Absence of Hormone-Sensitive Lipase (HSL) Impaires Adipogenesis and Reduces Obesity in Genetically Obese Mice; the Functions of HSL in Lep^ob/ob Mice

Motohiro Sekiya, Jun-ichi Osuga, Hiroaki Okazaki, Yoshiaki Tamura, Naoya Yahagi, Sachiko Okazaki, Yoko Iizuka, Ken Ohashi, Hitoshi Shimano, Nobuhiro Yamada, Takashi Kadowaki, Shun Ishibashi

Hormone-sensitive lipase (HSL) plays a crucial role in hydrolysis of triacylglycerol and cholesterol ester in various tissues including adipose tissues. HSL null mice, which we and others generated, revealed several functions of HSL in vivo, but the precise functions of this enzyme in obesity remains unclear. Lep^ob/ob mice are the obesity model mice induced by the genetical leptin deficiency. Here we show that mice lacking both leptin and HSL weighed less and had decreased white adipose tissue (WAT) weight (weight reduction by 26%). Histological analysis showed massive accumulation of preadipocytes in the WAT of Lep^ob/ob-HSL-/-, which were immunohistochemically positive in S-100 stain. As to the gene expression profile, late adipocyte differentiation markers were reduced such as PPAR��, C/EBP��, FAS and SREBP-1 (ADD1) and early markers were upregulated such as C/EBP�� and ADRP. TUNEL staininig/DNA ladder detection and BrdU incorporation study showed that the contribution of apoptosis was little and the proliferative activity of the preadipocytes was also nearly little. These indicated HSL deficiency inhibits adipocyte differentiation in especially obese model. Furthermore, Lep^ob/ob-HSL-/- ate less food than Lep^ob/ob mice and the hypothalamic expression of orexigenic peptides were decreased such as NPY and AgRP although anorexigenic POMC was not changed. In addition, HSL deficient Lep^ob/ob mice had hypoinsulinemic hyperglycemia in a fed state. We also confirmed impaired glucose stimulated insulin secretion in pancreatic islets by the collagenase digested isolation. Lipid extraction revealed accumulation of triglyceride in Lep^ob/ob-HSL-/- islets although no triglyceride accumulation was identified in Lep^+/+-HSL-/-. The leptin and HSL double mutant mice unmasked several functions of HSL in obesity and metabolic diseases.