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  • Title: Leptin administration activates irisin-induced myogenesis via nitric oxide-dependent mechanisms, but reduces its effect on subcutaneous fat browning in mice.
    Author: Rodríguez A, Becerril S, Méndez-Giménez L, Ramírez B, Sáinz N, Catalán V, Gómez-Ambrosi J, Frühbeck G.
    Journal: Int J Obes (Lond); 2015 Mar; 39(3):397-407. PubMed ID: 25199621.
    Abstract:
    UNLABELLED: 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. METHODS/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.
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