# Mechanisms underlying autonomic innervation plasticity in regulating energy balance

> **NIH NIH R00** · YALE UNIVERSITY · 2023 · $243,347

## Abstract

Project Summary
 Obesity is a major challenge for public health that predisposes individuals for metabolic diseases such
as diabetes. It arises because of a dysregulation in homeostatic maintenance of energy balance, resulting in
excess intake/storage relative to expenditure. By driving the storage of energy into white fat via
parasympathetic nerve driven release of the pancreatic hormone insulin, the autonomic nervous system plays
a key regulatory role in energy homeostasis. It also drives the expending of energy from fat by activation of the
sympathetic nervous system.
 The adipose hormone leptin orchestrates the communication between the nervous system and energy
storage organ, fat, that is necessary for homeostatic maintenance of energy balance. Leptin was previously
understood to do this by acting in a negative feedback loop with the brain to reduce fat mass via reduction of
food intake and sympatho-excitatory effects on adipose. Surprisingly, we discovered that leptin also regulates
plasticity in levels of sympathetic innervation inside of adipose tissue. These regulatory effects on the
sympathetic nerve architecture innervating adipose has functional implications for energy regulation by both
white fat lipolysis and brown fat thermogenesis. While we have delineated the brain circuit controlling this
process, the mechanisms that leptin uses to regulate adipose innervation plasticity, and whether this process
occurs in other metabolic organs, is still unknown.
 In the mentored phase of this grant, I will pursue a mechanistic understanding of how leptin-dependent
brain signals are translated into adipose sympathetic innervation plasticity. Specifically, I will dissect how
activity of a pre-autonomic neural population, BDNF-expressing neurons in the paraventricular hypothalamus,
dynamically regulates sympathetic innervation levels in adipose. Furthermore, to identify the molecular
changes associated with plasticity in sympathetic ganglia innervating fat, I will develop a proximity protein
tagging strategy to enrich these factors from nerves inside fat for quantitative proteomics. Finally, in the
independent phase, I will explore the generality of leptin’s effects on autonomic innervation plasticity in organs
beyond adipose tissue. Here, I will study the role of leptin on innervation plasticity in an organ important for
energy storage, the pancreas, using the tools developed during the mentored part of this proposal.
 Altogether, this work will uncover the mechanisms by which leptin regulates the plasticity of autonomic
innervation inside of adipose and the pancreas. Understanding these mechanisms will enable the identification
of downstream targets which directly modulate autonomic innervation and their functional role in regulating
energy balance, forming a foundation for new therapies to treat obesity and diabetes.

## Key facts

- **NIH application ID:** 10690748
- **Project number:** 5R00DK129712-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Huai Jin Ken Leon Loh
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $243,347
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690748

## Citation

> US National Institutes of Health, RePORTER application 10690748, Mechanisms underlying autonomic innervation plasticity in regulating energy balance (5R00DK129712-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10690748. Licensed CC0.

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