Obesity-associated kidney disease involves metabolic dysfunction accompanied by lipotoxicity, inflammation, and fibrosis. We previously showed that grape pomace extract (GPE), a polyphenol-rich byproduct of winemaking, exerts renoprotective effects in obese mice; however, the underlying mechanisms remain incompletely understood. This study aims to investigate whether adenosine monophosphate-activated protein kinase (AMPK) mediates the protective effects of dietary GPE supplementation in high-fat diet (HF)-induced obese mice. Male C57BL/6J mice were fed a standard diet (16% calories from fat) or a HF (60% calories from fat) with or without GPE (300 mg per kg body weight per day) for 16 weeks. A subset of animals was treated with compound C (CC), a widely used AMPK inhibitor, during the last 4 weeks. GPE attenuated HF-induced body weight gain, visceral adiposity, dyslipidemia, glucose intolerance, and renal dysfunction, while improving histopathological alterations. Mechanistically, GPE restored renal AMPK phosphorylation, increased autophagy markers (increased LC3-II/LC3-I ratio and Beclin-1 levels) and reduced renal lipid accumulation. In addition, GPE enhanced levels of the mitochondrial biogenesis regulator PGC-1α, while attenuating oxidative stress (Nox4, 4-HNE, and oxidant species production), inflammatory signaling (NF-κB-NLRP3 pathway), and renal fibrosis. Notably, pharmacological AMPK inhibition reversed the GPE effect, leading to worsening of renal injury, autophagy impairment, increased lipid deposition, and exacerbation of fibrotic and inflammatory markers. These findings demonstrate that AMPK activation is a mediator of the metabolic and renoprotective effects of GPE, positioning GPE as a promising functional food ingredient for attenuation of obesity-associated kidney disease.
