title: Over-expression of Follistatin-like 3 attenuates fat accumulation and improves insulin sensitivity in mice.
abstract: OBJECTIVE
  Follistatin-like 3 (fstl3), a natural inhibitor of members of the TGF-β family, increases during resistance training in human plasma. Fstl3 primarily binds myostatin and activin A, and thereby inhibits their functions. We hypothesize that blocking myostatin and activin A signalling through systemic fstl3 over-expression protects against diet-induced obesity and insulin resistance.
  
  
  METHODS
  Fstl3 was over-expressed by DNA electrotransfer in tibialis anterior, quadriceps and gastrocnemius muscles in female C57BL/C mice, and the mice were subsequently randomized to chow or high-fat feeding. Body weight, food intake, fat accumulation by MR scanning, and glucose, insulin and glucagon tolerance were evaluated, as was the response in body weight and metabolic parameters to 24h fasting. Effects of fstl3 on pancreatic insulin and glucagon content, and pancreatic islet morphology were determined.
  
  
  RESULTS
  Fstl3 over-expression reduced fat accumulation during high-fat feeding by 16%, and liver fat by 50%, as determined by MRI. No changes in body weight were observed, while the weight of the transfected muscles increased by 10%. No transcriptional changes were found in the subcutaneous adipose tissue. Fstl3 mice displayed improved insulin sensitivity and muscle insulin signalling. In contrast, glucose tolerance was impaired in high-fat fed fstl3 mice, which was explained by increased hepatic glucagon sensitivity and glucose output, as well as a decrease in the pancreatic insulin/glucagon ratio. Accordingly, fstl3 transfection improved counter-regulation to 24h fasting.
  
  
  CONCLUSIONS
  Fstl3 over-expression regulates insulin and glucagon sensitivities through increased muscular insulin action, as well as increased hepatic glucagon sensitivity and pancreatic glucagon content.
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Brandt
authors.affiliation: Research Group, Dept. of Radiology, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
authors.forename: Rasmus Hvass
authors.initials: RH
authors.lastname: Hansen
authors.affiliation: Immunoendocrinology lab, Section of Endocrinological Research, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
authors.forename: Jakob Bondo
authors.initials: JB
authors.lastname: Hansen
authors.affiliation: Department of Pathology, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
authors.forename: Caroline Holkmann
authors.initials: CH
authors.lastname: Olsen
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
authors.forename: Pia
authors.initials: P
authors.lastname: Galle
authors.affiliation: Immunoendocrinology lab, Section of Endocrinological Research, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark; Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna, SE-171 76, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
authors.affiliation: Department of Oncology, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
authors.forename: Julie
authors.initials: J
authors.lastname: Gehl
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
authors.forename: Bente Klarlund
authors.initials: BK
authors.lastname: Pedersen
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: phojman@inflammation-metabolism.dk.
authors.forename: Pernille
authors.initials: P
authors.lastname: Hojman
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D038702:Follistatin-Related Proteins; D005934:Glucagon / Q000378:metabolism; D018149:Glucose Intolerance / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000166:cytology / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D055435:Myostatin / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D050151:Subcutaneous Fat / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D038702:Follistatin-Related Proteins; C498620:Fstl3 protein, mouse; D007328:Insulin; C525912:Mstn protein, mouse; D055435:Myostatin; D011506:Proteins; D011994:Recombinant Proteins; C422405:activin A; D028341:Activins; D005934:Glucagon
keywords: Fasting response; Fstl3; Glucagon sensitivity; Insulin sensitivity; Whole-body metabolism