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Principal Investigator: Chen Liu
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $393,599
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <21+ years old><Adopted><Adult><Adult Human><Agonist><Alleles><Allelomorphs><Amino Acid Sequence><Appetite Stimulants><Appetite-Stimulating Drugs><Arcuate Nucleus><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Biology><Birth Defects><Brain><Brain Nervous System><CNS Nervous System><CRE Recombinase><Cell Locomotion><Cell Migration><Cell Movement><Cellular Migration><Cellular Motility><Central Nervous System><ChIP Sequencing><ChIP-seq><ChIPseq><Code><Coding System><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><D-Glucose><Defect><Development><Dextrose><Diabetes Mellitus><Discipline><Dysfunction><Encephalon><Energy Expenditure><Energy Metabolism><Enterobacteria phage P1 Cre recombinase><Equilibrium><European ancestry><Fore-Brain><Forebrain><Functional disorder><GWA study><GWAS><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Transcription><Gene variant><General Transcription Factor Gene><General Transcription Factors><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Glucose><Glucose Intolerance><Goals><Heterozygote><Homeo Domain><Homeostasis><Human><Human Genetics><Hypothalamic structure><Hypothalamus><Impairment><Individual><Infundibular Nucleus><KI mice><KO mice><Knock-in Mouse><Knock-out Mice><Knockout Mice><Label><Lead><LoxP-flanked allele><MC4 Receptor><Maps><Melanocortin 4 Receptor><Metabolic><Metabolic syndrome><Mice><Mice Mammals><Missense Mutation><Modern Man><Molecular><Morbid Obesity><Murine><Mus><Mutation><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neuroendocrine><Neuroendocrine System><Neurons><Neurosecretory Systems><Non obese><Nonobese><Null Mouse><Obesity><Paraventricular Hypothalamic Nucleus><Patients><Pb element><Perinatal Mortalities><Perinatal lethality><Perinatal mortality demographics><Phenotype><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Play><Population><Primary Protein Structure><Prosencephalon><Publishing><RNA Expression><Receptor Signaling><Receptor, Melanocortin, Type 4><Reporting><Role><Severe obesity><Single-Nucleus Sequencing><Site><Structure of nucleus infundibularis hypothalami><Testing><Therapeutic><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Variant><Variation><adiposity><adulthood><allele variant><allelic variant><analyze gene expression><bacteriophage P1 recombinase Cre><balance><balance function><blood glucose regulation><cell motility><chromatin immunoprecipitation-sequencing><cohort><corpulence><developmental><diabetes><energy balance><extreme obesity><floxed><floxed allele><gene expression analysis><gene expression assay><genetic variant><genome mutation><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic data><genomic data-set><genomic dataset><genomic variant><global gene expression><global transcription profile><glucose control><glucose homeostasis><glucose metabolism><glucose regulation><heavy metal Pb><heavy metal lead><heterozygosity><homeodomain><human model><human subject><hypothalamic><innervation><insight><knockin mice><model of human><mouse genetics><mutant><nerve supply><neural mechanism><neuromechanism><neuronal><novel><orexigenic><paraventricular nucleus><pathophysiology><perinatal deaths><postnatal><prevent><preventing><progenitor><protein sequence><sNuc-Seq><severe early onset obesity><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><tool><transcription factor><transcriptional profiling><transcriptome><whole genome association analysis><whole genome association studies><whole genome association study>