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: 10542817
• 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/10542817
• 关键词: Adopted; Adult; Agonist; Alleles; Amino Acid Sequence; Appetite Stimulants; Biology; Brain; Central Nervous System; ChIP-seq; Code; Congenital Abnormality; Defect; Development; Diabetes Mellitus; Discipline; Energy Metabolism; Enterobacteria phage P1 Cre recombinase; Equilibrium; European ancestry; Functional disorder; Gene Expression Profiling; Genetic; Genetic Transcription; Glucose; Glucose Intolerance; Goals; Heterozygote; Homeostasis; Human; Human Genetics; Hypothalamic structure; Impairment; Individual; Knock-in Mouse; Knockout Mice; Label; Lead; LoxP-flanked allele; Maps; Melanocortin 4 Receptor; Metabolic; Metabolic syndrome; Missense Mutation; Molecular; Morbid Obesity; Mus; Mutation; Neurons; Neurosecretory Systems; Non obese; Obesity; Patients; Perinatal mortality demographics; Phenotype; Physiological; Play; Population; Prosencephalon; Publishing; Receptor Signaling; Reporting; Role; Site; Structure of nucleus infundibularis hypothalami; Testing; Therapeutic; Variant; 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; single nucleus RNA-sequencing; 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.

项目摘要 最近在一组患有严重， 早发性肥胖像许多其他肥胖相关的变异，尽管有很强的关联，因果关系， 关系尚未建立。 Otp编码一种在多个物种中高度保守的转录因子。重要的是，小鼠和 人类共享相同的Otp氨基酸序列。为了研究OtpQ 153 R/+的功能影响，我们 产生了携带相同人类突变的新基因敲入小鼠。与人类受试者相似，我们发现， OtpQ 153 R杂合子小鼠（OtpQ 153 R/+）存活至成年期，但出现肥胖和葡萄糖 不容忍因此，这些发现强烈支持OtpQ 153 R/+在人类肥胖中的因果作用。 我们建议研究OtpQ 153 R诱导的肥胖和葡萄糖缺乏背后的机制。OTP广泛 分布在中枢神经系统。为了确定OTP缺乏损害能量的大脑部位， 为了维持葡萄糖平衡，我们产生并表征了floxed Otp等位基因（Otpflox）。我们新的初步研究显示 前脑Sim 1-Cre表达神经元中Otp的选择性缺失再现了Otp缺失小鼠中所见的致死性， 而其在这些神经元中的单倍不足导致肥胖。此外，我们发现OTP是瞬时的 在下丘脑弓状核（ARH）中的未成熟POMC神经元亚群中表达， 在发育过程中，POMC→NPY/AgRP命运转换所需。这些神经元中Otp的选择性缺失 导致POMC衍生的NPY/AgRP神经元身份的显著丧失。总的来说，我们的新发现表明 OTP在两个不同的下丘脑神经元群体中起着调节能量和葡萄糖的关键作用， 新陈代谢. 总之，这些研究的首要目标是更好地了解OtpQ 153 R诱导的病理生理学 并开发基于机制的治疗方法，以减轻人类OtpQ 153 R/+患者的代谢综合征。