Diurnal profiling of mouse liver of hepatocyte specific BMAL1 KO mice (Bmal1 HepKO)

Obesity and liver diseases are associated with the disruption of the circadian clock that orchestrates mammalian physiology to optimize nutrient metabolism and storage. We show here that the activity of the circadian clock regulator BMAL1 is perturbed during liver fibrosis in humans. To understand the impact of BMAL1 perturbation in obesity and liver diseases, we assessed the impact of a high fat diet or leptin deficiency on Bmal1 knockout mice. While Bmal1 knockout mice were prone to obesity, they were protected against insulin resistance, hepatic steatosis, inflammation, and fibrosis. In addition to direct transcriptional regulation of metabolic programs by BMAL1, we show that adaptation of the growth hormone and sex hormone pathways plays a critical role in this protection. Similar endocrine perturbations correlate with the development of liver fibrosis in humans, suggesting that endocrine perturbation associated with circadian disruption is critical for the pathogenesis of metabolic and liver diseases. Overall design: RNA-Seq from mouse liver mRNA of Alb::Cre_+/0 Bmal1_loxP/loxP (Bmal1 HepKO) and Alb::Cre_0/0 Bmal1_loxP/loxP (Bmal1 HepWT) genotypes