# ADIPOSE TISSUE MACROPHAGE PHENOTYPE AND FUNCTION

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $480,830

## Abstract

Lipid homeostasis in adipose tissue is a critical determinant of whole body metabolism. When the efficiency
with which adipocytes store or release triglycerides is perturbed, lipids accumulate in non-adipocytes, impairing
systemic metabolism and altering the function of key tissues, including liver, heart, skeletal muscle and pancreas.
Despite our understanding of canonical pathways that regulate lipolysis and lipogenesis in adipocytes, the factors
that contribute to lipid homeostasis in adipose tissue are incompletely defined. In our efforts to understand non-
inflammatory function of immune cells in adipose tissue, we have recently discovered that in addition to canonical
release of lipids via neutral lipases, adipocytes release lipid in triglyceride-rich exosomes which are taken up by
adipose tissue macrophages (ATMs) and catabolized in lysosomes.
 Studies supported by this grant originally identified immune cells, and in particular macrophages, as
important components of adipose tissue that respond to and contribute to adipocyte function. Since these
original observations most studies have focused on the inflammatory roles of immune cells and how they can
impair insulin signaling, and thereby perturb systemic lipid and carbohydrate metabolism. We have hypothesized
that ATMs have adaptive functions necessary for normal adipose tissue metabolism and indeed, others have
shown that ATMs participate in adipose tissue differentiation, thermogenesis and vascularization.
 During the current funding cycle we found that obesity increases not only the number of ATMs but their
uptake and lysosomal-dependent catabolism of neutral lipid. As we investigated the source of ATM lipid, we
found not unexpectedly nearly all the lipid is adipocyte derived. However, surprisingly lipid accumulation in ATMs
does not require the canonical lipolytic pathway mediated by neutral lipases. Instead, adipocytes release
triglyceride-rich exosomes that both provide lipid to and induce differentiation of ATMs. This establishes
exosomes as components of adipose tissue lipid metabolism and regulators of immune function. Based on our
preliminary data and previous clinical and murine studies, we propose that adipocyte-derived exosomes and
ATMs are necessary components in a lipid cycle required for normal adipose tissue maintenance and function.
The work proposed in this application will characterize these exosomes, how they affect ATM recruitment and
differentiation, and whether local lysosomal hydrolysis of lipid by ATMs is required to prevent lipoatrophy.

## Key facts

- **NIH application ID:** 10142441
- **Project number:** 5R01DK066525-18
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Anthony W Ferrante
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $480,830
- **Award type:** 5
- **Project period:** 2003-09-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142441

## Citation

> US National Institutes of Health, RePORTER application 10142441, ADIPOSE TISSUE MACROPHAGE PHENOTYPE AND FUNCTION (5R01DK066525-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10142441. Licensed CC0.

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