# Adipose Macrophage Iron Handling

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2021 · $500,861

## Abstract

Systemic control of iron mobilization serves two main functions: to provide iron for erythropoiesis and to
deplete iron during bacteriostasis. Yet, every cell in the body requires iron – for respiration, DNA synthesis, and
proliferation; while iron-overload can lead to oxidative damage to proteins, DNA, and lipid. Thus, iron
concentrations at the tissue and cellular level must be exquisitely controlled by mechanisms that compliment
and fine-tune systemic control. Reticuloendothelial Mϕs are distinctly suited to recycle Fe from senescent
erythrocytes by their high expression of CD163, the hemoglobin/haptoglobin receptor, which is uniquely
expressed on M2-like Mϕs. Our over-arching hypothesis is that tissue macrophages (Mϕs) are “ferrostats”,
sensing and responding to local tissue iron needs. This role of Mϕs is particularly important in adipose tissue
(AT); sufficient levels are required for adipogenesis in this tissue that must expand and contract more rapidly
than any other tissue, and prevention of free radical production is particularly important in a lipid-enriched
environment.
 Mϕs are not simply cells of the innate immune system that are critical defenders against infection. In fact,
they reside in all tissues and show remarkable plasticity based upon their local environment. This plasticity
requires rapid polarization on a spectrum of phenotypes ranging from M1-like inflammatory to M2-like tissue
repair phenotypes. We have identified a unique subpopulation of ATMϕs that have an iron-recycling phenotype
and are highly M2-polarized1. Furthermore, we show that these specialized Mϕs take up excess iron,
protecting the adipocytes from iron overload2. We refer to these iron cycling ATMϕs as MFehi and the remaining
ATMϕs as MFelo. MFehi Mϕs express high levels of iron-related genes such as CD163, transferrin receptor
(TfR1), and the iron exporter, ferroportin (Fpn). While our MFehi cells express some M2 genes, we have
intriguing preliminary data showing that MFehi bioenergetics are different than M2 bioenergetics, suggesting
that AT MFehi cells are uniquely polarized. Premised on our data, we hypothesize that: proper iron handling
creates a uniquely polarized ATMϕ phenotype that enhances their ability to influence adipogenesis
and insulin action in AT. In our three aims, we will determine the extent to which: 1) Mϕ iron processing
influences polarization and intrinsic immunometabolism, 2) ATMϕ iron handling impacts adipocyte
differentiation, insulin sensitivity and AT expansion, 3) Dysregulated ATMϕ polarization and iron handling
contribute to AT health and systemic insulin action during nutrient excess.

## Key facts

- **NIH application ID:** 10164771
- **Project number:** 5R01DK121520-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Alyssa H Hasty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $500,861
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164771

## Citation

> US National Institutes of Health, RePORTER application 10164771, Adipose Macrophage Iron Handling (5R01DK121520-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10164771. Licensed CC0.

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