Nuclear receptor corepressors non-canonically drive glucocorticoid receptor-dependent activation of hepatic gluconeogenesis.

Nuclear receptor corepressors (NCoRs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3) to alter transcriptional output primarily through repressive chromatin remodelling at target loci1-5. In the liver, loss of HDAC3 causes a marked hepatosteatosis largely because of de-repression of genes involved in lipid metabolism6,7; however, the individual roles and contribution of other complex members to hepatic and systemic metabolic regulation are unclear. Here we show that adult loss of both NCoR1 and NCoR2 (double knockout (KO)) in hepatocytes phenocopied the hepatomegalic fatty liver phenotype of HDAC3 KO. In addition, double KO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCoRs or HDAC3, resulting in profound fasting hypoglycaemia. This surprising HDAC3-independent activation function of NCoR1 and NCoR2 is due to an unexpected loss of chromatin accessibility on deletion of NCoRs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCoRs that is required for metabolic health.

Hepatic Vagal Afferents Convey Clock-Dependent Signals to Regulate Circadian Food Intake.

Circadian desynchrony induced by shiftwork or jetlag is detrimental to metabolic health, but how synchronous/desynchronous signals are transmitted among tissues is unknown. Here we report that liver molecular clock dysfunction is signaled to the brain via the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a previously unrecognized homeostatic feedback signal that relies on synchrony between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a therapeutic target for obesity in the setting of chrono-disruption. One Sentence Summary: The hepatic vagal afferent nerve signals internal circadian desynchrony between the brain and liver to induce maladaptive food intake patterns.