title: Leptin administration activates irisin-induced myogenesis via nitric oxide-dependent mechanisms, but reduces its effect on subcutaneous fat browning in mice.
abstract: BACKGROUND/OBJETIVES: Obese leptin-deficient ob/ob mice exhibit high adiposity and reduced muscle mass with leptin replacement promoting weight loss and inducing muscle accretion through PGC-1α-dependent mechanisms. Our aim was to analyze in vivo and in vitro the effect of leptin on FNDC5, a novel PGC-1α-dependent myokine that is synthesized and cleaved to form irisin that induces white adipose browning.
  
  
  RESULTS
  Twelve-week-old male wild-type and ob/ob mice were divided in three groups as follows: control, leptin-treated (1 mg kg(-1) day(-1)) and pair-fed. Leptin administration was associated with increased gastrocnemius weight and cell surface area, higher Pgc1a and Fndc5 transcript levels and a slight increase in circulating irisin. Leptin upregulated Fndc5 expression through nitric oxide (NO)-dependent mechanisms in murine C2C12 myocytes and stimulated both basal and irisin-stimulated myogenesis, as evidenced by increased myocyte cell proliferation, higher myogenin and myonectin transcript levels together with lower mRNA expression of myostatin and dystrophin and the muscle atrophy-related factors MuRF1 and MAFbx. Interestingly, leptin downregulated Fndc5 expression in a NO-independent manner in murine differentiated subcutaneous adipocytes. Furthermore, leptin prevented the irisin-induced upregulation of both brown (Ucp1 and Cidec) and beige (Tmem26) adipocyte-specific genes and the increase in uncoupling protein-1-positive cells.
  
  
  CONCLUSIONS
  Taken together, our results provide evidence for a regulatory role of leptin on FNDC5/irisin, favoring muscle accretion but reducing fat browning.
authors.affiliation: 1] Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Pamplona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez
authors.affiliation: 1] Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Pamplona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Becerril
authors.affiliation: 1] Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Pamplona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Méndez-Giménez
authors.affiliation: 1] Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Pamplona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Ramírez
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Sáinz
authors.affiliation: 1] Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Pamplona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Catalán
authors.affiliation: 1] Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Pamplona, Spain.
authors.forename: J
authors.identifier: 0000000156011604
authors.initials: J
authors.lastname: Gómez-Ambrosi
authors.affiliation: 1] Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Pamplona, Spain [3] Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Frühbeck
mesh_terms: D041721:3T3-L1 Cells; D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D005353:Fibronectins / Q000378:metabolism*; D015870:Gene Expression; D020738:Leptin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000473:pathology*; D010860:Pigments, Biological / Q000378:metabolism*; D050507:Subcutaneous Fat, Abdominal / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D015431:Weight Loss
chemical_list: C571428:FNDC5 protein, mouse; D005353:Fibronectins; D020738:Leptin; D010860:Pigments, Biological; D014157:Transcription Factors; D009569:Nitric Oxide