Defective Leptin–AMP-Dependent Kinase Pathway Induces Nitric Oxide Release and Contributes to Mitochondrial Dysfunction and Obesity inob/obMice

Considering that nitric oxide binds cytochrome oxidase and inhibits respiration, we explored NO as a direct effector of mitochondrial dysfunction in the leptin-deficient ob/ob mice

Paola V. Finocchietto; Silvia Holod; Fernando Barreyro; Jorge G. Peralta; Yael Alippe; Andrés Giovambattista; María C. Carreras; Juan J. Poderoso

2011

Scholarcy highlights

  • Obesity arises on defective neuroendocrine pathways that increase energy intake and reduce mitochondrial metabolism
  • Considering that nitric oxide binds cytochrome oxidase and inhibits respiration, we explored NO as a direct effector of mitochondrial dysfunction in the leptin-deficient ob/ob mice
  • Innovation: We evidenced that leptin increases mitochondrial respiration and fat utilization by potentially inhibiting NO release
  • Leptin administration to ob/ob mice prevented neuronal nitric oxide synthase overexpression and mitochondrial dysfunction in vivo and rescued leptin-dependent effects by matrix NO reduction, whereas leptin–Ob-Rb disruption increased the formation of mitochondrial NO in control adipocytes
  • We demonstrated that in ob/ob, hypoleptinemia is associated with critically low mitochondrial p-AMPK and that, oppositely to p-Akt, p-AMPK is a negative modulator of nNOS
  • Thereby, defective leptin–AMPK pathway links mitochondrial nitric oxide to obesity with complex I syndrome and dysfunctional mitochondria

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