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

A170是一种蛋白激酶C的支架蛋白，它的缺失会导致小鼠出现成熟性肥胖，但异常体重增加的机制尚不清楚。我发现吞噬过度是A170基因缺陷(KO)小鼠肥胖的主要原因。KO和野生型小鼠表现出相同的能量消耗，食物限制逆转了KO小鼠的肥胖和葡萄糖耐量。虽然它们对脑室注射厌食性α激动剂和增食肽NPY的摄食反应是正常的，但瘦素并不会导致厌食，即使是在年轻的、肥胖前的KO小鼠中也是如此。免疫组织化学分析表明，A170在下丘脑瘦素反应性POMC或NPY表达的神经元中正常表达。重要的是，尽管瘦素诱导的STAT3在酪氨酸上的磷酸化是正常的，但在KO下丘脑中，磷酸化的STAT3的移位到核中是有缺陷的。我们认为A170是瘦素在中枢神经系统中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.