Toorie Anika M, Nillni Eduardo A
Division of Endocrinology (A.M.T., E.A.N.), Department of Medicine, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island 02903; and Department of Molecular Biology, Cell Biology, and Biochemistry (E.A.N.), Brown University, Providence, Rhode Island 02912.
Mol Endocrinol. 2014 Sep;28(9):1423-34. doi: 10.1210/me.2014-1115. Epub 2014 Jun 20.
In developed nations, the prevalence of obesity and its associated comorbidities continue to prevail despite the availability of numerous treatment strategies. Accumulating evidence suggests that multiple inputs from the periphery and within the brain act in concert to maintain energy metabolism at a constant rate. At the central level, the hypothalamus is the primary component of the nervous system that interprets adiposity or nutrient-related inputs; it delivers hormonal and behavioral responses with the ultimate purpose of regulating energy intake and energy consumption. At the molecular level, enzymes called nutrient energy sensors mediate metabolic responses of those tissues involved in energy balance ( 1 ). Two key energy/nutrient sensors, mammalian target of rapamycin and AMP-activated kinase, are involved in the control of food intake in the hypothalamus as well as in peripheral tissues ( 2 , 3 ). The third more recently discovered nutrient sensor, Sirtuin1 (Sirt1), a nicotinamide adenine dinucleotide-dependent deacetylase, functions to maintain whole-body energy homeostasis. Several studies have highlighted a role for both peripheral and central Sirt1 in regulating body metabolism, but its central role is still heavily debated. Owing to the opaqueness of central Sirt1's role in energy balance are its cell-specific functions. Because of its robust central expression, targeting cell-specific downstream mediators of Sirt1 signaling may help to combat obesity. However, when placed in the context of a physiologically relevant model, there is compelling evidence that central Sirt1 inhibition in itself is sufficient to promote negative energy balance in both the lean and diet-induced obese state.
在发达国家，尽管有众多治疗策略，但肥胖及其相关合并症的患病率仍居高不下。越来越多的证据表明，来自外周和大脑内部的多种输入协同作用，以维持能量代谢的恒定速率。在中枢层面，下丘脑是神经系统解释肥胖或营养相关输入的主要组成部分；它产生激素和行为反应，最终目的是调节能量摄入和能量消耗。在分子层面，称为营养能量传感器的酶介导参与能量平衡的组织的代谢反应（1）。两种关键的能量/营养传感器，雷帕霉素哺乳动物靶蛋白和AMP激活的蛋白激酶，参与下丘脑以及外周组织的食物摄入控制（2,3）。最近发现的第三种营养传感器，沉默调节蛋白1（Sirt1），一种烟酰胺腺嘌呤二核苷酸依赖性脱乙酰酶，其功能是维持全身能量稳态。多项研究强调了外周和中枢Sirt1在调节身体代谢中的作用，但其核心作用仍存在激烈争议。由于中枢Sirt1在能量平衡中的作用不明确，是其细胞特异性功能所致。由于其在中枢的强大表达，靶向Sirt1信号通路的细胞特异性下游介质可能有助于对抗肥胖。然而，在生理相关模型的背景下，有令人信服的证据表明，中枢Sirt1抑制本身足以在瘦素和饮食诱导的肥胖状态下促进负能量平衡。
