Control of Circadian Glucose Metabolism through BMAL1-HIF Axis in Obesity

Disruptions of circadian rhythms is widespread in modern society and leads to accelerated and worsened symptoms of metabolic syndrome. In healthy mice, the circadian clock factor BMAL1 is required for skeletal muscle function and metabolism. However, the importance of muscle BMAL1 in the development of metabolic diseases, such as diet-induced obesity (DIO), remains unclear. Here, we demonstrate that skeletal muscle-specific BMAL1-deficient mice exhibit worsened glucose tolerance upon high fat diet feeding, despite no evidence of increased weight gain. Metabolite profiling from Bmal1-deficient muscles revealed impaired glucose utilization specifically at early steps in glycolysis that dictate the switch between anabolic and catabolic glucose fate. We provide evidence that this is due to abnormal control of the nutrient stress-responsive hypoxia inducible factor (HIF) pathway. Genetic HIF1α stabilization in muscle Bmal1-deficient mice restores glucose tolerance and expression of approximately 30% of dysregulated genes during DIO, including glycolytic enzymes. Together, these data indicate that during DIO, skeletal muscle BMAL1 is an important regulator of HIF-driven glycolysis and metabolic flexibility, which influences the development of high fat diet-induced glucose intolerance.