Effects of time-restricted feeding combined with physical exercise or REV-ERB agonist on obesity and liver metabolism of male and female mice

Abstract

The low-grade inflammation found in obesity induces impairments in insulin signaling and action, with notorious disturbances in metabolic processes in the liver. In this condition of insulin resistance, there is an increase in lipolysis and a greater flow of free fatty acids to the liver and, consequently, an accentuated accumulation of triacylglycerol (TAG) and, later, the onset of non-alcoholic fatty liver disease (NAFLD). This state of impaired insulin signal transduction is also associated with exacerbated hepatic glucose production and hyperglycemia. Therefore, the presence of NAFLD and increased glucose production favors the development of type 2 diabetes mellitus and cardiovascular diseases. An important area of investigation, then, is to identify risk factors and which alternatives are capable of contributing to the prevention and treatment of obesity and liver metabolism disorders. In this perspective, Time-restricted feeding (TRF) and physical exercise efficiently regulate metabolic processes that induce an improvement in obesity and associated disorders, including positive effects on liver metabolism. In addition, in recent years, therapeutic alternatives have been sought that, alone or in combination, can reflect metabolic benefits and prevent or treat NAFLD. Then emerge some drugs capable of interfering with proteins related to the control of the circadian cycle and with involvement in metabolism. REV-ERB is a promising candidate capable of inducing improvements in hepatic metabolism and attenuating the NAFLD condition. While these interventions have potential, there are still many gaps. In particular, the impacts of the combination TRF with exercise or TRF with the REVERB agonist on hepatic metabolism and whether the effects are similar and positive in males and females is not fully known. We speculate that when these interventions (TRF + Physical Exercise) and (TRF + REV-ERB Agonist) occur, they may be effective in regulating crucial pathways involved in glucose metabolism (glycogenolysis and gluconeogenesis) and lipid metabolism (lipid synthesis and oxidation) in the liver and reduce adiposity in mice fed a high-fat diet.