title: Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues.
abstract: OBJECTIVE
  In mice, a high-fat diet (HFD) induces obesity, insulin resistance and myostatin production. We tested whether inhibition of myostatin in mice can reverse these HFD-induced abnormalities.
  
  
  METHODS
  C57BL/6 mice were fed a HFD for 16 weeks including the final 4 weeks some mice were treated with an anti-myostatin peptibody. Body composition, the respiratory exchange ratio plus glucose and insulin tolerance tests were examined. Myostatin knock down in C2C12 cells was performed using small hairpin RNA lentivirus. Adipose tissue-derived stem cells were cultured to measure their responses to conditioned media from C2C12 cells lacking myostatin, or to recombinant myostatin or irisin. Isolated peritoneal macrophages were treated with myostatin or irisin to determine whether myostatin or irisin induce inflammatory mechanisms.
  
  
  RESULTS
  In HFD-fed mice, peptibody treatment stimulated muscle growth and improved insulin resistance. The improved glucose and insulin tolerances were confirmed when we found increased muscle expression of p-Akt and the glucose transporter, Glut4. In HFD-fed mice, the peptibody suppressed macrophage infiltration and the expression of proinflammatory cytokines in both the muscle and adipocytes. Inhibition of myostatin caused the conversion of white (WAT) to brown adipose tissue, whereas stimulating fatty acid oxidation and increasing energy expenditure. The related mechanism is a muscle-to-fat cross talk mediated by irisin. Myostatin inhibition increased peroxisome proliferator-activated receptor gamma, coactivator 1α expression and irisin production in the muscle. Irisin then stimulated WAT browning. Irisin also suppresses inflammation and stimulates macrophage polarization from M1 to M2 types.
  
  
  CONCLUSIONS
  These results uncover a metabolic pathway from an increase in myostatin that suppresses irisin leading to the activation of inflammatory cytokines and insulin resistance. Thus, myostatin is a potential therapeutic target to treat insulin resistance of type II diabetes as well as the shortage of brown/beige fat in obesity.
authors.affiliation: College of Life Sciences, Sichuan University, Chengdu 610065, China.|Baylor College of Medicine, Nephrology Division, Houston, TX, 77030.
authors.forename: Jiangling
authors.initials: J
authors.lastname: Dong
authors.affiliation: Baylor College of Medicine, Nephrology Division, Houston, TX, 77030.|Beijing Institutes of Heart, Lung, and Blood Vessel Diseases, An Zhen Hospital Affiliated to Capital Medical University, Beijing, 100029, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Baylor College of Medicine, Nephrology Division, Houston, TX, 77030.
authors.forename: Yanlan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: College of Life Sciences, Sichuan University, Chengdu 610065, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Baylor College of Medicine, Nephrology Division, Houston, TX, 77030.
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
authors.affiliation: Baylor College of Medicine, Nephrology Division, Houston, TX, 77030.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D018482:Muscle, Skeletal / Q000378:metabolism*; D055435:Myostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020239:Receptor Cross-Talk
chemical_list: D007328:Insulin; D055435:Myostatin; D051057:Proto-Oncogene Proteins c-akt