# Harnessing macrophage lysosomal lipid metabolism in obesity-associated diseases

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $625,037

## Abstract

Project Summary / Abstract
Obesity-related metabolic disorders, including insulin resistance, type 2 diabetes, and non-alcoholic fatty liver
disease, are thought to be caused by low-grade non-infectious inflammation as a result of lipid-mediated immune
cell activation, particularly macrophages. However, it has become clear that focusing on macrophage
inflammatory signaling is overly simplistic and fails to explain the complex relationship between increased
immune cell recruitment to metabolic tissues and disease pathogenesis. Phenotyping of macrophages in adipose
tissue and liver demonstrates induction of a lysosomal lipid metabolism program in diet-induced obesity,
suggesting that macrophage recruitment to lipid-overloaded tissues might be compensatory in nature. If so, then
enhancing a cell-intrinsic program of lipid hydrolysis and metabolism in macrophages should have
beneficial metabolic effects. In preliminary work, we show that overexpression of macrophage TFEB, a master
transcriptional regulator of lysosomal and fatty acid oxidation genes, enhances the ability of macrophages to
metabolize lipids in vitro and ameliorates diet-induced metabolic dysfunction in vivo, presumably because of
reduced fatty acid release from adipose tissue. In this proposal, we will investigate the consequences and
mechanisms by which activating macrophage lysosomal lipid metabolism in distinct macrophage subsets
impacts obesity-induced metabolic dysfunction and fatty liver disease. In Aim-1, we will explore the role of TFEB
in adipose tissue macrophages (ATM) in regulating adipose tissue and systemic metabolic function in obesity.
This includes assessing TFEB’s effects on the metabolic handling of lipid-rich exosomes and dying adipocytes
found in crown-like structures. Our findings in mice will also be confirmed in a human population where we will
determine if increased lysosomal lipid metabolism in ATM associates with metabolically normal or metabolically
abnormal obesity. In Aim-2, we will utilize unique genetic models to determine the impact of TFEB in liver
resident Kupffer cells vs. recruited monocyte-derived macrophages on diet-induced steatosis and fibrosis. Taken
together, this proposal will test the hypothesis that induction of a macrophage lysosomal lipid degradation-
mitochondrial fatty acid oxidation gene network via TFEB will enhance macrophage lipid handling and
could be leveraged to treat obesity-associated insulin resistance and fatty liver disease.

## Key facts

- **NIH application ID:** 10868727
- **Project number:** 5R01DK131188-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Bettina Mittendorfer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $625,037
- **Award type:** 5
- **Project period:** 2022-07-04 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868727

## Citation

> US National Institutes of Health, RePORTER application 10868727, Harnessing macrophage lysosomal lipid metabolism in obesity-associated diseases (5R01DK131188-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10868727. Licensed CC0.

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