Low Density Lipoprotein (LDL) Receptor-related Protein 6 (LRP6) Regulates Body Fat and Glucose Homeostasis by Modulating Nutrient Sensing Pathways and Mitochondrial Energy Expenditure
Low Density Lipoprotein (LDL) Receptor-related Protein 6 (LRP6) Regulates Body Fat and Glucose Homeostasis by Modulating Nutrient Sensing Pathways and Mitochondrial Energy Expenditure
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DOI：
10.1074/jbc.m111.286724
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发表时间：
2012-03-02
影响因子：
4.8
通讯作者：
Mani, Arya
中科院分区：
文献类型：
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作者：
Liu, Wenzhong;Singh, Rajvir;Mani, Arya
体脂、胰岛素抵抗和2型糖尿病经常被联系在一起，但将它们联系起来的分子机制却知之甚少。Wnt信号调节脂肪形成，其活性的改变与2型糖尿病和代谢综合征的发病机制有关。与野生型（WT）小鼠相比，高脂肪饮食的LRP6（+/-）小鼠可防止饮食引起的肥胖和肝脏和脂肪组织胰岛素抵抗。棕色脂肪组织胰岛素敏感性和LRP6（+/-）小鼠的脂肪减少是由wnt依赖性mTORC1活性降低和棕色脂肪组织pgc1 - α和UCP1表达增强引起的。LRP6（+/-）小鼠也表现出内源性肝脏葡萄糖输出减少，这是由于关键糖异生酶葡萄糖-6-磷酸酶（G6pase）的fox01依赖性表达减少。此外，体内和体外研究表明，LRP6等位基因的缺失与瘦素受体表达增加有关，这可能是LRP6（+/-）小鼠肝脏胰岛素敏感的原因。我们的研究确定LRP6是体重和葡萄糖代谢的营养敏感调节剂，是肥胖和糖尿病药物干预的潜在靶点。
Body fat, insulin resistance, and type 2 diabetes are often linked together, but the molecular mechanisms that unify their association are poorly understood. Wnt signaling regulates adipogenesis, and its altered activity has been implicated in the pathogenesis of type 2 diabetes and metabolic syndrome. LRP6(+/-) mice on a high fat diet were protected against diet-induced obesity and hepatic and adipose tissue insulin resistance compared with their wild-type (WT) littermates. Brown adipose tissue insulin sensitivity and reduced adiposity of LRP6(+/-) mice were accounted for by diminished Wnt-dependent mTORC1 activity and enhanced expression of brown adipose tissue PGC1-alpha and UCP1. LRP6(+/-) mice also exhibited reduced endogenous hepatic glucose output, which was due to diminished FoxO1-dependent expression of the key gluconeogenic enzyme glucose-6-phosphatase (G6pase). In addition, in vivo and in vitro studies showed that loss of LRP6 allele is associated with increased leptin receptor expression, which is a likely cause of hepatic insulin sensitivity in LRP6(+/-) mice. Our study identifies LRP6 as a nutrient-sensitive regulator of body weight and glucose metabolism and as a potential target for pharmacological interventions in obesity and diabetes.