2.4. Modulation of Obesity-Related Inflammation and Fatty Liver Disease by Cocoa: A Potential Role for the Mitochondria
Fatty liver disease is an important co-morbidity of obesity. Previously, we have reported that dietary cocoa (Theobroma cacao) supplementation can reduce obesity-related inflammation and markers of insulin resistance in high fat-fed mice. In the present study, we examined the effect of cocoa supplementation on obesity-related fatty liver disease. Male C57BL/6J were fed a high fat (HF) (60% kcal from fat) diet for eight weeks and then randomized to continue the HF diet or to consume an HF diet supplemented with 80 mg/g cocoa powder (HFÑHFC) for an additional 10 weeks. Dietary cocoa reduced hepatic lipid content by 40% and plasma alanine aminotransferase levels by 32% compared to obese mice. Cocoa treatment also reduced the expression of hepatic pro-inflammatory markers (monocyte chemoattractant protein 1 and macrophage inflammatory protein 1a), but increased expression of hepatic markers of alternative (anti-inflammatory) macrophage activation (interleukin 10 and CD163) compared to HF-fed obese controls. Analysis of data related to mitochondrial biogenesis, oxidative stress and antioxidant response showed that cocoa increased mitochondrial biogenesis and increased mitochondrial antioxidant response compared to obese controls. We found cocoa treatment increases hepatic mitochondrial DNA copy number by 48.6% compared to HF-fed mice, suggesting increased mitochondrial biogenesis. Using real-time PCR, we found that mRNA levels of sirtuin (sirt) 1, peroxisome proliferator-activated receptor gamma coactivator 1a, and nuclear respiratory factor 1, genes that regulate mitochondrial biogenesis, were significantly increased in HFÑHFC mice compared with HF-fed controls. Cocoa treatment reduced hepatic lipid peroxidation by 57% compared to HF-fed controls, indicating reduced oxidative stress.
These effects were related to an increase in the expression of Sirt3, an important mitochondrial redox regulator, as well as the expression and activity of manganese superoxide dismutase and glutathione peroxidase. In summary, our results demonstrate that the beneficial effects of cocoa supplementation on non-alcoholic fatty liver disease may be mediated by increases in mitochondrial biogenesis and related antioxidant response signaling.
Acknowledgements: supported by a grant from The National Center for Complementary and Alternative Medicine (AT004678).