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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：
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
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/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

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.

项目总结