Iron uptake mediated by TFRC and secretion of transferrin types stimulate thermogenic activation in human adipocytes

Alrifai, R.; Seo, M.; Karadsheh, G.; Mahendra, F. R.; Demeny, M. A.; Györy, F.; Motyan, J. A.; Fesüs, L.; Kristof, E.; Arianti, R.

doi:10.1101/2025.11.24.690185

bioRxiv · 10.1101/2025.11.24.690185

Iron uptake mediated by TFRC and secretion of transferrin types stimulate thermogenic activation in human adipocytes

Alrifai, R.·Seo, M.·Karadsheh, G.·Mahendra, F. R.·Demeny, M. A.·Györy, F.·Motyan, J. A.·Fesüs, L.·Kristof, E.·Arianti, R.

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Abstract

Adrenergic-driven thermogenic activation of brown adipose tissue requires high amounts of nutrients including iron supporting mitochondrial biogenesis. This was governed by rapid gene expression changes in human cervical-derived brown adipocytes. Transferrin receptor 1 (TFRC) was strongly upregulated in response to dibutyryl-cAMP. Pharmacological inhibition and siRNA-mediated knockdown of TFRC during adrenergic stimulation decreased intracellular iron content and prevented elevation of oxygen consumption and induction of thermogenic markers. Deferoxamine-mediated iron chelation also showed comparable effects. Contrarily, the expression of ferroportin iron exporter was suppressed during activation, however, its pharmacological inhibition did not further increase thermogenesis. Brown adipocytes constitutively expressed and secreted high amounts of transferrin while the released melanotransferrin at activated condition was predicted to further augment iron influx stimulating heat production.

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Alrifai, R., Seo, M., Karadsheh, G., Mahendra, F. R., Demeny, M. A., Györy, F., Motyan, J. A., Fesüs, L., Kristof, E., Arianti, R.. 2025-11-26. Iron uptake mediated by TFRC and secretion of transferrin types stimulate thermogenic activation in human adipocytes. https://doi.org/10.1101/2025.11.24.690185

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