# Macrophage inflammasome activation and the mechanism of lipolysis resistance in  aged adipose

> **NIH NIH R00** · UNIVERSITY OF MINNESOTA · 2020 · $368,265

## Abstract

Project Summary
 Increased visceral adiposity and inflammation seen in the elderly are associated with elevated risk for
metabolic diseases, such as diabetes and atherosclerosis. Moreover, inflammaging and metabolic disease are
correlated with increased risk to develop dementia and neurodegenerative diseases including Alzheimer’s
disease (AD). One major overlapping pathway driving both metabolic and Alzheimer’s disease is the NLRP3
inflammasome pathway, which becomes activated in myeloid and macrophage-like cells following exposure to
a wide range of damage associated molecular patterns, like fatty acids and amyloid-beta (Aβ).
Tissue resident macrophages control homeostatic functions that are disrupted during aging. Our data reveals
adipose macrophage transcriptional changes lead to impaired lipolysis in aged visceral adipose tissue. We
identified macrophage-expressed growth differentiation factor (GDF)-3, a member of the TGFβ family, as a
negative regulator of adipose lipolysis and driver of NLRP3 inflammasome activation and aging-pathologies.
Our ongoing project examines the role for macrophage-expressed GDF3 in increasing inflammation,
senescence and fibrosis to aggravate tissue functioning in the aged adipose tissue. The specifics aims, which
are unchanged, of this project include (1) determine how GDF3 increases NLRP3 inflammasome activation
and lipolysis resistance, (2) characterize senescent macrophages and then determine whether GDF3 drives
senescence in adipose tissue immune cells, and (3) identify whether GDF3 is required for ECM production and
increased fibrosis in aged adipose.
Aβ activates the NLRP3 inflammasome driving microglial inflammation, Aβ-pathology and neurocognitive
impairments. In this supplement we propose to investigate GDF3 as an activator of Nlrp3 inflammasome-driven
neuroinflammation and cerebral amyloid pathology. In unexpected findings, TGFb/GDF signaling pathway and
GDF3 protein are reduced in human patients with AD, potentially by limiting neurogenesis. Thus it will be
critical to test whether GDF3-deficiency regulates inflammasome activation in specific cells. To identify whether
GDF3 controls inflammasome activation, a widely used transgenic mouse model of AD, (5xFAD mice),
expressing or with GDF3-deficiency will be used to evaluate neuroinflammation, AD-pathology and cognitive
function. To complement in vivo studies, inflammasome activation in primary microglia and neurons from
GDF3-expressing or deficient animals will be evaluated in the presence or absence of Aβ. Together, these
projects will study GDF3-deficiency in age-related inflammasome activation during metabolic disease and
Alzheimer’s disease. This project is well-situated to generate publications and preliminary data supporting
additional funding for investigating the GDF3-NLRP3 inflammasome axis in AD-pathology

## Key facts

- **NIH application ID:** 10121181
- **Project number:** 3R00AG058800-03S1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Christina Camell
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,265
- **Award type:** 3
- **Project period:** 2019-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121181

## Citation

> US National Institutes of Health, RePORTER application 10121181, Macrophage inflammasome activation and the mechanism of lipolysis resistance in  aged adipose (3R00AG058800-03S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10121181. Licensed CC0.

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