The therapeutic application of lipolytic machinery to obesity and its related disorders

激素敏感脂肪酶(HSL)在包括脂肪组织在内的各种组织中对三酰甘油(TG)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^&lt；-/-&gt；小鼠与遗传性肥胖的Lep^&lt；ob/ob&gt；小鼠杂交，产生了同时缺乏瘦素和HSL的小鼠(Lep^&lt；ob/ob&gt；/Hsl^&lt；-1-&gt；)。出乎意料的是，与Lep^&lt；ob/ob&gt；/HSL^&lt；+/+&gt；小鼠相比，Lep^&lt；ob/ob&gt；/HSL^&lt；-/-&gt；小鼠吃的食物更少，体重增加更少，肥胖度也更低。小鼠在白色脂肪组织(WAT)中有大量的前脂肪细胞积聚，前脂肪细胞特异性基因(C/EBPβ和ADRP)的表达增加，成熟脂肪细胞的特征基因(C/EBPα、PPARγ和ADD-1/SREBP-1)的表达降低。与进食量减少相一致的是，下丘脑神经肽Y(NPY)和刺鼠相关肽(AgRP)的表达减少。由于HSL在下丘脑中表达，我们推测由于缺乏HSL导致下丘脑中游离脂肪酸的生成缺陷，从而介导了这些促食欲素神经肽的表达变化。因此，瘦素和HSL的缺乏揭示了HSL在脂肪形成和摄食行为中的新作用。

Hormone-sensitive lipase (HSL) plays a crucial role in the hydrolysis of triacylglycerol (TG) 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^<-1->) by crossbreeding 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 (WAT) with increased expression of preadipocyte-specific genes (C/EBPβ and ADRP) and decreased expression of genes characteristic of mature adipocytes (C/EBPα, PPARγ and ADD-1/SREBP-1). Consistent with the reduced food intake, hypothalamic expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) 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.