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

> **NIH NIH R00** · UNIVERSITY OF MINNESOTA · 2020 · $246,107

## Abstract

Project Summary
Visceral adiposity is increased in the elderly, despite a normal body-mass-index, and this increase is
associated with increased risk for metabolic diseases. Lipolysis is the first step in the generation of free fatty
acids and glycerol as energy substrates, is reduced with age and may be responsible for the increased
adiposity in the elderly. The changes that drive reduced lipolysis are unclear, but understanding those changes
may provide ways to restore lipolysis and reduce visceral adiposity in the elderly. Adipose macrophages are
tissue resident cells that are critical in maintaining tissue homeostasis. During aging they have elevated levels
of inflammasome activation and control lipolysis reduction. Senescence and fibrosis are also increased with
aging, but whether they contribute to reduced lipolysis is unclear. We have identified macrophage-expressed
growth differentiation factor (GDF)-3, a member of the TGFβ family, as a negative regulator of adipose lipolysis
and potential trigger of inflammation, senescence and fibrosis in aging. The overall goal of this study is to
identify the role for macrophage-expressed GDF3 in promoting inflammation, senescence and fibrosis to drive
lipolysis resistance in the aged adipose tissue. Specifically, we propose to (1) determine how GDF3 increases
NLRP3 inflammasome activation and lipolysis resistance, (2) characterize senescent macrophages and the
determine whether GDF3 drives senescence in adipose macrophages and (3) identify whether GDF3 is
required for ECM production and increased fibrosis in aged adipose. In Aim 1, we will identify activin receptors
and whether SMAD signaling alters inflammasome activation in macrophages in vitro. We will extend these in
vitro results and examine whether GDF3 is required for age-induced lipolysis resistance and inflammation
using aged mouse models of Gdf3-deficiency. In Aim 2, we will define senescent macrophages using a unique
transgenic mouse model permitting the identification of senescent cells using flow cytometry. To test for a
requirement of GDF3, we will delete GDF3 in the transgenic mice to analyze adipose macrophages using flow
cytometry and gene expression. Aim 3 will identify extracellular matrix proteins that are produced by
macrophages in response to GDF3. Additionally, Gdf3+/+ and Gdf3-/- mouse models of aging and RNA
sequencing will be used to identify novel candidates regulating GDF3 in adipose fibrosis. Completion of this
project will permit identification of the role for GDF3 in age-induced lipolysis resistance and as a potential
therapeutic target in treatment of inflammation and lipolysis resistance for humans during aging. The long term
goals of the candidate are to obtain an independent academic career with research focused on understanding
the mechanisms driving adipose dysfunction in aging.

## Key facts

- **NIH application ID:** 10012936
- **Project number:** 5R00AG058800-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Christina Camell
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $246,107
- **Award type:** 5
- **Project period:** 2019-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10012936

## Citation

> US National Institutes of Health, RePORTER application 10012936, Macrophage inflammasome activation and the mechanism of lipolysis resistance in aged adipose (5R00AG058800-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10012936. Licensed CC0.

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