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

脂肪分解机制在肥胖及其相关疾病中的治疗应用

• 批准号: 15590930
• 负责人: OSUGA Jun-ichi
• 金额: $ 2.24万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590930/
• 关键词: lipase; adipocyte; obesity; ホルモン感受性リパーゼ; トリグリセリド

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.

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（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^<-/->小鼠与遗传性肥胖的Lep^<ob/ob>小鼠杂交，产生了既缺乏瘦素又缺乏HSL （Lep^<ob/ob>/HSL^<-1->）的小鼠。出乎意料的是，Lep^<ob/ob>/HSL^<-/->小鼠比Lep^<ob/ob>/HSL^<+/+>小鼠吃得更少，体重增加更少，肥胖更低。Lep^<ob/ob>/HSL^<-/->小鼠在白色脂肪组织（WAT）中大量积累前脂肪细胞，前脂肪细胞特异性基因（C/EBPβ和ADRP）表达增加，成熟脂肪细胞特征基因（C/EBPα、PPARγ和ADD-1/SREBP-1）表达减少。与食物摄取量减少一致，下丘脑神经肽Y （NPY）和针刺相关肽（AgRP）表达降低。由于HSL在下丘脑中表达，我们推测，由于HSL的缺失，下丘脑中游离脂肪酸的生成缺陷介导了这些产氧神经肽的表达改变。因此，瘦素和HSL缺乏症揭示了HSL在脂肪形成和摄食行为中的新作用。

项目成果

Scavenger receptor expressed by endothelial cells I(SREC-I)mediates the uptake of acetylated low density lipoproteins by macrophagea stimulated with lipopolysaccharide.

内皮细胞表达的清道夫受体 I(SREC-I) 介导脂多糖刺激的巨噬细胞对乙酰化低密度脂蛋白的摄取。

• 发表时间: 2004
• 期刊: J Biol Chem 279(30)
• 作者: Tamura Y;Osuga J;Adachi H;Tozawa R;Takanezawa Y;Ohashi K;Yahagi N;Sekiya M;Okazaki H;Tomita S;Iizuka Y;Koizumi H;Inaba T;Yagyu H;Kamada N;Suzuki H;Shimano H;Kadowaki T;Tsujimoto M;Arai H;Yamada N;Ishibashi S.;Sskiya M;Yahagi N;Tamura Y
• 通讯作者: Tamura Y

Tamura, Yoshiaki: "FEEL-1 and FEEL-2 are endocytic receptors for advanced glycation end products."J Biol Chem. 278(15). 12613-12617 (2003)

Tamura, Yoshiaki：“FEEL-1 和 FEEL-2 是晚期糖基化终产物的内吞受体。”J Biol Chem。

Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice

• DOI: 10.1152/ajpendo.00259.2003
• 发表时间: 2003-12-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
• 影响因子: 5.1
• 作者: Harada, K;Shen, WJ;Kraemer, FB
• 通讯作者: Kraemer, FB

Insulin-independent induction of sterol regulatory element-binding protein-1c expression in the livers of streptozotocin-treated mice

• DOI: 10.2337/diabetes.53.3.560
• 发表时间: 2004-03-01
• 期刊: DIABETES
• 影响因子: 7.7
• 作者: Matsuzaka, T;Shimano, H;Yamada, N
• 通讯作者: Yamada, N

Hormone-sensitive lipase is required for high-density lipoprotein cholesteryl ester-supported adrenal steroidogenesis

• DOI: 10.1210/me.2003-0179
• 发表时间: 2004-03-01
• 期刊: MOLECULAR ENDOCRINOLOGY
• 作者: Kraemer, FB;Shen, WJ;Azhar, S
• 通讯作者: Azhar, S