Sex-Specific Effects of Cocoa on Hepatic Redox Regulation and Lipid Homeostasis in High-Fat Diet-Fed Mice

Non-alcoholic fatty liver disease (NAFLD) is a comorbidity of obesity, and sex influences disease progression. Cocoa can mitigate NAFLD, but the impact of sex has never been investigated. Herein, we compared the hepatoprotective effects of cocoa with different processing histories (unfermented/unroasted, unfermented/roasted, fermented/unroasted, fermented/roasted) in obese male and female mice. C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks to induce obesity and then randomized to HFD or HFD supplemented with 80 mg cocoa/g diet for an additional 8 weeks. Hepatic responses were analyzed at the mRNA and protein levels. Cocoa-treated male mice had decreased liver weight and enhanced expression of mitochondrial oxidative and endoplasmic reticulum (ER) stress response markers (p < 0.05). Cocoa-treated female mice had lower ER stress response markers and increased markers of very low-density lipoprotein biogenesis compared to HFD-fed controls (p < 0.05). Two-way multivariate analysis of variance revealed significant main effects of sex and diet, and a significant interaction. Canonical variate analysis demonstrated the efficacy of fermented/unroasted and fermented/roasted cocoas in both sexes, and unfermented/unroasted and unfermented/roasted cocoas in females. Cocoa mitigated obesity-related NAFLD by sexually dimorphic mechanisms. Further research is needed to develop personalized nutritional recommendations incorporating cocoa.