Role of the AMPK-C/EBPα/PPARγ and AMPK-UCP1/Sirt1 Axes in the Anti-obesogenic Activities of Gallotannin Derivatives from Mango (Mangifera indica L.)

Obesity is an escalating global epidemic associated with increased risk of developing type 2 diabetes, cardiovascular diseases and cancer. Dietary modifications, particularly increasing consumption of polyphenol-rich foods, are considered some of the most effective strategies in the prevention of obesity-related chronic diseases. Mango (Mangifera indica L.) contains high content of phenolic compounds (e.g., gallic acid (GA), gallotannin (GT), and galloyl glycosides), showing anti-inflammatory and antiobesogenic potential in chronic diseases. Lactobacillus plantarum (L.plantarum) possesses enzymatic activities to degrade GT into GA and PG, allowing for absorption and excretion. Thus, the interaction between gut microbiota and GT derivatives may affect the subsequent biological activities exerted by the microbial metabolites. Anti-obesogenic potential of GT derivatives from mango in modulating lipid metabolism was investigated in 3T3-L1 adipocytes. GT derivatives suppressed adipogenesis and increased thermogenesis in adipocytes in part through the interactions with the AMPK-C/EBPα/PPARγ and AMPK-UCP1/Sirt1 axes. In gnotobiotic mice fed a high-fat diet (HFD), GT alone decreased lipid accumulation in white adipose tissue and increased thermogenesis in brown adipose tissue. Intestinal colonization with L.plantarum enhanced these effects and additionally lowered levels of inflammation and insulin resistance. GT and L.plantarum reduced HFD-induced inflammation and insulin resistance and promoted thermogenesis in adipose tissue potentially through the activity of GT-metabolizing bacterial enzymes yielding absorbable bioactive of GT-metabolizing bacterial enzymes yielding absorbable bioactive GT metabolites, which implies the potential role of prebiotic-probiotic interactions in the prevention of diet-induced metabolic disorders. These findings were expected to translate into a human clinical trial, which examined the influence of 6 weeks of daily mango supplementation on inflammation and metabolic functions. Mango supplementation improved the plasma levels of proinflammatory cytokines and metabolic hormones in obese participants partly due to increased systemic exposure to polyphenolic metabolites. In summary, health benefits of mango-derived polyphenols in obesity and insulin resistance are mainly attributed to the production of microbial metabolites of GT, which is in part through the interactions with the AMPK-C/EBPα/PPARγ and AMPKUCP1/Sirt1 axes in adipose tissue. Improving the abundance of probiotics in gut microbiota may improve the bioavailability of mango-derived polyphenols, resulting in enhanced efficacy of the microbial metabolites in the prevention of lipid accumulation and metabolic dysfunction in obesity