# Molecular and Neural Mechanisms of Leptin Action

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $559,957

## Abstract

Abstract
 Currently, obesity afflicts almost 40% of adult Americans, predisposing these people to diabetes and
other diseases that reduce their quality of life and longevity and costing the US health care system over $150
billion/year. Unfortunately, our incomplete understanding of the processes that control energy balance
continues to impede the design of new medical therapies to prevent and treat obesity.
 Leptin acts via its receptor (LepRb) on specialized hypothalamic neurons to control food intake, energy
expenditure, and other aspects of energy balance-related neuroendocrine function and behavior.
Understanding how leptin modulates LepRb neurons and how these neurons control energy balance (thereby
identifying processes that may be targeted for the therapy of obesity) represent the long-term goals of our
previous and proposed studies under this project (DK056731). In addition to our other work under this award,
we determined roles in energy balance and metabolism for specific groups of LepRb neurons, revealing the
importance of previously unidentified sets of LepRb neurons. We therefor used single-nucleus RNA-seq
(snRNA-seq) and unbiased clustering to identify transcriptionally-defined groups of hypothalamic LepRb
neurons (LepRb populations). This analysis identified previously-described (e.g., LepRbAgRP and LepRbPOMC)
and novel (e.g., LepRbGlp1r and LepRbPirt) LepRb populations.
 Using new molecular tools that we have developed, we now propose to study several novel LepRb T-
types, including DMH LepRbGlp1r neurons and ARC LepRbPirt cells. We hypothesize that leptin activates
GABAergic LepRbGlp1r neurons, inhibiting downstream ARC AgRP cells to restrain food intake and body
weight. We also postulate that leptin inhibits GABAergic LepRbPirt cells to activate specific endocrine axes.
We propose to: Aim 1. Understand the regulation of individual LepRb populations; Aim 2. Determine the
downstream targets and effects of individual LepRb populations; and Aim 3. Define physiologic roles for
individual LepRb populations, including in leptin action.
 In addition to providing insight into the neural circuits and processes that modulate the control of food
intake, energy expenditure, and neuroendocrine function, these studies may identify novel targets for
therapeutic intervention in obesity and other metabolic diseases.

## Key facts

- **NIH application ID:** 10877859
- **Project number:** 5R01DK056731-26
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Martin G Myers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $559,957
- **Award type:** 5
- **Project period:** 1999-03-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877859

## Citation

> US National Institutes of Health, RePORTER application 10877859, Molecular and Neural Mechanisms of Leptin Action (5R01DK056731-26). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10877859. Licensed CC0.

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