A human genetic variant ties defective hypothalamic development to obesity and diabetes

人类遗传变异将下丘脑发育缺陷与肥胖和糖尿病联系起来

• 批准号: 10339209
• 负责人: Chen Liu
• 金额: $ 41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339209
• 关键词: Adopted; Adult; Agonist; Alleles; Amino Acid Sequence; Appetite Stimulants; Biology; Brain; ChIP-seq; Code; Congenital Abnormality; Defect; Development; Diabetes Mellitus; Energy Metabolism; Enterobacteria phage P1 Cre recombinase; Equilibrium; European; Functional disorder; Gene Expression Profiling; Genetic; Genetic Transcription; Glucose; Glucose Intolerance; Goals; Homeostasis; Human; Human Genetics; Hypothalamic structure; Impairment; Individual; Knock-in Mouse; Knockout Mice; Label; Lead; LoxP-flanked allele; Melanocortin 4 Receptor; Metabolic; Metabolic syndrome; Missense Mutation; Molecular; Morbid Obesity; Mus; Mutation; Neuraxis; Neurons; Neurosecretory Systems; Non obese; Obesity; Patients; Perinatal mortality demographics; Phenotype; Physiological; Play; Population; Prosencephalon; Publishing; Receptor Signaling; Reporting; Role; Site; Small Nuclear RNA; Structure of nucleus infundibularis hypothalami; Testing; Therapeutic; Variant; base; blood glucose regulation; cell motility; cohort; energy balance; genetic variant; genome wide association study; genomic data; glucose metabolism; homeodomain; human model; human subject; insight; mouse genetics; mutant; nerve supply; neuromechanism; novel; paraventricular nucleus; postnatal; prevent; progenitor; severe early onset obesity; tool; transcription factor; transcriptome

PROJECT SUMMARY A heterozygous missense mutation OtpQ153R/+ has recently been discovered in a cohort of individuals with severe, early-onset obesity. Like many other obesity-associated variants, despite a strong association, a causal relationship has yet been established. Otp encodes a transcription factor that is highly conserved across multiple species. Importantly, mice and humans share the identical amino acid sequence of Otp. To study the functional impact of OtpQ153R/+, we have generated new knock-in mice that carry the same human mutation. Similar to the human subjects, we found that mice heterozygous for OtpQ153R (OtpQ153R/+) survive through adulthood but develop obesity and glucose intolerance. These findings, therefore, strongly support a causal role for OtpQ153R/+ in human obesity. We propose to investigate the mechanisms behind OtpQ153R-induced obesity and glucose deficits. Otp is broadly distributed in the central nervous system. To determine the brain site where Otp deficiency impairs energy and glucose balance, we generated and characterized a floxed Otp allele (Otpflox). Our new preliminary studies show that selective loss of Otp in forebrain Sim1-Cre-expressing neurons reproduces lethality seen in Otp null mice, whereas its haploinsufficiency in these neurons results in obesity. Furthermore, we find that Otp is transiently expressed in a subset of immature POMC neurons in the arcuate nucleus of the hypothalamus (ARH) and is required for the POMC→NPY/AgRP fate switch during development. Selective deletion of Otp in these neurons leads to a significant loss of POMC-derived NPY/AgRP neuron identity. Collectively, our new findings suggest that Otp plays critical roles in two distinct populations of hypothalamic neurons to regulate energy and glucose metabolism. In summary, the overarching goals of these studies are to better understand OtpQ153R-induced pathophysiology and develop mechanism-based therapeutics to mitigate metabolic syndrome in human OtpQ153R/+ patients.

项目总结 一种杂合性错义突变OtpQ153R/+最近在一组严重、 早发性肥胖症。像许多其他与肥胖相关的变种一样，尽管存在很强的关联性，但 关系还没有建立起来。 OTP编码一种在多种物种中高度保守的转录因子。重要的是，老鼠和 人类拥有相同的OTP氨基酸序列。为了研究OtpQ153R/+的功能影响，我们有 产生了携带相同人类突变的新的基因敲入小鼠。与人类受试者相似，我们发现 OtpQ153R杂合小鼠(OtpQ153R/+)成年期存活，但出现肥胖和血糖 不宽容。因此，这些发现有力地支持了OtpQ153R/+在人类肥胖中的因果作用。 我们建议研究OtpQ153R诱导肥胖和葡萄糖缺乏症的机制。动态口令被广泛地 分布在中枢神经系统。确定OTP缺乏损害能量和脑部的大脑部位 为了达到葡萄糖平衡，我们产生并鉴定了OTP等位基因(Otpflx)。我们新的初步研究表明 前脑Sim1-Cre表达神经元中OTP的选择性丢失复制了OTP缺失小鼠的致死性， 而它在这些神经元中的单倍性不足会导致肥胖。此外，我们还发现动态口令是瞬变的 在下丘脑弓状核(ARH)的未成熟POMC神经元亚群中表达，并在 POMC→NPY/AgRP Fate开关在开发过程中需要。这些神经元中OTP的选择性缺失 导致POMC来源的NPY/AgRP神经元身份的显著丧失。总体而言，我们的新发现表明 OTP在调节能量和血糖的两种不同的下丘脑神经元中起着关键作用 新陈代谢。 总之，这些研究的首要目标是更好地理解OtpQ153R诱导的病理生理学 并开发基于机制的疗法来缓解人类OtpQ153R/+患者的代谢综合征。