Disruption of the circadian clock component BMAL1 elicits an endocrine adaption impacting on insulin sensitivity and liver disease

Obesity and liver diseases are associated with the disruption of the circadian clock that orchestrates mammalian physiology to optimize nutrient metabolism and storage. Here, we show that the activity of the circadian clock regulator Brain and Muscle Aryl hydrocarbon receptor nuclear translocator-like 1 (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 the transcriptional regulation of metabolic programs by BMAL1, we show that the disruption 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 but were absent in hepatocyte-specific Bmal1 knockout mice. This suggests that systemic endocrine perturbation associated with the global disruption of BMAL1 activity is critical for the pathogenesis of metabolic and liver diseases.