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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要最近在一组患有严重、与许多其他与肥胖相关的变体一样，尽管存在很强的关联性，但存在因果关系。关系尚未建立。 Otp 编码的转录因子在多个物种中高度保守，尤其是小鼠和人类。人类具有相同的 Otp 氨基酸序列为了研究 OtpQ153R/+ 的功能影响，我们有我们发现，与人类受试者相似，产生了携带相同人类突变的新基因敲入小鼠。 OtpQ153R 杂合子 (OtpQ153R/+) 小鼠可存活至成年期，但出现肥胖和血糖升高因此，这些发现有力地支持了 OtpQ153R/+ 在人类肥胖中的因果作用。我们建议调查 OtpQ153R 诱导的肥胖和葡萄糖缺乏背后的机制。确定 Otp 缺乏会损害能量和能量的大脑部位。我们新的初步研究表明，我们生成并表征了 floxed Otp 等位基因 (Otpflox)。前脑 Sim1-Cre 表达神经元中 Otp 的选择性丢失重现了 Otp 缺失小鼠中所见的致死性，而这些神经元中的单倍体不足会导致肥胖。此外，我们发现 Otp 是短暂的。在下丘脑弓状核 (ARH) 的未成熟 POMC 神经元子集中表达，并且发育过程中 POMC→NPY/AgRP 命运转换所需的 Otp 选择性删除。总的来说，我们的新发现表明，POMC 衍生的 NPY/AgRP 神经特性显着丧失。 Otp 在两个不同的下丘脑神经元群中发挥着关键作用，以调节能量和葡萄糖代谢。总之，这些研究的总体目标是更好地了解 OtpQ153R 诱导的病理生理学并开发基于机制的疗法来减轻人类 OtpQ153R/+ 患者的代谢综合征。