# A Neural Circuit of Energy Expenditure Preventing Obesity

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2020 · $77,139

## Abstract

Project Summary
Alzheimer’s disease (AD) is the most common type of age-associated dementia affecting millions
of people in the United States, featured with both cognitive decline and memory loss. Although
extensive studies have been performed and many mechanisms have been proposed for AD
pathology, there are still no interventions that can cure, prevent or even slow AD progression;
early diagnosis of the disease is also missing. Among various metabolic and non-cognitive
dysfunctions observed in AD patients, body weight loss has long been accepted as a critical
clinical manifestation, which occurs even before the onset of cognitive syndromes, worsens along
with disease progression, and correlates with increased morbidity, mortality, and amyloid-beta
(Ab) aggregation. Similar changes have also been observed in multiple AD transgenic mouse
lines, suggesting that body weight loss is a fundamental feature of AD pathology. However, the
underlying physiological and pathological mechanisms responsible for the metabolic alterations
of AD still remain unknown. Given the recent findings that interventions to improve metabolism
could ameliorate cognitive deficits and amyloid pathology in transgenic AD mice, understanding
of AD-related body weight loss could have both basic and translational meanings. Here, we
hypothesize that body weight loss in AD is caused by increased energy expenditure, given the
observations of dysregulated appetite and increased feeding in both AD patients and mouse
models (Aim-1). In addition, since amyloid plaques are observed early in the hypothalamus of
AD, particularly in the paraventricular nucleus (PVH) region that control energy balances, and
both AD patients and mouse models exhibit notably increased GABA levels in the brain with
enhanced GABA release around plaques, we further hypothesize that increased GABA
production and release exist in the PVH of AD animals (Aim-2). Finally, as demonstrated in the
parent grant, we have identified that RIP neurons in the arcuate nucleus (ARC) release GABA,
inhibit the PVH neurons that project to the NTS, and prevent HFD-induced obesity by stimulating
brown adipose tissue (BAT)-mediated thermogenesis. We then hypothesize that increased
GABAergic neurotransmission in the PVH contributes to the elevated energy expenditure and
body weight loss in AD (Aim-3). We propose multiple ex vivo and in vivo experiments to assess
these hypotheses. Fulfillment of these studies would reveal novel insights into the hypothalamic
dysfunctions and weight loss in AD and provide additional targets to treat the disease.

## Key facts

- **NIH application ID:** 10123649
- **Project number:** 3R01DK108797-05S1
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Dong Kong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $77,139
- **Award type:** 3
- **Project period:** 2016-04-01 → 2021-02-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123649

## Citation

> US National Institutes of Health, RePORTER application 10123649, A Neural Circuit of Energy Expenditure Preventing Obesity (3R01DK108797-05S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10123649. Licensed CC0.

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