Study of molecular function of A170 as a factor for food intake regulation

A170是aPKC的支架蛋白，缺乏A170会导致小鼠成熟型肥胖，但体重异常增加的机制尚不清楚。我发现，在A170缺陷（KO）小鼠中，暴食是肥胖的主要原因。KO和野生型小鼠表现出相同的能量消耗，并且食物限制逆转了KO小鼠的肥胖和葡萄糖耐受不良。尽管它们对侧脑室注射促食欲α-MSH激动剂和促食欲肽NPY的摄食反应正常，但瘦素没有诱导厌食，即使在年轻的肥胖前期KO小鼠中也是如此。免疫组化分析显示，A170通常表达在瘦素反应POMC或NPY表达下丘脑神经元。重要的是，虽然瘦素诱导的STAT 3酪氨酸磷酸化是正常的，磷酸化的STAT 3易位到核中是有缺陷的KO下丘脑。我们认为A170是中枢神经系统中瘦素厌食信号级联的一种新的调节因子。

Deficiency of A170, a scaffold protein for aPKC, causes mature-onset obesity in mice, but the mechanisms of the abnormal weight gain are unclear. I found that hyperphagia is the major cause of obesity in A170-deficient (KO) mice. KO and wild-type mice exhibited the same energy expenditure, and food restriction reversed obesity and glucose intolerance in the KO mice. Although their feeding responses to intracerebroventricular administration of an anorexigenic αMSH agonist and the orexigenic peptide NPY were normal, leptin did not induce anorexia, even in young, pre-obese KO mice. Immunohistochemical analyses revealed that A170 was normally expressed in leptin-responsive POMC- or NPY-expressing hypothalamic neurons. Importantly, although the leptin-induced phosphorylation of STAT3 on tyrosine was normal, the translocation of the phosphorylated STAT3 into the nucleus was defective in the KO hypothalamus. We propose that A170 is a novel regulator of leptin's anorectic signaling cascade in the central nervous system.