# Lateral Hypothalamic circuit dysfunction underlying the development of diet-induced obesity

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $423,471

## Abstract

Project Summary
The brain is a critical mediator of energy homeostasis, and neurocircuit dysfunction is thought to underlie obesity
pathogenesis. Within the brain, the lateral hypothalamic area (LHA) exerts control over feeding behavior and
body weight. Because of its considerable molecular and functional complexity, the role of LHA neurons in the
development of diet-induced obesity (DIO) is still poorly understood. Addressing the LHA mechanisms governing
feeding behavior and how they are remodeled during DIO will help to develop more targeted therapeutic
interventions for obesity. Our overarching goal is to gain a mechanistic understanding of LHA neuronal
dysfunction in DIO. Our previous work has demonstrated that the two most abundant cell types in the LHA—
glutamatergic (LHAGlut) and GABAergic (LHAGABA) neurons—are transcriptionally remodeled by DIO. LHAGlut and
LHAGABA neurons functionally oppose one another: LHAGlut neurons suppress feeding and reduce body weight,
whereas LHAGABA neurons promote feeding and increase body weight. Our preliminary data confirm that LHAGlut
and LHAGABA neurons show opposing changes in activity during acute manipulations of energy state and exhibit
opponent transcriptional changes during DIO. These results highlight a potential role for LHA neuron dysfunction
as a cause for overeating and DIO. However, the mechanisms underlying LHAGlut and LHAGABA neuron
dysfunction in DIO are unknown. One factor that influences energy homeostasis, feeding behavior, and LHA
activity is glucose. We therefore hypothesize that alterations in responsivity to glucose contribute to LHAGlut and
LHAGABA neuron dysfunction in acute and chronic overnutrition and that restoration of LHA neuron activity can
reverse the metabolic and behavioral impairments observed in DIO. To test this, we will determine the temporal
dynamics of LHAGlut and LHAGABA neuron remodeling in DIO using longitudinal multiphoton in vivo imaging and
electrophysiology. We will then test the hypothesis that glucose changes the activity of LHAGlut and LHAGABA
neurons in vivo after acute and chronic overfeeding. Finally, we will test the hypothesis that restoration of LHAGlut
and LHAGABA neuron activity can reverse the adverse consequences of chronic overnutrition. The results of this
project will advance our conceptual understanding of the brain's involvement in DIO and identify novel
therapeutic targets for the treatment of eating disorders and obesity.

## Key facts

- **NIH application ID:** 10916460
- **Project number:** 5R01DK136641-02
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Mark Allen Rossi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,471
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916460

## Citation

> US National Institutes of Health, RePORTER application 10916460, Lateral Hypothalamic circuit dysfunction underlying the development of diet-induced obesity (5R01DK136641-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10916460. Licensed CC0.

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