The Adipocyte Na/K-Atpase Oxidant Amplification Loop is the Central Regulator of Western Diet-Induced Obesity and Associated Comorbidities

Obesity has become a worldwide epidemic.We have previously reported that systemic administration of pNaKtide which targets the Na/K-ATPase oxidant amplification loop (NKAL) was able to decrease systemic oxidative stress in mice.As adipocytes are believed to play a central role in the development of oxidative stress and its related comorbidities, we examined whether lentiviralmediated adipocyte-specific expression of NaKtide, a peptide derived from the N domain of the Na/K-ATPase 1 subunit, could ameliorate the effects of the WD.C57BL/6 mice were fed a WD, which activated Na/K-ATPase signaling in the adipocytes and induced an obese phenotype, causing increases in plasma levels of leptin, IL-6, and TNF.WD also showed decreased locomotor activity and downregulated tyrosine hydroxylase in brain tissue, but increased markers of neurodegeneration and neuronal apoptosis.Lentiviral-mediated adipocyte-specific expression of NaKtide in mice fed a WD attenuated all these changes including the brain biochemical alterations and behavioral adaptations.These data suggest that adipocyte-derived cytokines play an essential role in the development of obesity induced by a WD and that targeting the adipocyte NKAL loop may serve as an effective therapeutic strategy.