Genetic impairment of ketone body signalling is a prevalent contributor to human metabolic dysfunction

Abstract Emerging evidence that circulating levels of key metabolic intermediates are sensed by a range of G-Protein Coupled receptors (GPCRs) is providing critical new insights into the control of systemic metabolic homeostasis, and how disturbances in such sensing may contribute to metabolic disease. The hydroxycarboxylic acid receptors for lactate (HCAR1), β-hydroxybutyrate (HCAR2), and octanoate (HCAR3) are encoded by three closely homologous GPCR genes co-located in a region where common genetic variation has been reportedly associated with lipid levels and body fat distribution. By resolving sequence homology in this region, we were able to refine this signal to a coding variant (R311C) in HCAR2. Using corrected genotypes from ∼500K participants from UK Biobank and direct genotyping of four other studies, we found that carriage of the HCAR2 p.R311C variant was significantly associated with type 2 diabetes risk, reduced gynoid fat mass, increased waist-hip ratio, higher circulating triglycerides, glucose and alanine aminotransferase levels, lower levels of HDL cholesterol and adiponectin and impaired suppression of circulating levels of non-esterified fatty acids after oral glucose. Adipose tissue explants from mice engineered to express the equivalent mutation variant (p.R308C) in the mouse ortholog showed increased lipolytic activity, basally and after β-hydroxybutyrate (BHB) treatment. In vivo, the mice were insulin resistant and had increased liver fat and impaired post-prandial suppression of NEFAs. The variant alters an amino acid located in the intracellular C-terminal tail of HCAR2, increasing recruitment of β-arrestin and resulting in enhanced internalisation and reduced cell surface expression. In conclusion, a common variant in the human ketone body receptor results in impaired control of adipocyte lipolysis and adversely impacts systemic lipid and glucose metabolism. These findings highlight the importance of anti-lipolytic ketone body signalling in adipocytes for the maintenance of metabolic health Graphical Abstract