Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
Cell Rep. 2016 Jan 12;14(2):255-68. doi: 10.1016/j.celrep.2015.12.028. Epub 2015 Dec 31.
Obesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis. Here, we show that the p75 neurotrophin receptor (p75(NTR)) controls energy expenditure in obese mice on a high-fat diet (HFD). Despite no changes in food intake, p75(NTR)-null mice were protected from HFD-induced obesity and remained lean as a result of increased energy expenditure without developing insulin resistance or liver steatosis. p75(NTR) directly interacts with the catalytic subunit of protein kinase A (PKA) and regulates cAMP signaling in adipocytes, leading to decreased lipolysis and thermogenesis. Adipocyte-specific depletion of p75(NTR) or transplantation of p75(NTR)-null white adipose tissue (WAT) into wild-type mice fed a HFD protected against weight gain and insulin resistance. Our results reveal that signaling from p75(NTR) to cAMP/PKA regulates energy balance and suggest that non-CNS neurotrophin receptor signaling could be a target for treating obesity and the metabolic syndrome.
肥胖和代谢综合征反映了控制能量平衡的分子途径失调。在这里，我们表明，p75 神经营养因子受体 (p75(NTR)) 控制高脂肪饮食 (HFD) 肥胖小鼠的能量消耗。尽管食物摄入量没有变化，但 p75(NTR) 缺失的小鼠能够防止 HFD 诱导的肥胖，并由于能量消耗增加而保持苗条，而不会产生胰岛素抵抗或肝脂肪变性。p75(NTR) 与蛋白激酶 A (PKA) 的催化亚基直接相互作用，并调节脂肪细胞中的 cAMP 信号，导致脂肪分解和产热减少。脂肪细胞特异性敲除 p75(NTR) 或向 HFD 喂养的野生型小鼠移植 p75(NTR) 缺失的白色脂肪组织 (WAT) 可防止体重增加和胰岛素抵抗。我们的研究结果表明，p75(NTR) 向 cAMP/PKA 的信号转导调节能量平衡，并提示非 CNS 神经营养因子受体信号可能是治疗肥胖和代谢综合征的靶点。
