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

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $410,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10339209
- **Project number:** 1R01DK130892-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Chen Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $410,000
- **Award type:** 1
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339209

## Citation

> US National Institutes of Health, RePORTER application 10339209, A human genetic variant ties defective hypothalamic development to obesity and diabetes (1R01DK130892-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10339209. Licensed CC0.

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