OR21-06 Hepatocyte Period 1 Prevents Diet-Induced Obesity Through Inhibiting PP2A Independent of The Core Circadian Clock

Abstract Disclosure: J. Sun: None. J.A. Adams: None. C.B. Higgins: None. Y. Zhang: None. S.C. Kelly: None. B.J. DeBosch: None. The liver coordinates metabolic and circadian inputs to optimize substrate utilization, and both overnutrition and disruption of circadian feeding patterns render deleterious consequences to the host. However, precise mechanisms of interaction between core circadian genes and hepatic glucose and lipid metabolism during overnutrition and the development of metabolic diseases are incompletely understood. Our recent publication demonstrates a core circadian gene - Period 1 (Per1) - is induced by fasting and regulates key fasting-induced metabolic responses. To further study the metabolic role of Per1 in obesity, we challenged male mice with Western diet (WD) for 12 weeks. We found that mice lacking hepatocyte Per1 expression (Per1LKO) exhibit increased body weight gain and hepatic steatosis, enhanced hepatic de novo lipogenesis (DNL) gene expression, and elevated nuclear translocation of transcription factor carbohydrate response element binding protein (ChREBP). Mechanistically, to assess the extent to which forced hepatocyte Per1 expression attenuates WD-induced metabolic disease, and the interaction between Per1 and the core clock, we generated two Per1 mutant constructs, one lacks the key circadian functional domain - the CRY-binding domain (Per1ΔCBD), and the other only expresses the CRY-binding domain (CBD). Strikingly, full-length Per1, Per1ΔCBDand CBD overexpression driven by hepatocyte-specific promoter all attenuate serum or hepatic TG accumulation and hepatic DNL gene expression in wildtype mice and mice with hepatocyte-specific Bmal1-deletion (Bmal1LKO). Immunoprecipitation and mass spectrometry reveal a ChREBP-regulatory enzyme protein phosphatase, PP2A, as a common interacting protein among full-length and two Per1 mutant constructs. In vivo, pharmacologic PP2A blockade through LB-100 administration reverse the increased weight gain observed in WD-fed Per1LKO mice. In addition, LB-100 treatment in Per1LKO mice successfully attenuates upregulated DNL gene expression and hepatic lipid accumulation. This is associated with a decrease in nuclear ChREBP translocation. Taken together, we conclude that Per1 suppresses hepatic lipogenesis and TG accumulation by binding to and inhibiting PP2A, independent of its core clock function. The data define a novel function of Per1 as a potential mechanism by which the hepatocyte links circadian and metabolic inputs to optimize fuel utilization. Further studies are required to reveal the binding sites between PP2A and Per1 along with its two mutant constructs, and Per1-mediated connection between PP2A activity and the circadian clock during the progression of metabolic diseases. Presentation: Saturday, July 12, 2025