The thermogenic characteristics of adipocytes are dependent on the regulation of iron homeostasis

• Published in: The Journal of biological chemistry 2021-01, Vol.296, p.100452-100452, Article 100452
• Main Authors: Yook, Jin-Seon, You, Mikyoung, Kim, Yongeun, Zhou, Mi, Liu, Zhenhua, Kim, Young-Cheul, Lee, Jaekwon, Chung, Soonkyu
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Acclimatization; Aconitate Hydratase - metabolism; Adipocytes - metabolism; Adipocytes, Beige - metabolism; Adipocytes, Brown - metabolism; Adipocytes, White - metabolism; adipose iron; Animals; Body Temperature Regulation - physiology; brown fat; Cell Differentiation; Homeostasis; Iron - metabolism; iron homeostasis; Iron Regulatory Protein 1 - genetics; Iron Regulatory Protein 1 - metabolism; Iron Regulatory Protein 2 - genetics; Iron Regulatory Protein 2 - metabolism; iron regulatory proteins; iron-response element; labile iron pool; Male; Mice; Mice, Inbred C57BL; mitochondria; Mitochondria - metabolism; Organelle Biogenesis; RNA, Messenger - metabolism; Signal Transduction; thermogenesis; Thermogenesis - physiology; uncoupling protein
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2021.100452

The development of thermogenic adipocytes concurs with mitochondrial biogenesis, an iron-dependent pathway. Iron regulatory proteins (IRP) 1 and 2 are RNA-binding proteins that regulate intracellular iron homeostasis. IRPs bind to the iron-response element (IRE) of their target mRNAs, balancing iron uptake and deposition at the posttranscriptional levels. However, IRP/IRE-dependent iron regulation in adipocytes is largely unknown. We hypothesized that iron demands are higher in brown/beige adipocytes than white adipocytes to maintain the thermogenic mitochondrial capacity. To test this hypothesis, we investigated the IRP/IRE regulatory system in different depots of adipose tissue. Our results revealed that 1) IRP/IRE interaction was increased in proportional to the thermogenic function of the adipose depot, 2) adipose iron content was increased in adipose tissue browning upon β3-adrenoceptor stimulation, while decreased in thermoneutral conditions, and 3) modulation of iron content was linked with mitochondrial biogenesis. Moreover, the iron requirement was higher in HIB1B brown adipocytes than 3T3-L1 white adipocytes during differentiation. The reduction of the labile iron pool (LIP) suppressed the differentiation of brown/beige adipocytes and mitochondrial biogenesis. Using the 59Fe-Tf, we also demonstrated that thermogenic stimuli triggered cell-autonomous iron uptake and mitochondrial compartmentalization as well as enhanced mitochondrial respiration. Collectively, our work demonstrated that IRP/IRE signaling and subsequent adaptation in iron metabolism are a critical determinant for the thermogenic function of adipocytes.