Skeletal muscle secreted myonectin maintains systemic metabolic homeostasis

BACKGROUND Skeletal muscle is the largest organ in lean individuals with high secretory capacity, regulating systemic metabolism by exerting endocrine, paracrine and autocrine effects. Myonectin, also designated as family with sequence similarity 132B (FAM132B), is a novel cytokine predominantly secreted by skeletal muscle. Despite its role as a potent regulator of lipid uptake in cultured cells, the physiological function of myonectin in maintaining systemic metabolic homeostasis remains to be fully elucidated. OBJECTIVE This study aimed to investigate the physiological function of myonectin in maintaining metabolic homeostasis by assessing the effect of deficiency in mice. METHODS Microarray dataset GSM103563 from gene expression omnibus (GEO) repository was analyzed to determine myonectin expression in human vastus lateralis muscle biopsies isolated before and after 48‐hours of knee immobilization. Myonectin gene expression in mice was assessed by quantitative polymerase chain reaction (q‐PCR) performed on soleus muscle isolated from heterozygous (Fam132b +/− , HT) and homozygous (Fam132b −/− , KO) myonectin‐deficient mice and wildtype (Fam132b +/+ , WT) littermates. Body weights of myonectin‐deficient mice and wildtype littermates were monitored from weaning for 6‐month. At 16‐weeks of age, body composition was assessed by dual‐energy X‐ray absorptiometry (DEXA). At 18‐weeks of age, glucose metabolism was assessed with glucose tolerance test (GTT). At 20‐weeks of age, basal metabolic rate and substrate utilization were assessed by 24‐hour indirect calorimetry (IDC). RESULTS We found myonectin is expressed in adult human skeletal muscle, and the expression level significantly decreases with muscle inactivity. Myonectin expression is also found in skeletal muscle of WT mice but is significantly attenuated in myonectin‐deficient HT and KO littermates. Notably, myonectin deficiency in HT and KO mice leads to substantial and sustained weight gain over a 6‐month period on normal chow diet in both males and females, primarily due to increased adiposity relative to WT littermates as suggested by body composition analysis. In addition, we found myonectin deficiency decreased basal metabolic rate in mice as determined by rates of O 2 consumption and CO 2 production. Furthermore, we did not observe any significant changes in food intake, suggesting the primary cause of weight gain and adiposity is the impaired energy expenditure. The measured respiratory exchange ratio (RER) was persistently higher in myonectin‐deficient mice, suggesting impaired lipid metabolism and metabolic inflexibility in substrate utilization. Finally, glucose tolerance test revealed the impaired glucose clearance in mice with myonectin deficiency, suggesting that myonectin is a regulator of systemic glucose homeostasis. CONCLUSION Skeletal muscle‐secreted myonectin is essential for maintaining metabolic homeostasis in mice. Our study suggests that myonectin is an important mediator for the well‐established protective effect of exercise against wide‐range of metabolic diseases.