# Leptin in the VMH and energy balance

> **NIH NIH R01** · GEORGIA STATE UNIVERSITY · 2023 · $390,000

## Abstract

Leptin was identified as a potential feedback signal in the regulation of energy balance in 1994,
but little progress has been made in using leptin to prevent or reverse human obesity. This may
be due to a failure to fully understand the central mechanisms by which leptin can control food
intake which can only be evaluated when they are functioning normally. Control of energy
balance is often investigated in models in which components of the system have been genetically
modified, the animal has been fed an obesogenic diet or pharmacologic doses of leptin are used
to investigate an endogenous physiologic system. Preliminary data using threshold doses of
leptin in normal weight animals demonstrate the presence of a leptin sensitive pathway that
inhibits food intake when circulating leptin concentrations rise above basal levels as a signal of
positive energy balance. We have demonstrated that activation of leptin receptors in the
hindbrain nucleus of the solitary tract (NTS) lowers the threshold for activation of hypothalamic
leptin receptors through a neural network. This effect is most dramatic in the dorsomedial
ventromedial nucleus of the hypothalamus (VMHdm), where there is a 3-fold increase in leptin
receptor activation. Additional experiments demonstrated that loss of NTS leptin-receptor
expressing cells raised the threshold for a hypothalamic response to leptin and that loss of leptin
receptor expressing cells in the VMHdm abolished weight loss caused by hindbrain infusions of
leptin. Based on these data and evidence that hypothalamic leptin suppresses food intake by
amplifying the response to peripheral satiety signals, we hypothesize that small increases in
circulating leptin amplify the response to peripheral satiety signals through a circuit in which
NTS leptin enhances VMHdm leptin sensitivity. This application will establish the function and
anatomy of the hypothesized network. The first Aim will test whether activation of VMHdm
leptin receptors amplifies the response to peripheral satiety signals. The second Aim will test
whether these receptors protect against diet-induced obesity. The third Aim will use tract
tracing to identify the organization of the proposed neural network and in situ hybridization to
identify the neurochemical phenotype of leptin receptor-expressing neurons in the NTS and
VMHdm. Successful completion of these Aims will provide new information on the synergy
between long-term signals of energy balance and peripheral short-term satiety signals as an
integral component of a network that facilitates precise control of energy balance.

## Key facts

- **NIH application ID:** 10706486
- **Project number:** 5R01DK132673-02
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** Ruth B Harris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2022-09-19 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10706486

## Citation

> US National Institutes of Health, RePORTER application 10706486, Leptin in the VMH and energy balance (5R01DK132673-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10706486. Licensed CC0.

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