Department of Internal Medicine, Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Nat Med. 2011 May;17(5):623-6. doi: 10.1038/nm.2349. Epub 2011 May 1.
The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that is activated by lipids to induce the expression of genes involved in lipid and glucose metabolism, thereby converting nutritional signals into metabolic consequences. PPAR-γ is the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs, which have been widely prescribed to treat type 2 diabetes mellitus. A common side effect of treatment with TZDs is weight gain. Here we report a previously unknown role for central nervous system (CNS) PPAR-γ in the regulation of energy balance. We found that both acute and chronic activation of CNS PPAR-γ, by either TZDs or hypothalamic overexpression of a fusion protein consisting of PPAR-γ and the viral transcriptional activator VP16 (VP16-PPAR-γ), led to positive energy balance in rats. Blocking the endogenous activation of CNS PPAR-γ with pharmacological antagonists or reducing its expression with shRNA led to negative energy balance, restored leptin sensitivity in high-fat-diet (HFD)-fed rats and blocked the hyperphagic response to oral TZD treatment. These findings have implications for the widespread clinical use of TZD drugs and for understanding the etiology of diet-induced obesity.
过氧化物酶体增殖物激活受体-γ（PPAR-γ）是一种核受体，可被脂质激活，从而诱导参与脂质和葡萄糖代谢的基因表达，将营养信号转化为代谢后果。PPAR-γ 是噻唑烷二酮（TZD）类胰岛素增敏药物的靶点，这些药物已被广泛用于治疗 2 型糖尿病。TZD 治疗的常见副作用是体重增加。在这里，我们报告了中枢神经系统（CNS）PPAR-γ 在调节能量平衡中的一个先前未知的作用。我们发现，无论是通过 TZD 还是通过将由 PPAR-γ 和病毒转录激活剂 VP16（VP16-PPAR-γ）组成的融合蛋白在大脑中过度表达来急性或慢性激活 CNS PPAR-γ，都会导致大鼠的正能量平衡。用药理学拮抗剂阻断内源性 CNS PPAR-γ 的激活，或用 shRNA 降低其表达，会导致负能量平衡，恢复高脂饮食（HFD）喂养大鼠对瘦素的敏感性，并阻断口服 TZD 治疗的过度进食反应。这些发现对 TZD 药物的广泛临床应用以及对饮食引起的肥胖的病因学有重要意义。
