Fat storage in adipocytes requires inactivation of leptin's paracrine activity: Implications for treatment of human obesity
Fat storage in adipocytes requires inactivation of leptin's paracrine activity: Implications for treatment of human obesity
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DOI：
10.1073/pnas.0509001102
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发表时间：
2005-12-13
影响因子：
11.1
通讯作者：
Unger, RH
中科院分区：
文献类型：
--
作者：
Wang, MY;Orci, L;Unger, RH
高瘦素血症快速消耗瘦大鼠脂肪细胞脂肪，而饮食诱导的肥胖症中脂肪细胞产生的类似高瘦素血症则不会，这意味着营养过剩期间脂肪细胞中的瘦素能阻滞。事实上，正常大鼠白色脂肪组织（WAT）中激活的STAT-3在60%高脂饮食（HFD）中比在4%脂肪中更少，尽管血浆瘦素高10倍。在6天的HFD，mRNA的受体后瘦素抑制剂，抑制细胞因子信号传导-3，增加22倍，WAT，而瘦素受体（Lepr-b）mRNA逐渐消失，这意味着在受体后和受体水平的瘦素阻滞。Lepr-b转基因的脂肪细胞特异性Lepr-b过表达完全阻止了HFD诱导的野生型小鼠脂肪细胞肥大和增生以及体脂增加。活化的STAT-3和AMP-活化蛋白激酶（AMPK），以及脂氧化酶、过氧化物酶体增殖物激活受体-γ-共激活因子-1 α和解偶联蛋白-1和2的mRNA在WAT中增加。转基因小鼠的体温升高，表明过剩脂肪酸的非偶联脂肪酸氧化。总之，多余的热量储存在WAT和饮食诱导的肥胖症的发展需要一个潜在的瘦素刺激的热量库在白色脂肪细胞的封锁。
Hyperleptinemia rapidly depletes adipocyte fat in lean rats, whereas comparable hyperleptinemia produced by adipocytes in diet-induced obesity does not, implying a leptinergic blockade in adipocytes during overnutrition. Indeed, activated STAT-3 in white adipose tissue (WAT) of normal rats was less on a 60% high fat diet (HFD) than on 4% fat, despite a 10-fold higher plasma leptin. In 6 days of a HFD, mRNA of the postreceptor leptin inhibitor, suppressor of cytokine signaling-3, increased 22-fold in WAT, while leptin receptor (Lepr-b) mRNA gradually disappeared, implying leptinergic blockade at both postreceptor and receptor levels. Adipocyte-specific Lepr-b overexpression of a Lepr-b transgene completely prevented the adipocyte hypertrophy and hyperplasia and the increase in body fat induced in wild-type mice by HFD. Activated STAT-3 and AMP-activated protein kinase (AMPK), and the mRNA of lipooxidative enzymes, peroxisome proliferator-activated receptor-gamma-coactivator-1 alpha, and uncoupling protein-1 and -2 were increased in WAT. Body temperature was elevated in the transgenic mice, suggesting uncoupled fatty acid oxidation of surplus fatty acids. In conclusion, storage of surplus calories in WAT and the development of diet-induced obesity require the blockade of a latent leptin-stimulated caloric sump in white adipocytes.