JOURNAL ARTICLE

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, Shun Ishibashi
Journal of Biological Chemistry 2004 April 9, 279 (15): 15084-90
14752112
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 beta and adipose differentiation-related protein) and decreased expression of genes characteristic of mature adipocytes (CCAAT/enhancer-binding protein alpha, peroxisome proliferator activator receptor gamma, 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.

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