Adipose tissue macrophages exert systemic metabolic control by manipulating local iron concentrations

Nolwenn Joffin, Christy M. Gliniak, Jan Bernd Funcke, Vivian A. Paschoal, Clair Crewe, Shiuhwei Chen, Ruth Gordillo, Christine M. Kusminski, Da Young Oh, Werner J. Geldenhuys, Philipp E. Scherer

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Iron is essential to many fundamental biological processes, but its cellular compartmentalization and concentration must be tightly controlled. Although iron overload can contribute to obesity-associated metabolic deterioration, the subcellular localization and accumulation of iron in adipose tissue macrophages is largely unknown. Here, we show that macrophage mitochondrial iron levels control systemic metabolism in male mice by altering adipocyte iron concentrations. Using various transgenic mouse models to manipulate the macrophage mitochondrial matrix iron content in an inducible fashion, we demonstrate that lowering macrophage mitochondrial matrix iron increases numbers of M2-like macrophages in adipose tissue, lowers iron levels in adipocytes, attenuates inflammation and protects from high-fat-diet-induced metabolic deterioration. Conversely, elevating macrophage mitochondrial matrix iron increases M1-like macrophages and iron levels in adipocytes, exacerbates inflammation and worsens high-fat-diet-induced metabolic dysfunction. These phenotypes are robustly reproduced by transplantation of a small amount of fat from transgenic to wild-type mice. Taken together, we identify macrophage mitochondrial iron levels as a crucial determinant of systemic metabolic homeostasis in mice.

Original languageEnglish
Pages (from-to)1474-1494
Number of pages21
JournalNature Metabolism
Volume4
Issue number11
DOIs
StatePublished - Nov 2022

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