UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143-0669, USA.
Cell Metab. 2012 Mar 7;15(3):395-404. doi: 10.1016/j.cmet.2012.01.019.
Brown adipose tissue dissipates energy through heat and functions as a defense against cold and obesity. PPARγ ligands have been shown to induce the browning of white adipocytes; however, the underlying mechanisms remain unclear. Here, we show that PPARγ ligands require full agonism to induce a brown fat gene program preferentially in subcutaneous white adipose. These effects require expression of PRDM16, a factor that controls the development of classical brown fat. Depletion of PRDM16 blunts the effects of the PPARγ agonist rosiglitazone on the induced brown fat gene program. Conversely, PRDM16 and rosiglitazone synergistically activate the brown fat gene program in vivo. This synergy is tightly associated with an increased accumulation of PRDM16 protein, due in large measure to an increase in the half-life of the protein in agonist treated cells. Identifying compounds that stabilize PRDM16 protein may represent a plausible therapeutic pathway for the treatment of obesity and diabetes.
棕色脂肪组织通过热量消耗能量，作为抵御寒冷和肥胖的防御机制。已经证明过过氧化物酶体增殖物激活受体γ（PPARγ）配体可诱导白色脂肪细胞的“褐变”；然而，其潜在机制尚不清楚。在这里，我们表明，PPARγ 配体需要完全激动剂才能优先诱导皮下白色脂肪中的棕色脂肪基因程序。这些作用需要 PRDM16 的表达，PRDM16 是控制经典棕色脂肪发育的一个因素。PRDM16 的耗竭削弱了 PPARγ 激动剂罗格列酮对诱导的棕色脂肪基因程序的作用。相反，PRDM16 和罗格列酮在体内协同激活棕色脂肪基因程序。这种协同作用与 PRDM16 蛋白的积累密切相关，这在很大程度上是由于激动剂处理细胞中蛋白半衰期的增加。鉴定稳定 PRDM16 蛋白的化合物可能代表治疗肥胖和糖尿病的合理治疗途径。
