Wang Liheng, De Solis Alain J, Goffer Yossef, Birkenbach Kathryn E, Engle Staci E, Tanis Ross, Levenson Jacob M, Li Xueting, Rausch Richard, Purohit Manika, Lee Jen-Yi, Tan Jerica, De Rosa Maria Caterina, Doege Claudia A, Aaron Holly L, Martins Gabriela J, Brüning Jens C, Egli Dieter, Costa Rui, Berbari Nicolas, Leibel Rudolph L, Stratigopoulos George
Naomi Berrie Diabetes Center and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany.
JCI Insight. 2019 Feb 7;4(3):e123337. doi: 10.1172/jci.insight.123337.
Intronic polymorphisms in the α-ketoglutarate-dependent dioxygenase gene (FTO) that are highly associated with increased body weight have been implicated in the transcriptional control of a nearby ciliary gene, retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L). Previous studies have shown that congenital Rpgrip1l hypomorphism in murine proopiomelanocortin (Pomc) neurons causes obesity by increasing food intake. Here, we show by congenital and adult-onset Rpgrip1l deletion in Pomc-expressing neurons that the hyperphagia and obesity are likely due to neurodevelopmental effects that are characterized by a reduction in the Pomc/Neuropeptide Y (Npy) neuronal number ratio and marked increases in arcuate hypothalamic-paraventricular hypothalamic (ARH-PVH) axonal projections. Biallelic RPGRIP1L mutations result in fewer cilia-positive human induced pluripotent stem cell-derived (iPSC-derived) neurons and blunted responses to Sonic Hedgehog (SHH). Isogenic human ARH-like embryonic stem cell-derived (ESc-derived) neurons homozygous for the obesity-risk alleles at rs8050136 or rs1421085 have decreased RPGRIP1L expression and have lower numbers of POMC neurons. RPGRIP1L overexpression increases POMC cell number. These findings suggest that apparently functional intronic polymorphisms affect hypothalamic RPGRIP1L expression and impact development of POMC neurons and their derivatives, leading to hyperphagia and increased adiposity.
与体重增加高度相关的α-酮戊二酸依赖性双加氧酶基因（FTO）内含子多态性，与附近一个纤毛基因——视黄醛结合蛋白1样视网膜色素变性GTP酶调节相互作用蛋白（RPGRIP1L）的转录调控有关。先前的研究表明，小鼠阿黑皮素原（Pomc）神经元中先天性Rpgrip1l功能减退通过增加食物摄入量导致肥胖。在此，我们通过在表达Pomc的神经元中进行先天性和成年期Rpgrip1l基因敲除表明，摄食亢进和肥胖可能是由于神经发育效应所致，其特征是Pomc/神经肽Y（Npy）神经元数量比降低以及下丘脑弓状核-下丘脑室旁核（ARH-PVH）轴突投射显著增加。双等位基因RPGRIP1L突变导致人诱导多能干细胞来源（iPSC来源）的纤毛阳性神经元减少，且对音猬因子（SHH）的反应减弱。在rs8050136或rs1421085位点携带肥胖风险等位基因纯合的同基因人ARH样胚胎干细胞来源（ESc来源）的神经元，其RPGRIP1L表达降低，POMC神经元数量减少。RPGRIP1L过表达增加POMC细胞数量。这些发现表明，明显具有功能的内含子多态性影响下丘脑RPGRIP1L表达，并影响POMC神经元及其衍生物的发育，导致摄食亢进和肥胖增加。
