br A conflict of interest statement br A
A conflict of interest statement
A funding statement This work was supported by CAMS Initiative for Innovative Medicine (Grant number: 2016-I2M-1-019); National Natural Science Foundation of China (Grant number: 31700154); Science and Technology Project of Yunnan Province—general program(Grant number: 2016FB034); Standardization of Experimental Tree Shrews and the Integrated Demonstration of Creation and Application of Major Human Disease Models of Tree Shrews (2014BAI01B01-01); The State Project for Essential Drug Research and Development, the national “Twelfth Five-Year” plan (Grant number: 2014ZX09102041004); Science and Technology Project of Yunnan Province - Key New Product Development (2014BC008).
Introduction Non-alcoholic fatty liver disease (NAFLD) associated with obesity, has a global prevalence of 25% in adults . It is a spectrum of progressive liver damage ranging from benign steatosis, to non-alcoholic steatohepatitis (NASH) characterised by necro-inflammation and hepatocyte injury . In about 10% of patients, NASH leads to fibrosis and cirrhosis and an increased risk of liver failure and hepatocellular carcinoma . Increased CVD incidence is the most prevalent clinical feature of NAFLD . The pathogenic progression of NAFLD is characterised by a loss of insulin sensitivity and hepatocyte accumulation of fat, which can induce lipotoxicity through oxidative stress and a pro-inflammatory state, leading to cellular damage . Emerging evidence indicates that alterations in bile 2-NBDG metabolism and associated farnesoid X nuclear receptor (Fxr) signalling also contribute to the development of NAFLD and obesity . At present no licensed medication or surgical procedure have been approved for NAFLD. Available rodent data is encouraging regarding the efficacy of fish derived n-3 fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) in NAFLD , regulating lipogenesis and fatty acid oxidation (via Srebp-1c and Ppara, respectively) . However, in human randomised controlled trials (RCT), fish oil supplementation has shown mixed findings , with largely marginal effects on histologically defined NAFLD  and no impact on insulin action. Flavan-3-ols (FLAV), a class of plant bioactive flavonoid compounds found in cocoa, tea and berries, are also emerging as a dietary strategy for NAFLD prevention, with efficacy attributed to their insulin sensitising, indirect antioxidant and anti-inflammatory effects .
Materials and methods
Discussion Given the collinearity between the FLAV induced changes in weight and insulin responses, the weight independent influence of FLAV on insulin sensitivity and NASH development cannot be established. The weight gain associated with HF/HFr was accompanied by elevated plasma leptin. Leptin is secreted in proportion to white adipose tissue mass and is essential in the regulation of energy homeostasis, glucose and lipid metabolism functions . The role of leptin in the progression of NAFLD remains unknown, but clinical data summarised in a meta-analysis (evaluating 33 studies and 2612 individuals), reported that circulatory leptin levels were associated with the severity of NAFLD . Obesity is commonly associated with hyperleptinemia that can progress to leptin resistance with attenuated hypothalamic leptin signalling which fails to reduce the excess of adiposity , . Here we showed that FLAVn-3 reduced the weight gain induced by the HF/HFr diet, and was associated with lower circulating leptin levels, which may suggest improved leptin signalling. In agreement with this observation and our FLAV induced lowering of leptin concentrations, Park et al.  recently reported that a flavonoid-rich grape extract reduced leptin, which together with our results suggest that altered leptin metabolism may partly underlie the FLAV induced reduction in NAFLD. These novel findings expand the state-of-the-art regarding the mechanism underlying the benefits of flavonoids in NAFLD .