近日，国际学术期刊cell reports发表了美国加州大学旧金山分校研究人员的一项最新研究进展，他们发现脂肪细胞的神经营养因子受体能够参与调节机体的能量平衡，该分子或可成为治疗肥胖以及代谢综合症的一个新靶点。
肥胖以及代谢综合症的发生反映了体内调节能量平衡的信号途径的紊乱。在这项最新研究中，研究人员发现p75神经营养因子受体（p75NTR）能够调节高脂饮食诱导的肥胖小鼠的能量消耗。尽管小鼠的进食没有变化，但研究人员发现p75NTR缺失小鼠能够抵抗高脂饮食诱导的肥胖，这主要是由于小鼠能量消耗增加所导致，同时p75NTR缺失小鼠没有出现胰岛素抵抗以及脂肪肝。
通过对分子机制进行详细研究发现，p75NTR能够在脂肪细胞内与蛋白激酶A（PKA）的催化亚基发生直接相互作用，调节cAMP信号途径，从而导致脂解和产热下降。随后研究人员利用在脂肪细胞中特异性敲除p75NTR或将p75NTR缺失小鼠的白色脂肪组织移植到野生型小鼠体内的方法均发现p75NTR在脂肪组织内缺失可以保护小鼠抵抗饮食诱导的体重增加以及胰岛素抵抗。
这项研究结果揭示了从p75NTR到cAMP/PKA这条信号途径在调节能量平衡方面的重要作用，同时表明非中枢神经系统的神经营养因子受体信号可能是治疗肥胖以及代谢综合症的一个很好的靶点。
DOI: http://dx.doi.org/10.1016/j.celrep.2015.12.028
p75 Neurotrophin Receptor Regulates Energy Balance in Obesity
Bernat Baeza-Raja, Benjamin D. Sachs, Pingping Li, Frank Christian, Eirini Vagena, Dimitrios Davalos, Natacha Le Moan, Jae Kyu Ryu, Shoana L. Sikorski, Justin P. Chan, Miriam Scadeng, Susan S. Taylor, Miles D. Houslay, George S. Baillie, Alan R. Saltiel, Jerrold M. Olefsky, Katerina Akassoglou
Obesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis. Here, we show that the p75 neurotrophin receptor (p75NTR) controls energy expenditure in obese mice on a high-fat diet (HFD). Despite no changes in food intake, p75NTR-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. p75NTR 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 p75NTR or transplantation of p75NTR-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 p75NTR 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.