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

Authors

Jin-Seon Yook, University of Massachusetts Amherst
Mikyoung You, University of Massachusetts Amherst
Jiyoung Kim, Kyungnam College of Information & Technology, Pusan, Korea
University of Nebraska-Lincoln, University of Nebraska-Lincoln
Rong Fan, University of Nebraska-Lincoln
Bhanwar Lal Puniya, University of Nebraska-LincolnFollow
Tomáš Helikar, University of Nebraska-LincolnFollow
Sophie Vaulont, National Institute for Health and Medical Research
Jean-Christophe Deschemin, National Institute for Health and Medical Research
Meshail Oklar, King Saud University
Liwei Xie, Guangdong Academy of Sciences, Guangzhou
Manik C. Ghosh, National Institute of Child Health and Human Development, NIH
Tracey A. Rouault, National Institute of Child Health and Human Development, NIH
Jaekwon Lee, University of Nebraska-LincolnFollow
Soonkyu Chung, University of Massachusetts AmherstFollow

ORCID IDs

Bhanwar Lal Puniya https://orcid.org/0000-0001-7528-3568

Tomáš Helikar https://orcid.org/0000-0003-3653-1906

Jean-Christophe Deschemin https://orcid.org/0000-0002-1256-8459

Liwei Xie https://orcid.org/0000-0002-4747-1753

Manik C. Ghosh https://orcid.org/0000-0002-6461-9545

Tracey A. Rouault https://orcid.org/0000-0003-0062-0245

Soonkyu Chung https://orcid.org/0000-0001-6279-7017

Document Type

Article

Date of this Version

2021

Citation

PNAS 2021 Vol. 118 No. 40 e2109186118

doi:10.1073/pnas.2109186118

Comments

U.S. government work

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 irondemanding 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.

Includes supplemental materials.