J. Biol. Chem., Vol. 279, Issue 15, 15084-15090, April 9, 2004

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Absence of Hormone-sensitive Lipase Inhibits Obesity and Adipogenesis in Lep^ob/ob Mice^*

Motohiro Sekiya, Jun-ichi Osuga, Hiroaki Okazaki, Naoya Yahagi, Kenji Harada, Wen-Jun Shen, Yoshiaki Tamura, Sachiko Tomita, Yoko Iizuka, Ken Ohashi, Mitsuyo Okazaki¶, Masataka Sata||, Ryozo Nagai||, Toshiro Fujita, Hitoshi Shimano**, Fredric B. Kraemer, Nobuhiro Yamada**, and Shun Ishibashi

From the Departments of Metabolic Diseases and ^||Cardiovascular Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan, Veterans Affairs Palo Alto Health Care System and Division of Endocrinology, Stanford University, Palo Alto, California 94304, the ^¶Laboratory of Chemistry, College of Liberal Arts and Sciences, Tokyo Medical and Dental University, Chiba 272-0827, Japan, ^**Metabolism, Endocrinology, and Atherosclerosis, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan, and the Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, Tochigi 329-0498, Japan

Hormone-sensitive lipase (HSL) plays a crucial role in the hydrolysis of triacylglycerol and cholesteryl ester in various tissues including adipose tissues. To explore the role of HSL in the metabolism of fat and carbohydrate, we have generated mice lacking both leptin and HSL (Lep^ob/ob/HSL^-/-) by cross-breeding HSL^-/- mice with genetically obese Lep^ob/ob mice. Unexpectedly, Lep^ob/ob/HSL^-/- mice ate less food, gained less weight, and had lower adiposity than Lep^ob/ob/HSL^+/+ mice. Lep^ob/ob/HSL^-/- mice had massive accumulation of preadipocytes in white adipose tissues with increased expression of preadipocyte-specific genes (CAAT/enhancer-binding protein and adipose differentiation-related protein) and decreased expression of genes characteristic of mature adipocytes (CCAAT/enhancer-binding protein , peroxisome proliferator activator receptor , and adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1). Consistent with the reduced food intake, hypothalamic expression of neuropeptide Y and agouti-related peptide was decreased. Since HSL is expressed in hypothalamus, we speculate that defective generation of free fatty acids in the hypothalamus due to the absence of HSL mediates the altered expression of these orexigenic neuropeptides. Thus, deficiency of both leptin and HSL has unmasked novel roles of HSL in adipogenesis as well as in feeding behavior.

Received for publication, October 6, 2003 , and in revised form, December 28, 2003.

^* This work was supported in part by grant-in-aid for Scientific Research from the Ministry of Education, Science, and Culture and research grants from Otsuka Pharmaceutical Co., Japan Diabetes Foundation, Takeda Medical Research Foundation, and Asahi Life Foundation. 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.

To whom correspondence should be addressed: Division of Endocrinology and Metabolism, Dept. of Medicine, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi-machi, Kawachi-gun, Tochigi 329-0498, Japan. Tel.: 81-285-58-7355; Fax: 81-285-40-6035; E-mail: ishibash{at}jichi.ac.jp.

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