Control of circadian muscle glucose metabolism through the BMAL1–HIF axis in obesity
Abstract
Disruptions of circadian rhythms are widespread in modern society and lead 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 217/736 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Claire A. Chaikin
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine
Abhishek V. Thakkar
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine
Adam W. T. Steffeck
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine
Eric M. Pfrender
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine
Kaitlyn Hung
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine
Pei Zhu
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine
Nathan J. Waldeck
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine
Rino Nozawa
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine
Weimin Song
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine
Christopher R. Futtner
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine
Mattia Quattrocelli
Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital
Joseph Bass
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine
Issam Ben-Sahra
Clara B. Peek
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine