title: Postnatal PPARdelta activation and myostatin inhibition exert distinct yet complimentary effects on the metabolic profile of obese insulin-resistant mice.
abstract: BACKGROUND
  Interventions for T2DM have in part aimed to mimic exercise. Here, we have compared the independent and combined effects of a PPARdelta agonist and endurance training mimetic (GW501516) and a myostatin antibody and resistance training mimetic (PF-879) on metabolic and performance outcomes in obese insulin resistant mice.
  
  
  RESULTS
  Male ob/ob mice were treated for 6 weeks with vehicle, GW501516, PF-879, or GW501516 in combination with PF-879. The effects of the interventions on body composition, glucose homeostasis, glucose tolerance, energy expenditure, exercise capacity and metabolic gene expression were compared at the end of study. GW501516 attenuated body weight and fat mass accumulation and increased the expression of genes of oxidative metabolism. In contrast, PF-879 increased body weight by driving muscle growth and altered the expression of genes involved in insulin signaling and glucose metabolism. Despite their differences, both interventions alone improved glucose homeostasis. Moreover, GW501516 more effectively improved serum lipids, and PF-879 uniquely increased energy expenditure, exercise capacity and adiponectin levels. When combined the robust effects of GW501516 and/or PF-879 on body weight, adiposity, muscle mass, glycemia, serum lipids, energy expenditure and exercise capacity were highly conserved.
  
  
  CONCLUSIONS
  The data, for the first time, demonstrate postnatal inhibition of myostatin not only promotes gains in muscle mass similar to resistance training,but improves metabolic homeostasis. In several instances, these effects were either distinct from or complimentary to those of GW501516. The data further suggest that strategies to increase muscle mass, and not necessarily oxidative capacity, may effectively counter insulin resistance and T2DM.
authors.affiliation: Cardiovascular, Metabolic and Endocrine Diseases, Pfizer Global Research and Development, Groton, Connecticut, United States of America.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Bernardo
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Wachtmann
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Cosgrove
authors.forename: Max
authors.initials: M
authors.lastname: Kuhn
authors.forename: Alan C
authors.initials: AC
authors.lastname: Opsahl
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Judkins
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Freeman
authors.forename: John R
authors.initials: JR
authors.lastname: Hadcock
authors.forename: Nathan K
authors.initials: NK
authors.lastname: LeBrasseur
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001823:Body Composition; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055435:Myostatin / Q000037:antagonists & inhibitors* / Q000276:immunology; D009765:Obesity / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists*; D010805:Physical Conditioning, Animal; D016133:Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D052242:Adiponectin; D000911:Antibodies, Monoclonal; D007328:Insulin; D055435:Myostatin; D047494:PPAR delta; D014280:Triglycerides; D002950:Citrate (si)-Synthase; D005947:Glucose