# Intercellular mechanisms of microglia activation in diet-induced obesity

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $405,000

## Abstract

This is an administrative supplement request (PA-18-591) in response to NOT-AG-20-034 (Alzheimer's -focused
Administrative supplements for NIH grants that are not focused on Alzheimer's disease) to our ongoing NIH grant
1R01DK120321-03 entitled “Intracellular mechanisms of microglia activation in diet-induced obesity”. This
project aims to unmask the role of uncoupling protein 2 (UCP2)-mediated mitochondrial dynamics in microglia
activation in the central regulation of energy homeostasis in order to develop better strategies for the treatment
of metabolic disorders, such as obesity and type 2 diabetes. There are no Alzheimer’s Disease-related studies
proposed in this grant.
In response to NOT-AG-20-034, we request funds to test the hypothesis that UCP2-dependent microglia
activation and neuroinflammation may impact the onset of the development of Alzheimer’s disease (AD) in
genetic mouse model of AD by affecting histological and behavioral changes. Our preliminary studies show that
inhibiting UCP2-dependent microglia activation in mice exposed to HFD feeding prevents neuroinflammation
(microgliosis), protects from the development of metabolic disorders, such as obesity and type 2 diabetes, and
also prevents changes in behaviors and hippocampal structure that are associated with aging and AD. As aging
and obesity are risk factors for the development of neurodegenerative disorders such as Alzheimer’s disease
(AD), we hypothesize that HFD-induced UCP2-dependent microglia activation plays a role in the onset of
the development of AD and inhibition of this mechanism, by reducing chronic neuroinflammation,
prevents and/or delays the onset of cortical and hippocampal histological and behavioral changes in
AD.
Thus, in this supplement we propose to assess the effect of selective and inducible deletion of UCP2 in microglial
cells on the histology and behavior of AD mice [5xFAD mice (B6.Cg-
Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax; Oakley H et al., 2006)] exposed to either standard
chow diet or HFD, at different time points. Several littermate mice will be used as controls. Both male and female
mice will be studied. Behavioral and histological studies will be performed at different time points to assess the
role of microglia in the onset of AD development in this AD mouse model. The execution of these studies will
deliver novel insights into the role of microglia and metabolism in AD.

## Key facts

- **NIH application ID:** 10287448
- **Project number:** 3R01DK120321-04S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Sabrina Diano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,000
- **Award type:** 3
- **Project period:** 2020-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10287448

## Citation

> US National Institutes of Health, RePORTER application 10287448, Intercellular mechanisms of microglia activation in diet-induced obesity (3R01DK120321-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10287448. Licensed CC0.

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