title: Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis.
abstract: Skeletal muscle plays important roles in whole-body glucose and fatty acid metabolism. However, muscle also secretes cytokines and growth factors (collectively termed myokines) that can potentially act in an autocrine, a paracrine, and/or an endocrine manner to modulate metabolic, inflammatory, and other processes. Here, we report the identification and characterization of myonectin, a novel myokine belonging to the C1q/TNF-related protein (CTRP) family. Myonectin transcript was highly induced in differentiated myotubes and predominantly expressed by skeletal muscle. Circulating levels of myonectin were tightly regulated by the metabolic state; fasting suppressed, but refeeding dramatically increased, its mRNA and serum levels. Although mRNA and circulating levels of myonectin were reduced in a diet-induced obese state, voluntary exercise increased its expression and circulating levels. Accordingly, myonectin transcript was up-regulated by compounds (forskolin, epinephrine, ionomycin) that raise cellular cAMP or calcium levels. In vitro, secreted myonectin forms disulfide-linked oligomers, and when co-expressed, forms heteromeric complexes with other members of the C1q/TNF-related protein family. In mice, recombinant myonectin administration reduced circulating levels of free fatty acids without altering adipose tissue lipolysis. Consistent with this, myonectin promoted fatty acid uptake in cultured adipocytes and hepatocytes, in part by up-regulating the expression of genes (CD36, FATP1, Fabp1, and Fabp4) that promote lipid uptake. Collectively, these results suggest that myonectin links skeletal muscle to lipid homeostasis in liver and adipose tissue in response to alterations in energy state, revealing a novel myonectin-mediated metabolic circuit.
authors.affiliation: Department of Physiology and Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Seldin
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Peterson
authors.forename: Mardi S
authors.initials: MS
authors.lastname: Byerly
authors.forename: Zhikui
authors.initials: Z
authors.lastname: Wei
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006031:Glycosylation; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009752:Nutritional Status / Q000235:genetics; D009765:Obesity / Q000097:blood / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011817:Rabbits; D014158:Transcription, Genetic
chemical_list: D054392:Adipokines; C568466:C1qtnf12 protein, mouse; D016207:Cytokines; C572502:Erfe protein, mouse; D005227:Fatty Acids; D009124:Muscle Proteins