title: Irisin exerts dual effects on browning and adipogenesis of human white adipocytes.
abstract: To better understand the role of irisin in humans, we examined the effects of irisin in human primary adipocytes and fresh human subcutaneous white adipose tissue (scWAT). Human primary adipocytes derived from 28 female donors' fresh scWAT were used to examine the effects of irisin on browning and mitochondrial respiration, and preadipocytes were used to examine the effects of irisin on adipogenesis and osteogenesis. Cultured fragments of scWAT and perirenal brown fat were used for investigating signal transduction pathways that mediate irisin's browning effect by Western blotting to detect phosphorylated forms of p38, ERK, and STAT3 as well as uncoupling protein 1 (UCP1). Individual responses to irisin in scWAT were correlated with basal expression levels of brown/beige genes. Irisin upregulated the expression of browning-associated genes and UCP1 protein in both cultured primary mature adipocytes and fresh adipose tissues. It also significantly increased thermogenesis at 5 nmol/l by elevating cellular energy metabolism (OCR and ECAR). Treating human scWAT with irisin increased UCP1 expression by activating the ERK and p38 MAPK signaling. Blocking either pathway with specific inhibitors abolished irisin-induced UCP1 upregulation. However, our results showed that UCP1 in human perirenal adipose tissue was insensitive to irisin. Basal levels of brown/beige and FNDC5 genes correlated positively with the browning response of scWAT to irisin. In addition, irisin significantly inhibited adipogenic differentiation but promoted osteogenic differentiation. We conclude that irisin promotes "browning" of mature white adipocytes by increasing cellular thermogenesis, whereas it inhibits adipogenesis and promotes osteogenesis during lineage-specific differentiation. Our findings provide a rationale for further exploring the therapeutic use of irisin in obesity and exercise-associated bone formation.
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida; Center for Stem Cell and Regenerative Medicine, The Second Hospital of Shandong University, Jinan, China;
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Chao
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Robin M
authors.initials: RM
authors.lastname: Foss
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Morgan
authors.initials: M
authors.lastname: Clare
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Eva Vertes
authors.initials: EV
authors.lastname: George
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Shiwu
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Adam
authors.initials: A
authors.lastname: Katz
authors.affiliation: Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana;
authors.forename: Henrique
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery, and Development, College of Pharmacy, University of Florida, Gainesville, Florida; and.
authors.forename: Yousong
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Center for Stem Cell and Regenerative Medicine, The Second Hospital of Shandong University, Jinan, China;
authors.forename: Dongqi
authors.initials: D
authors.lastname: Tang
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Westley H
authors.initials: WH
authors.lastname: Reeves
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida; yanglj@pathology.ufl.edu.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Yang
mesh_terms: D052437:Adipocytes, Brown / Q000187:drug effects / Q000378:metabolism; D052438:Adipocytes, White / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects* / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D015444:Exercise; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D050151:Subcutaneous Fat / Q000166:cytology; D022722:Thermogenesis / Q000187:drug effects* / Q000235:genetics; D000071256:Uncoupling Protein 1 / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: C577593:FNDC5 protein, human; D005353:Fibronectins; D010750:Phosphoproteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: adipocytes browning; adipogenesis; brown adipose tissue; human white adipose tissue; irisin; osteogenesis; thermogenesis