Essential role of systemic iron mobilization and redistribution for adaptive thermogenesis through HIF2-α/hepcidin axis

Jin Seon Yook, Mikyoung You, Jiyoung Kim, Ashley M. Toney, Rong Fan, Bhanwar Lal Puniya, Tomáš Helikar, Sophie Vaulont, Jean Christophe Deschemin, Meshail Okla, Liwei Xie, Manik C. Ghosh, Tracey A. Rouault, Jaekwon Lee, Soonkyu Chung

Research output: Contribution to journalArticlepeer-review

Abstract

Iron is an essential biometal, but is toxic if it exists in excess. Therefore, iron content is tightly regulated at cellular and systemic levels to meet metabolic demands but to avoid toxicity. We have recently reported that adaptive thermogenesis, a critical metabolic pathway to maintain whole-body energy homeostasis, is an iron-demanding process for rapid biogenesis of mitochondria. However, little information is available on iron mobilization from storage sites to thermogenic fat. This study aimed to determine the iron-regulatory network that underlies beige adipogenesis. We hypothesized that thermogenic stimulus initiates the signaling interplay between adipocyte iron demands and systemic iron liberation, resulting in iron redistribution into beige fat. To test this hypothesis, we induced reversible activation of beige adipogenesis in C57BL/6 mice by administering a β3-adrenoreceptor agonist CL 316,243 (CL). Our results revealed that CL stimulation induced the iron-regulatory protein–mediated iron import into adipocytes, suppressed hepcidin transcription, and mobilized iron from the spleen. Mechanistically, CL stimulation induced an acute activation of hypoxia-inducible factor 2-α (HIF2-α), erythropoietin production, and splenic erythroid maturation, leading to hepcidin suppression. Disruption of systemic iron homeostasis by pharmacological HIF2-α inhibitor PT2385 or exogenous administration of hepcidin-25 significantly impaired beige fat development. Our findings suggest that securing iron availability via coordinated interplay between renal hypoxia and hepcidin down-regulation is a fundamental mechanism to activate adaptive thermogenesis. It also provides an insight into the effects of adaptive thermogenesis on systemic iron mobilization and redistribution.

Original languageEnglish (US)
Article numbere2109186118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number40
DOIs
StatePublished - Oct 5 2021
Externally publishedYes

Keywords

  • Adaptive thermogenesis
  • HIF2-α
  • Hepcidin
  • Hypoxia
  • Iron

ASJC Scopus subject areas

  • General

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