Figure 1.

Metabolic Inflexibility. In physiological conditions, fasting state is associated with relatively low insulin levels leading to increased lipolysis and free fatty acid oxidation in adipose tissue and muscles. Glucose oxidation increased in muscles, and gluconeogenesis is activated in the liver. During fed state, food intake increases insulin release which subsequently stimulates lipogenesis and triglyceride accumulation in adipose tissue. There is increase in glucose and free fatty acid oxidation in muscles, and inhibition of gluconeogenesis in the liver. Inability of the body to maintain this balance or to adequately handle substrates at appropriate times is referred to as metabolic inflexibility. The liver loses its ability to flexibly switch back and forth between prandial and fasting states due to exacerbated insulin resistance (hallmark of NAFLD/NASH). Metabolic inflexibility is associated with hyperinsulinemia, systemic lipotoxic cell stress leading to inflammation and fibrogenesis, and eventually NASH. (Adapted from Chakravarthy MV, Siddiqui MS, Forsgren MF and Sanyal AJ (2020), Harnessing Muscle–Liver Crosstalk to Treat Nonalcoholic Steatohepatitis. Front. Endocrinol. 11:592373. doi: 10.3389/fendo.2020.592373.). DNL, de novo lipogenesis; FAO, fatty acid oxidation; FFA, free fatty acid; IR, insulin resistance.