ß-Hydroxybutyrate is Reduced in Humans with Obesity-Related NAFLD and Displays a Dose-Dependent Effect on Skeletal Muscle Mitochondrial Respiration In Vitro.

: Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation and skeletal muscle insulin resistance. Reduced hepatic ketogenesis may promote these pathologies, but data are inconclusive in humans and the link between NAFLD and exacerbated skeletal muscle insulin resistance remains obscure. Objective We investigated individuals with obesity-related NAFLD and hypothesized that s-hydroxybutyrate (sOHB; the predominant ketone species) would be reduced and related to hepatic fat accumulation and skeletal muscle insulin resistance. Further, we hypothesized ketones would impact skeletal muscle mitochondrial respiration in vitro. Methods Hepatic fat was assessed by ¹H-MRS in 22 participants in a parallel design, case control study (Control: n=7, age 50±6 yrs, BMI 30±1 mg/kg²; NAFLD: n=15, age 57±3 yrs, BMI 35±1 mg/kg²). Plasma assessments were conducted in the fasted state. Skeletal muscle insulin sensitivity was determined by hyperinsulinemic-euglycemic clamp. The effect of ketone dose (0.5-5.0 mM) on mitochondrial respiration was conducted in human skeletal muscle cell culture. Results sOHB was reduced in NAFLD (-15.6%, p<0.01) and negatively correlated with liver fat (r²=0.21, p=0.03) and insulin resistance (r²=0.30, p=0.01). Skeletal muscle mitochondrial oxygen consumption increased with low-dose ketones, attributable to increases in basal respiration (135%, p<0.05) and ATP-linked oxygen consumption (136%, p<0.05). Conclusions NAFLD pathophysiology includes impaired hepatic ketogenesis, which is related hepatic fat accumulation and skeletal muscle insulin resistance. This reduced capacity to produce ketones may be a potential link between NAFLD and skeletal muscle insulin resistance, whereby ketone concentrations impact skeletal muscle mitochondrial respiration.