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 and young adults 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 and young adults with overweigh/obesity and MASLD.

Inclusion criteria

• Age: ≥18 and ≤40 years;
• BMI 25.0 - 49.9 kg/m2;
• Intrahepatic triglyceride content >5% assessed by using magnetic resonance imaging-proton density fat fraction (MRI-PDFF).

Exclusion criteria

• HbA1C ≥6.5%;
• taking dietary supplements or medications known to affect our study outcomes including corticosteroids and other drugs associated with steatosis (metformin use will be allowable if participants have taken a stable dose for at least 3 months without any gastrointestinal-related symptoms);
• active eating disorder, any anaphylactic food allergy and/or consuming a very-low-carbohydrate (<50 g/day) diet;
• Fibroscan controlled attenuation parameter (CAP) score <240 dB/m assessed within last 2 months before entering the study;
• recent (<2 months) history of moderate-severe nausea, vomiting, diarrhea, or other significant gastrointestinal symptoms;
• consume tobacco products, excessive alcohol (females: >14 drinks/week; males: >21 drinks/week), or illegal drugs determined by medical history;
• evidence of significant active organ system dysfunction, liver disease other than MASLD (e.g., Wilson disease, viral hepatitis, inborn errors of metabolism, or alpha-1 antitrypsin deficiency) or cirrhosis as a results of any condition or disease;
• have had bariatric surgery or plan to have endoscopic or bariatric surgery therapy for obesity;
• have undergone organ transplantation;
• have HIV and any other type of congenital or acquired lipodystrophy;
• unwilling or unable to provide informed consent;
• major psychiatric illness;
• metal implants that are not MRI-compatible;
• pregnancy, as determined by a urine HCG screening test assessed performed at all screening, baseline testing, and follow-up visits. In addition, male and female participants of reproductive and childbearing age who wish to enroll will be required to agree to use contraception throughout the study period, and for 30 days after the last dose of C8 ketone di-ester;
• female participants who are currently lactating;
• Structured exercise: ≥75 min/wk of vigorous exercise (e.g., jogging, activity that causes heavy breathing and sweating) or ≥200 min/wk of low intensity physical activity (e.g., brisk walking);
• Unstable weight (>3% change during the last 2 months before entering the study);
• Anemia (hemoglobin <10.5 g/dL in females and <11.0 g/dL in males);
• Unable or unwilling to follow the study protocol or who, for any reason, is considered an inappropriate candidate for the study by the research team.