# Epigenetic Mechanisms and Developmental Actions of Leptin in the Hypothalamus

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2020 · $590,876

## Abstract

PROJECT SUMMARY
Accumulating data indicate that environmental influences during prenatal and early postnatal
development can affect individual susceptibility to obesity throughout life. The long-term goal of this line
of research is to define molecular events that mediate environmental influences on development of
neuronal circuitry involved in the regulation of mammalian energy homeostasis. The hypothalamus is a
likely site for coupling early environmental signals to lifelong control of body weight, and neuronal
projections from the arcuate (ARH) to the paraventricular (PVH) nucleus of the hypothalamus are
essential in regulating energy balance. The adipocyte-derived hormone leptin directs formation of
neuronal projections from the ARH to the PVH, and distinct aspects of body weight regulation are
dependent on these developmental actions of leptin, specifically during a postnatal critical period. The
mechanisms that restrict formation of neuronal pathways to discrete developmental periods are largely
unknown. But DNA methylation, which appears to function as a major epigenetic mark stably modulating
expression of genes that control development in a variety of neural systems, is an excellent candidate.
The overall hypotheses of the proposed research are that 1) the critical developmental window during
which ARH neurons are responsive to the neurotrophic actions of leptin is dictated by epigenetic
mechanisms, and 2) cell type-specific methylation of genic and other regulatory regions is essential for
accurate targeting of functionally distinct classes of neurons, with consequences for normal metabolic
physiology. We will test these hypotheses by mapping cell type-specific epigenetic expression modules in
the ARH during and after closure of this critical developmental window (Aim 1). In addition, we will
identify leptin-mediated epigenetic changes within subpopulations of ARH neurons that display leptin-
dependent patterns of projections to the PVH (Aim 2). We will also use transgenic mice with targeted
disruption of the DNA methylation machinery to determine if DNA methylation is required for closure of
the critical developmental period for the neurotrophic action of leptin on ARH projections and associated
metabolic physiology (Aim 3). The proposed research will objectively and definitively assess whether
epigenetic mechanisms specify critical periods of brain development when leptin and perhaps other
environmental factors impact brain architecture and the regulation of energy balance throughout life.

## Key facts

- **NIH application ID:** 9889122
- **Project number:** 5R01DK111831-04
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** RICHARD B SIMERLY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $590,876
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889122

## Citation

> US National Institutes of Health, RePORTER application 9889122, Epigenetic Mechanisms and Developmental Actions of Leptin in the Hypothalamus (5R01DK111831-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9889122. Licensed CC0.

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