Functional loss of ketogenesis in odontocete cetaceans

Abstract

Odontocete cetaceans exhibit genomic mutations in key ketogenesis genes. In order to validate an inferred lack of ketogenesis made by observations from genome sequencing, we biochemically analyzed tissues from several odontocete cetacean species and demonstrate that they indeed do not exhibit appreciable hepatic β-hydroxybutyrate (βHB) or its carnitine ester. Furthermore, liver tissue exhibited significantly lower long chain acylcarnitines and increased odd chain acylcarnitines indicative of a decreased reliance on hepatic long chain fatty acid oxidation in these carnivorous mammals. Finally, we performed single molecule, real-time next generation sequencing of liver and brain RNA of Tursiops truncatus and demonstrate that the succinyl-CoA transferase required for acetoacetate catabolism is expressed in the nervous system. These data show that odontocete cetaceans have lost the ability to perform ketogenesis and suggest a hepatocentric coenzyme A recycling function rather than a predominantly systemic-bioenergetic role for ketogenesis in other ketogenic competent mammals such as humans.

Keywords: Dolphin; Fasting; Ketogenic diet.

Fig. 1.

Tursiops truncatus does not generate β-hydroxybutyrate (βHB) and suppresses hepatic fatty acid oxidation. (A) Schematic representation of ketone body metabolism. Red indicates that the corresponding gene is mutated in odontocete cetaceans; green indicates that the corresponding gene is present in odontocete cetaceans. CoA, coenzyme A; Acac, acetoacetate; HMGCS2, hydroxymethylglutaryl CoA synthase 2; BDH1, d-β-hydroxybutyrate dehydrogenase 1; OXCT1, succinyl-CoA:3-oxoacid-CoA transferase. (B) Liver βHB and βHB-carnitine, (C) long chain acylcarnitines and (D) additional acylcarnitines in T. truncatus brain/liver (n=6) and mouse liver (n=4). *P<0.05, ***P<0.01.