Lin Li, Hales Chadwick M, Garber Kathryn, Jin Peng
Department of Human Genetics and.
Department of Neurology and Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA 30322, USA.
Hum Mol Genet. 2014 Jun 15;23(12):3299-306. doi: 10.1093/hmg/ddu043. Epub 2014 Jan 31.
Polymorphisms in the fat mass and obesity-associated (FTO) gene have been associated with obesity in humans. FTO is a nuclear protein and its physiological function remains largely unknown, but alterations in its expression in mice influence energy expenditure, food intake and, ultimately, body weight. To understand the molecular functions of FTO, we performed a yeast two-hybrid screen to identify the protein(s) that could directly interact with human FTO protein. Using multiple assays, we demonstrate that FTO interacts with three isoforms of calcium/calmodulin-dependent protein kinase II: α, β and γ, which are protein kinases that phosphorylate a broad range of substrates. This interaction is functional; overexpression of FTO delays the dephosphorylation of cAMP response element-binding protein (CREB) in human neuroblastoma (SK-N-SH) cells, which in turn leads to a dramatic increase in the expression of the CREB targets neuropeptide receptor 1 (NPY1R) and brain-derived neurotrophic factor (BDNF), which already are known to regulate food intake and energy homeostasis. Thus, our results suggest that FTO could modulate obesity by regulating the activity of the CREB signaling pathway.
脂肪量与肥胖相关基因（FTO）的多态性与人类肥胖有关。FTO是一种核蛋白，其生理功能在很大程度上仍不清楚，但它在小鼠体内表达的改变会影响能量消耗、食物摄入，并最终影响体重。为了了解FTO的分子功能，我们进行了酵母双杂交筛选，以鉴定能够与人FTO蛋白直接相互作用的蛋白质。通过多种检测方法，我们证明FTO与钙/钙调蛋白依赖性蛋白激酶II的三种亚型相互作用：α、β和γ，它们是能使多种底物磷酸化的蛋白激酶。这种相互作用具有功能性；FTO的过表达会延迟人神经母细胞瘤（SK-N-SH）细胞中cAMP反应元件结合蛋白（CREB）的去磷酸化，这反过来会导致CREB靶标神经肽受体1（NPY1R）和脑源性神经营养因子（BDNF）的表达显著增加，而这两种因子已知可调节食物摄入和能量稳态。因此，我们的结果表明，FTO可能通过调节CREB信号通路的活性来调节肥胖。
