# Role of Lateral Hypothalamic Neurotensin Neurons in Energy Balance

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2021 · $410,192

## Abstract

Project Summary:
Overconsumption of food and reduced physical activity cause obesity, but limited understanding
of the neuronal circuits regulating these behaviors has hindered development of therapies. Since
the lateral hypothalamic area (LHA) of the brain controls the motivation to ingest and move it has
been studied for potential to support weight loss, but most LHA neurons promote ingestion and
weight gain. In contrast, during the last funding period we identified LHA neurons expressing the
neuropeptide neurotensin (Nts) that restrain feeding and promote energy expenditure to decrease
weight. Curiously, activating LHA Nts neurons also invokes a burst of water intake that acutely
causes weight gain, but once drinking normalizes then feeding suppression and increased energy
expenditure lead to weight loss. Taken together, these data suggest that preventing dipsic
behavior and biasing specifically for LHA Nts-mediated feeding restraint and physical activity
might improve the degree of weight loss. This could be possible, based on our preliminary data
that LHA Nts neurons densely project to two separate sites in the brain that are implicated in the
control of drinking and feeding, respectively. These data led to the central hypothesis of this
renewal application: LHA Nts neurons coordinate feeding suppression and drinking via
the VTA and LPO, respectively, which requires signaling via neurotensin receptor-1
(NtsR1). To investigate this we will use tract tracers and in vivo calcium imaging to define the
specific LHA cells and circuits that organize feeding vs. drinking, and hence precise neural targets
to mediate weight loss behaviors (Aim 1). To define the functions of Nts projections to the VTA
vs. the LPO we will optogenetically stimulate LHA Nts terminals in each site, thereby revealing if
there are dedicated circuits sufficient to direct feeding vs. drinking (Aim 2). We will then define
the necessity of Nts signaling via NtsR1 in the VTA or LPO for energy balance, and the ability of
these NtsR1 neurons to mediate weight loss without adverse effects (Aim 3). Taken together,
these studies will define the circuits, signals and behaviors by which LHA Nts neurons mediate
weight loss, suggesting where and how to target future pharmacological therapies to treat obesity.

## Key facts

- **NIH application ID:** 10102230
- **Project number:** 5R01DK103808-07
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Gina Marie Leinninger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,192
- **Award type:** 5
- **Project period:** 2014-09-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102230

## Citation

> US National Institutes of Health, RePORTER application 10102230, Role of Lateral Hypothalamic Neurotensin Neurons in Energy Balance (5R01DK103808-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102230. Licensed CC0.

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