2176-LB: Circadian Clock Regulation of HIF1a-Dependent Skeletal Muscle Metabolism during Diet-Induced Obesity

by sugaradmin



Introduction and Objective: Epidemiological and genetic studies have shown that disruption of circadian rhythms leads to accelerated and worsened symptoms of metabolic syndrome. Studies indicate that core clock factor, BMAL1, is required for insulin-dependent skeletal muscle glucose uptake in lean mice. However, the role of the clock in skeletal muscle metabolism during metabolic stress is unclear. Recent work uncovered a link between the molecular clock and the hypoxia inducible factor (HIF) response pathway, which is known to control the induction of glycolytic metabolism in skeletal muscle during nutrient stress. We hypothesize that the skeletal muscle clock may mediate glucose utilization and muscle metabolism during diet-induced obesity (DIO) through regulation of HIF activity.Methods: We generated muscle-specific BMAL1-deficient mice and muscle-specific BMAL1-deficient, HIF1a stabilized mice to investigate the impact of the interaction between these factors during DIO. We looked at metabolic parameters, muscle phenotypes, and transcriptional signatures in these conditions.Results: During DIO, HIF1α pathway target gene expression is elevated in skeletal muscle and loss of clock activator, BMAL1, leads to reduced HIF1α pathway target gene expression and impaired glucose tolerance in mice. However, HIF1α target genes were not reduced in RC fed mice, suggesting that BMAL1 regulates HIF1α target gene expression during HFD but not RC. Clock-disrupted mice have reduced muscle mass and cross-sectional area, along with elevated levels of free amino acids, suggesting impaired muscle protein homeostasis. Using our BMAL1-deficient, HIF1a stabilized mice, we found that HIF1a stabilization restores glucose disposal in muscle-specific BMAL1-deficient mice during DIO and 1/3 of downregulated genes.Conclusion: These data provide evidence of an interaction between the molecular clock and HIF response pathways during DIO that impacts whole-body glucose metabolism and skeletal muscle specific gene expression.

Disclosure

C. Chaikin: None. A.V. Thakkar: None. A.W. Steffeck: None. E. Pfrender: None. C. Peek: None.

Funding

NIH (R01DK123358); NIH (F31DK139621)



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