Effect of Ketone Esters on Liver Fat Content and Metabolic Function

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common complication of obesity and is associated with multiorgan insulin resistance, dyslipidemia (high plasma triglyceride and low HDL cholesterol concentrations), and an increased risk of diabetes and coronary heart disease. The prevalence of MASLD continues to rise dramatically in children and adolescents, with approximately 13 to 19% of adolescents and young adults in the United States estimated to have hepatic steatosis (elevated amount of fat in the liver), the hallmark feature of MASLD. Evidence is emerging that increasing blood ketone concentrations can markedly improve hepatic steatosis, insulin sensitivity, and blood glucose in rodent models of obesity. Ketones are produced by the liver from fatty acid metabolism; increased ketone production is observed during fasting or very-low carbohydrate (ketogenic) diet consumption when plasma nonesterified fatty acid concentrations are high and glucose concentrations are low. Circulating ketone concentrations can also be increased by exogenous ketone administration. Ketogenic diets ameliorate hepatic steatosis in adults with MASLD. Whether exogenous ketone administration affects hepatic steatosis in adolescents with MASLD is not known. However, several studies have found exogenous ketone administration improves blood glucose control in people, suggesting that exogenous ketones could also reduce intrahepatic triglyceride (IHTG) content. The therapeutic use of ketone drinks has been limited by poor palatability and the high sodium content of ketone salts. To overcome these limitations, ketone esters have recently been developed, including bis-octanoyl (R)-1,3-butanediol (C8 ketone di-ester), which is hydrolyzed in the intestine to generate the ketone precursors octanoic acid and (R)-1,3-butanediol, which are then converted to beta-hydroxybutyrate by the liver. These ketone precursors are palatable, do not contain sodium, and have been shown to increase plasma ketone concentrations. The purpose of the present study is to conduct a randomized double blind, placebo-controlled 6-week trial to assess the effect of C8 ketone di-ester supplementation (25 g/day) on IHTG content and blood glucose control (insulin sensitivity, beta-cell function, glucose tolerance) in 40 adolescents with obesity and MASLD.