Control of circadian muscle glucose metabolism through the BMAL1–HIF axis in obesity

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 <i>Bmal1</i>-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 <i>Bmal1</i>-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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-03-24
DOI
https://doi.org/10.1073/pnas.2424046122
Citations
11
Primary Topic
Adipose Tissue and Metabolism
Type
article
Field-Weighted Citation Impact
12.81

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article

Control of circadian muscle glucose metabolism through the BMAL1–HIF axis in obesity

Clara Bien Peek, Adam W. T. Steffeck, Eric M. Pfrender, Joseph T. Bass et al.
11 citations
Proceedings of the National Academy of Sciences
Adipose Tissue and Metabolism
12.81
article

Control of circadian muscle glucose metabolism through the BMAL1–HIF axis in obesity

Clara Bien Peek, Adam W. T. Steffeck, Eric M. Pfrender, Joseph T. Bass, Issam Ben‐Sahra, Nathan J. Waldeck, Christopher R. Futtner, Abhishek Vijay Thakkar, Rino Nozawa, Mattia Quattrocelli, Claire Chaikin, Kaitlyn Hung, Pei Zhu, Weimin Song
article en
11 citations

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 <i>Bmal1</i>-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 <i>Bmal1</i>-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.

Proceedings of the National Academy of SciencesVol. 122(13)
Northwestern University (US), Cincinnati Children's Hospital Medical Center (US), University of Cincinnati (US)
Children's Cancer Research Fund, Northwestern University, Cincinnati Children's Hospital Medical Center, National Institutes of Health, Robert H. Lurie Comprehensive Cancer Center, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Openalex Percentile: Top 1%
Adipose Tissue and Metabolism
12.81
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