# MCHergic control of feeding and energy balance in the LH area

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $418,750

## Abstract

In the United States, Alzheimer’s disease (AD) affects more than 5.8 million people of all ages, which
creates tremendous burdens for patients, their families and their communities. Intensive investigations have
been conducted to determine the factors leading to AD and produce therapeutic approaches to treat and
manage AD. The current understanding of the development of AD in the field mostly focuses on the
amyloid beta peptide ( ) and hyperphosphorylation of tau protein in the brain. However,
failures in developments of effective treatments for AD through targeting and tau pathways indicate an
urgent need to identify other critical pathways participating in AD-relevant pathological changes.
accumulation of Aβ
Aβ
The
neuropeptide hypocretin/orexin (Hcrt), selectively synthesized in the perifornical/lateral hypothalamus (Pf/LH),
is at a central role for the integration of a wide range of signals encoding metabolic, behavioral and
environmental cues in the brain. Hypocretinergic cells, regulating both physiological homeostasis and complex
have long been implicated in the development of AD and other forms of
dementias. Firstly, a significant loss of Hcrt cells was reported in AD and Lewy body dementia patients.
Secondly, recent evidence revealed that the Hcrt system maight provide protections against the AD
development in humans, although other evidence suggested that Hcrt might promote the progression of AD
under certain conditions. Therefore, it is both essential and urgent to understand the exact roles of the Hcrt
system in the development of AD, which is understudied currently. In addition, although the exact mechanisms
are not yet clear, the contribution of mid-life obesity to AD development has been well documented. It is both
conceptually and clinically critical to tackle this question, since obesity or over-nutrition has developed as a
pandemic in developed countries, which is likely relevant to the increased prevalence of AD in these countries.
behaviors in animals and humans,
In our recent studies relevant to the parent grant, our results suggest that diet-induced obesity (DIO) impairs
the Hcrt system, leading to deficiencies in brain areas (such as the hippocampus) responsible for cognitive
functions. Based on our new results and the role of obesity in AD development, we propose this proof of
concept study to test the hypothesis that Hcrt provides protections against obesity-induced progression and
pathophysiologic deterioration of AD. Specifically, we will determine whether a dysregulated Hcrt system
causally mediates expressions of AD-like biomarkers, altered activities in the hippocampal neural network and
cognitive behaviors in a murine model of AD (5xFAD mice) and whether the high-fat diet induced obesity
exaggerates this process by further weakening the Hcrt system. We hope that our results from the proposed
investigations will lead to new studies on the role of Hcrt playing in effects of metabolic statuses (DIO and
caloric restrict...

## Key facts

- **NIH application ID:** 10498949
- **Project number:** 3R01DK120891-03S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** XIAO-BING GAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,750
- **Award type:** 3
- **Project period:** 2020-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498949

## Citation

> US National Institutes of Health, RePORTER application 10498949, MCHergic control of feeding and energy balance in the LH area (3R01DK120891-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10498949. Licensed CC0.

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