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Leptin administration activates irisin-induced myogenesis via nitric oxide-dependent mechanisms, but reduces its effect on subcutaneous fat browning in mice

International Journal of Obesity volume 39, pages 397–407 (2015)Cite this article

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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.

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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Acknowledgements

We gratefully acknowledge the valuable collaboration of all the staff of the breeding house of the University of Navarra, in particular, Elena Ciordia, Alberto Espinal and Juan Percaz. This work was funded by the Instituto de Salud Carlos III and fondos FEDER (FIS PI10/01677, PI12/00515 and PI13/1430) and by Plan de Investigación de la Universidad de Navarra (PIUNA) (2011–2014). CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of the Instituto de Salud Carlos III, Spain.

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Authors and Affiliations

  1. Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain

    A Rodríguez, S Becerril, L Méndez-Giménez, B Ramírez, N Sáinz, V Catalán, J Gómez-Ambrosi & G Frühbeck

  2. CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Pamplona, Spain

    A Rodríguez, S Becerril, L Méndez-Giménez, B Ramírez, V Catalán, J Gómez-Ambrosi & G Frühbeck

  3. Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain

    G Frühbeck

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Rodríguez, A., Becerril, S., Méndez-Giménez, L. et al. Leptin administration activates irisin-induced myogenesis via nitric oxide-dependent mechanisms, but reduces its effect on subcutaneous fat browning in mice. Int J Obes 39, 397–407 (2015). https://doi.org/10.1038/ijo.2014.166

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