Endocrine Abstracts

Metabolic fluxes in the liver demonstrate circadian rhythms. The hepatic circadian clock is a cell- autonomous protein network that governs the switch between the fasted and fed states via a series of transcriptional-translational feedback loops (TTLs). Diet is a powerful zeitgeber which can reprogramme the liver clock to follow eating schedule rather than the geophysical day-night cycle. Diet- induced circadian disruption has been implicated in the pathogenesis of common metabolic diseases including type two diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) which may be ameliorated via ROR-α and cryptochrome (CRY) stabilisation. Reciprocity between nutrition, core clock gene (CCG) expression, and hepatic metabolic flux exists. However, precise mechanisms of this relationship, particularly the actions of nutritional challenges, are not well characterised. In this study, two mammalian hepatocyte-derived in vitro models of circadian metabolism were used to profile how individual nutritional challenges interact with the liver clock, and if these can be potentially manipulated for therapeutic benefit. Gene expression analysis demonstrated that nutritional challenges individually disrupt mRNA expression of different CCGs, and the clock is sensitive to fatty acid (FA) composition. Glucose and FA challenges were found to directly attenuate CRY and ROR-α gene expression. ROR-α agonism and CRY stabilisation during modelled hyperglycaemia were both found to antagonistically modulate hepatic circadian amplitude (CA), and attenuate expression of genes are known to regulate insulin resistance (IR): PPAR-γ and glycogen synthase respectively. This study reveals that diet-induced hyperglycaemia and free FAs may alter hepatic circadian metabolism and suggests that pharmacological agonism of these CCGs may provide therapeutic benefit in T2DM and NASH.