title: Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans.
abstract: Rediscovery of cold-activated brown adipose tissue (BAT) in humans has boosted research interest in identifying BAT activators for metabolic benefits. Of particular interest are cytokines capable of fat browning. Irisin, derived from FNDC5, is an exercise-induced myokine that drives brown-fat-like thermogenesis in murine white fat. Here we explored whether cold exposure is an afferent signal for irisin secretion in humans and compared it with FGF21, a brown adipokine in rodents. Cold exposure increased circulating irisin and FGF21. We found an induction of irisin secretion proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. FNDC5 and/or FGF21 treatment upregulated human adipocyte brown fat gene/protein expression and thermogenesis in a depot-specific manner. These results suggest exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21. Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis that is exploitable in obesity therapeutics development.
authors: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Paul
authors: P
authors: Lee
authors: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Joyce D
authors: JD
authors: Linderman
authors: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Sheila
authors: S
authors: Smith
authors: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Robert J
authors: RJ
authors: Brychta
authors: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Juan
authors: J
authors: Wang
authors: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Christopher
authors: C
authors: Idelson
authors: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Rachel M
authors: RM
authors: Perron
authors: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Charlotte D
authors: CD
authors: Werner
authors: Surgery Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Giao Q
authors: GQ
authors: Phan
authors: Surgery Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Udai S
authors: US
authors: Kammula
authors: Endocrine Oncology Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Electron
authors: E
authors: Kebebew
authors: National Cancer Institute and Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Karel
authors: K
authors: Pacak
authors: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Kong Y
authors: KY
authors: Chen
authors: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: fsceli@vcu.edu.
authors: Francesco S
authors: FS
authors: Celi
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D054392:Adipokines / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000328:Adult; D015444:Exercise / Q000502:physiology*; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000378:metabolism; D005353:Fibronectins / Q000097:blood* / Q000378:metabolism; D006801:Humans; D008297:Male; D012768:Shivering / Q000502:physiology; D055815:Young Adult
chemical_list: D054392:Adipokines; C577593:FNDC5 protein, human; D005353:Fibronectins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors