title: SMAD3 negatively regulates serum irisin and skeletal muscle FNDC5 and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) during exercise.
abstract: Beige adipose cells are a distinct and inducible type of thermogenic fat cell that express the mitochondrial uncoupling protein-1 and thus represent a powerful target for treating obesity. Mice lacking the TGF-β effector protein SMAD3 are protected against diet-induced obesity because of browning of their white adipose tissue (WAT), leading to increased whole body energy expenditure. However, the role SMAD3 plays in WAT browning is not clearly understood. Irisin is an exercise-induced skeletal muscle hormone that induces WAT browning similar to that observed in SMAD3-deficient mice. Together, these observations suggested that SMAD3 may negatively regulate irisin production and/or secretion from skeletal muscle. To address this question, we used wild-type and SMAD3 knock-out (Smad3(-/-)) mice subjected to an exercise regime and C2C12 myotubes treated with TGF-β, a TGF-β receptor 1 pharmacological inhibitor, adenovirus expressing constitutively active SMAD3, or siRNA against SMAD3. We find that in Smad3(-/-) mice, exercise increases serum irisin and skeletal muscle FNDC5 (irisin precursor) and its upstream activator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) to a greater extent than in wild-type mice. In C2C12 myotubes, TGF-β suppresses FNDC5 and PGC-1α mRNA and protein levels via SMAD3 and promotes SMAD3 binding to the FNDC5 and PGC-1α promoters. These data establish that SMAD3 suppresses FNDC5 and PGC-1α in skeletal muscle cells. These findings shed light on the poorly understood regulation of irisin/FNDC5 by demonstrating a novel association between irisin and SMAD3 signaling in skeletal muscle.
authors: From the Diabetes, Endocrinology, and Obesity Branch, NIDDK and.
authors: Joseph P
authors: JP
authors: Tiano
authors: the Murine Phenotyping Core, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
authors: Danielle A
authors: DA
authors: Springer
authors: From the Diabetes, Endocrinology, and Obesity Branch, NIDDK and ranes@niddk.nih.gov.
authors: Sushil G
authors: SG
authors: Rane
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D005353:Fibronectins / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D051900:Smad3 Protein / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: C571428:FNDC5 protein, mouse; D005353:Fibronectins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta
keywords: Exercise; Irisin; Obesity; SMAD Transcription Factor; Skeletal Muscle; Transforming Growth Factor Beta (TGF-B)
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