A Mediterranean Diet‐Based Food Mix Ameliorates Diabetes‐ and Obesity‐Associated Liver Alterations Through Mitochondrial and Metabolic Reprogramming

Metabolic syndrome (MetS)-related diseases, such as type 2 diabetes (T2D) and obesity, are among the leading causes of liver damage, and their prevalence poses an increasing clinical challenge. The Mediterranean diet (MD) has shown promising effects in managing MetS, reducing mortality and morbidity. However, the precise biochemical and molecular mechanisms underlying the MD efficacy remain unclear. This study evaluated the effects of a lab-designed balanced food mix, simulating the 1960s MD, on hepatic metabolic dysfunction in obese and diabetic db/db mice. The MD cocktail, naturally rich in polyphenols, fructose, and monounsaturated fatty acids, prevented hyperlipidemia while not reversing diabetes and obesity. Gene expression, protein representation, and metabolomic analyses of liver tissues from MD-fed db/db mice revealed reduced oxidative damage, preserved mitochondrial quality control, enhanced autophagy markers, and reduced fibrosis markers. The MD cocktail also enhanced liver mitochondrial mass and stimulated the OXPHOS system. It also preserved the hepatic pool of acylated carnitine derivatives and chenodeoxycholic acid, suggesting protective effects on mitochondrial β-oxidation and bile acid biosynthesis, with an overall improvement of metabolite profiles. The experimental MD cocktail exerted significant hepatoprotective effects, mitigating several diabetes- and obesity-induced hepatic disturbances and beneficially affecting metabolic fluxes and tissue texture.