Unraveling the complexities of diet induced obesity and glucolipid dysfunction in metabolic syndrome

The consumption of a high-fat high-calorie diet with or without fructose (western or cafeteria diet) increases body mass due to calorie excess, inducing glucolipid metabolism dysfunctions culminating in development of unhealthy obesity and metabolic syndrome (MetS). Understanding the sequelae of events that translates caloric excess to the development of MetS symptoms interlinking metabolic interrelationship between organs is paramount in the development of new treatment strategies. This review aims to create a compendium of evidence from mammalian studies (rodents, humans) to elucidate the metabolic changes induced by overnutrition. This review explores gut microbiome alterations, gut barrier dysfunctions, and immune dysregulation induced by a high-fat diet that changes gut tryptophan and biliary metabolism, which, with concomitant elevations in free fatty acids and ceramides, promote insulin insensitivity. Immunometabolic alteration induce adipose tissue dysfunction, which alters the secretion of adipokines and lipid metabolites that contribute to dyslipidemia, hepatosteatosis, cardiovascular dysfunction, and endocrine disruption. This review provides insights into the mechanism underlying unhealthy adipose expansion, shedding light on some of the exosome-mediated epigenomic alterations affecting obesity or MetS pathogenesis, which may help in the future design of microRNA biomarkers. The review also highlights areas where more supportive evidence may be needed to elucidate metabolic syndrome pathogenesis.