Novel targets of β‐TrCP cooperatively accelerate carbohydrate and fatty acid consumption

Abstract Cellular energy is primarily produced from glucose and fat through glycolysis and fatty acid oxidation (FAO) followed by the tricarboxylic acid cycle in mitochondria; energy homeostasis is carefully maintained via numerous feedback pathways. In this report, we uncovered a new master regulator of carbohydrate and lipid metabolism. When ubiquitin E3 ligase β‐TrCP2 was inducibly knocked out in β‐TrCP1 knockout adult mice, the resulting double knockout mice (DKO) lost fat mass rapidly. Biochemical analyses of the tissues and cells from β‐TrCP2 KO and DKO mice revealed that glycolysis, FAO, and lipolysis were dramatically upregulated. The absence of β‐TrCP2 increased the protein stability of metabolic rate‐limiting enzymes including 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase (PFKFB3), adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1A (CPT1A), and carnitine/acylcarnitine translocase (CACT). Our data suggest that β‐TrCP is a potential regulator for total energy homeostasis by simultaneously controlling glucose and fatty acid metabolism and that targeting β‐TrCP could be an effective strategy to treat obesity and other metabolic disorders.