Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Cell. 2012 Aug 3;150(3):620-32. doi: 10.1016/j.cell.2012.06.027.
Brown adipose tissue (BAT) can disperse stored energy as heat. Promoting BAT-like features in white adipose (WAT) is an attractive, if elusive, therapeutic approach to staunch the current obesity epidemic. Here we report that gain of function of the NAD-dependent deacetylase SirT1 or loss of function of its endogenous inhibitor Deleted in breast cancer-1 (Dbc1) promote "browning" of WAT by deacetylating peroxisome proliferator-activated receptor (Ppar)-γ on Lys268 and Lys293. SirT1-dependent deacetylation of Lys268 and Lys293 is required to recruit the BAT program coactivator Prdm16 to Pparγ, leading to selective induction of BAT genes and repression of visceral WAT genes associated with insulin resistance. An acetylation-defective Pparγ mutant induces a brown phenotype in white adipocytes, whereas an acetylated mimetic fails to induce "brown" genes but retains the ability to activate "white" genes. We propose that SirT1-dependent Pparγ deacetylation is a form of selective Pparγ modulation of potential therapeutic import.
棕色脂肪组织 (BAT) 可以将储存的能量散发为热量。促进白色脂肪 (WAT) 中类似于 BAT 的特征是一种有吸引力的治疗方法，如果难以捉摸，可以遏制当前的肥胖流行。在这里，我们报告 NAD 依赖性去乙酰化酶 SirT1 的功能获得或其内源性抑制剂乳腺癌缺失基因 1 (Dbc1) 的功能丧失会通过去乙酰化过氧化物酶体增殖物激活受体 (Ppar)-γ 在赖氨酸 268 和赖氨酸 293 上促进 WAT 的“褐变”。SirT1 依赖性赖氨酸 268 和赖氨酸 293 的去乙酰化对于募集 BAT 程序共激活因子 Prdm16 到 Pparγ 是必需的，导致选择性诱导 BAT 基因和抑制与胰岛素抵抗相关的内脏 WAT 基因。乙酰化缺陷型 Pparγ 突变体在白色脂肪细胞中诱导褐色表型，而乙酰化模拟物不能诱导“褐色”基因，但保留激活“白色”基因的能力。我们提出，SirT1 依赖性 Pparγ 去乙酰化是一种潜在治疗重要性的 Pparγ 选择性调节形式。
