Department of Pharmacology, Second Military Medical University, Shanghai, China.
Mol Med. 2011 May-Jun;17(5-6):523-32. doi: 10.2119/molmed.2010.00134. Epub 2011 Jan 21.
Obesity is an important risk factor for cardiovascular disease, diabetes and certain cancers. The fat mass- and obesity-associated (FTO) gene is tightly associated with the pathophysiology of obesity, whereas the exact role of FTO remains poorly understood. Here, we investigated the alternations of FTO mRNA and protein expression in the peripheral metabolic tissues and the brain upon energy restriction (ER) and explored the involvement of the leptin signaling pathway in FTO regulation under ER status. ER decreased the FTO mRNA and protein expression in hypothalamus and brainstem but not in periphery. Using double-immunofluorescence staining, FTO was found to be colocalized with the leptin receptor long isoform (LepRb) in arcuate nucleus of hypothalamus and the nucleus of the solitary tract. In LepRb mutant db/db mice, the FTO downregulation in brain and body weight reduction induced by ER were completely abolished. The enhanced phosphorylation of signal transducer and activator of transcription 3 (STAT3) induced by ER was also impaired in db/db mice. Moreover, leptin directly activated the STAT3 signaling pathway and downregulated FTO in in vitro arcuate nucleus of hypothalamus cultures and in vivo wild-type mice but not db/db mice. Thus, our results provide the first evidence that the LepRb-STAT3 signaling pathway is involved in the brain FTO downregulation during ER.
肥胖是心血管疾病、糖尿病和某些癌症的重要危险因素。脂肪量和肥胖相关（FTO）基因与肥胖的病理生理学密切相关，而 FTO 的确切作用仍知之甚少。在这里，我们研究了能量限制（ER）对周围代谢组织和大脑中 FTO mRNA 和蛋白表达的改变，并探讨了瘦素信号通路在 ER 状态下对 FTO 调节的参与。ER 降低了下丘脑和脑干中的 FTO mRNA 和蛋白表达，但在外周组织中没有降低。通过双重免疫荧光染色，发现 FTO 与长型瘦素受体（LepRb）在下丘脑弓状核和孤束核中共定位。在 LepRb 突变型 db/db 小鼠中，ER 诱导的大脑和体重减轻导致的 FTO 下调完全被消除。在 db/db 小鼠中，ER 诱导的信号转导子和转录激活子 3（STAT3）的磷酸化增强也受到损害。此外，瘦素直接激活 STAT3 信号通路，并下调体外下丘脑弓状核培养物和体内野生型小鼠中的 FTO，但不能下调 db/db 小鼠中的 FTO。因此，我们的研究结果首次提供了证据表明，LepRb-STAT3 信号通路参与了 ER 期间大脑中 FTO 的下调。
