Targeting peroxisomal fatty acid β-oxidation lowers fasting glucose by suppressing gluconeogenesis.

Fatty acids play an important role in regulating gluconeogenesis through the metabolite acetyl-CoA, however, the underlying mechanisms on how fatty acid oxidation provides acetyl-CoA for the stimulation of pyruvate carboxylase and gluconeogenesis are not fully demonstrated. As a fatty acid β-oxidation system exists in peroxisomes and the acetyl-CoA derived from peroxisomal β-oxidation can be transported into mitochondria through the intermediate acetyl-carnitine, we hypothesize that this β-oxidation system might play a role in regulating pyruvate carboxylase and gluconeogenesis. The study demonstrates a mechanism by which fatty acids activate pyruvate carboxylase through the acetyl-CoA derived from peroxisomal β-oxidation. Induction of peroxisomal fatty acid β-oxidation results in excessive generation of acetyl-carnitine, which significantly elevates liver acetyl-CoA level and stimulates pyruvate carboxylase and gluconeogenesis in fasting mice. Specific inhibition of peroxisomal β-oxidation suppresses glucose production and lowers fasting glucose by reducing acetyl-CoA generation in the liver of diabetic mice. It is proposed that induction of peroxisomal β-oxidation serves as a pathogenic mechanism for fatty acids induced hyperactivation of pyruvate carboxylase and gluconeogenesis and targeting peroxisomal β-oxidation might be a potential pathway in treating diabetes through reducing acetyl-CoA generation and suppressing gluconeogenesis.