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Myeloid-specific deletion of ferroportin impairs macrophage bioenergetics but is
disconnected from systemic insulin action in adult mice.

Authors	Winn NC, Wolf EM, Cottam MA, Bhanot M, Hasty AH
Submitted By	Submitted Externally on 12/3/2021
Status	Published
Journal	American journal of physiology. Endocrinology and metabolism
Year	2021
Date Published	9/1/2021
Volume : Pages	321 : E376 - E391
PubMed Reference	34338042
Abstract	Tissue iron overload is associated with insulin resistance and mitochondrial dysfunction in rodents and humans; however, the mechanisms or cell types that mediate this phenotype are not completely understood. Macrophages (M?s) are known to contribute to iron handling; thus, we hypothesized that perturbed iron handling by M?s impairs mitochondrial energetics and evokes systemic insulin resistance in mice. Male and female mice with myeloid-targeted (LysMCre) deletion of the canonical iron exporter, ferroportin (Fpn, encoded by Slc40a1), floxed littermates, and C57BL/6J wild-type mice were used to test our hypotheses. Myeloid-targeted deletion of Fpn evoked multitissue iron accumulation and reduced mitochondrial respiration in bone marrow-derived M?s, liver leukocytes, and M?-enriched populations from adipose tissue (AT). In addition, a single bolus of exogenous iron administered to C57BL/6J mice phenocopied the loss of Fpn, resulting in a reduction in maximal and mitochondrial reserve capacity in M?-enriched cellular fractions from liver and AT. In vivo exogenous iron chelation restored mitochondrial reserve capacity in liver leukocytes from Fpn LysMCre mice, but had no effect in AT myeloid populations. However, despite the impairments in mitochondrial respiration, neither loss of myeloid-specific Fpn nor exogenous iron overload perturbed glucose homeostasis or systemic insulin action in lean or obese mice, whereas aging coupled with lifelong loss of Fpn unmasked glucose intolerance. Together these data demonstrate that iron handling is critical for the maintenance of macrophage mitochondrial function, but perturbing myeloid iron flux via the loss of Fpn action is not sufficient to evoke systemic insulin resistance in young adult mice. These findings also suggest that if M?s are capable of storing iron properly, they have a pronounced ability to withstand iron excess without evoking overt collateral damage and associated insulin resistance that may be age dependent.NEW & NOTEWORTHY We used myeloid-specific knockout of ferroportin to determine whether macrophage iron enrichment alters systemic metabolism. We found that macrophages in several tissues showed mitochondrial defects such as a reduction in mitochondrial reserve capacity. However, insulin action in the mice was preserved. These findings also suggest that M?s have a pronounced ability to withstand iron excess without evoking overt collateral damage and associated insulin resistance, which appears to be age dependent.

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