Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lepob/ob mice
Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lepob/ob mice
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DOI：
10.1074/jbc.m310985200
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发表时间：
2004-04-09
影响因子：
4.8
通讯作者：
Ishibashi, S
中科院分区：
文献类型：
--
作者：
Sekiya, M;Osuga, JI;Ishibashi, S
激素敏感脂肪酶（HSL）在包括脂肪组织在内的多种组织中对甘油三酯和胆固醇酯的水解起着至关重要的作用。为了探索HSL在脂肪和碳水化合物代谢中的作用，我们通过将HSL-/-小鼠与遗传性肥胖的Lep（ob/ob）小鼠杂交来产生同时缺乏瘦素和HSL的小鼠（Lep（ob/ob）/HSL-/-）。出乎意料的是，Lep（ob/ob）/ HSL-/-小鼠比Lep（ob/ob）/HSL+/+小鼠进食更少，体重增加更少，并且具有更低的肥胖。Lep（ob/ob）/ HSL-/-小鼠在白色脂肪组织中有大量前脂肪细胞积聚，前脂肪细胞特异性基因表达增加（CAAT/增强子结合蛋白β和脂肪分化相关蛋白）和成熟脂肪细胞特征性基因表达降低（CCAAT/增强子结合蛋白α，过氧化物酶体增殖物激活物受体γ，和脂肪细胞决定和分化因子1/固醇调节元件结合蛋白-1）。与食物摄入量减少一致，下丘脑神经肽Y和刺豚鼠相关肽的表达减少。由于HSL是在下丘脑中表达，我们推测，由于缺乏HSL介导的这些食欲神经肽的表达改变，在下丘脑中的游离脂肪酸的缺陷产生。因此，瘦素和HSL的缺乏揭示了HSL在脂肪形成以及摄食行为中的新作用。
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.