# Proopiomelanocortin gene expression and obesity

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $445,831

## Abstract

Project Summary
Obesity predisposes humans to diabetes and cardiovascular disease and is a universal threat to health. Fat
storage is dynamically controlled by orchestrated hormonal, neural and metabolic signals between the brain and
periphery. Proopiomelanocortin (POMC) neurons that synthesize melanocortin peptides are a primary integrative
site for these diverse signals related to energy homeostasis. In the past funding cycles, we made significant
progress towards explaining how Pomc transcription is restricted to a subset of hypothalamic neurons in the
arcuate nucleus. A modular locus comprised of two evolutionarily distinct enhancers, nPE1 and nPE2, directs
neuron-specific Pomc expression. Targeted deletion of the individual or combination of enhancers revealed that
they act synergistically during hypothalamic development and additively in adult life to maintain sufficiently robust
Pomc transcription to avoid obesity. A bioinformatic analysis of core nucleotide sequence motifs within the
enhancers combined with anatomic and functional interrogation of candidate homeobox transcription factors
(TFs) in animal models identified a major contribution of Isl1 and Nkx2.1 in directing the unique temporal and
spatial patterns of Pomc expression in the arcuate nucleus. The Rax TF also contributes to the identity of POMC
neurons developmentally, but acts indirectly upstream of Isl1. Although necessary, these factors alone are not
sufficient to fully account for the complexities of neuronal Pomc regulation. Translating Ribosome Affinity
Purification (TRAP) seq of POMC neurons has identified additional, highly differentially expressed TF genes that
are putatively involved in the control of Pomc expression. Therefore, we propose the following specific aims for
this project renewal: 1) Uncover the complete genetic program controlling hypothalamic Pomc expression
through the functional characterization of candidate TFs that define the early identity of POMC neurons and their
maintenance throughout the entire lifetime, using mouse molecular genetics and human pluripotential stem cells
(hPSCs) that can be differentiated into POMC neurons in vitro; 2) Determine the cis-acting code that defines
hypothalamic Pomc expression through the in vivo functional analysis of the entire set of neuron-specific
enhancers, their critical binding motifs and local insulators to assemble a fully functional transcriptional locus;
and 3) Dissect the physiological significance of individual enhancers and critical motifs involved in the hormonal
regulation of Pomc expression by leptin and in response to altered dietary conditions and caloric demands.
These studies will provide fundamental knowledge about a gene essential for regulating body mass and possibly
identify novel genetic or signaling pathways that can be exploited for therapeutic purposes.

## Key facts

- **NIH application ID:** 10141222
- **Project number:** 5R01DK068400-17
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MALCOLM James LOW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $445,831
- **Award type:** 5
- **Project period:** 2004-08-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141222

## Citation

> US National Institutes of Health, RePORTER application 10141222, Proopiomelanocortin gene expression and obesity (5R01DK068400-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10141222. Licensed CC0.

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