Chrono overexpression blunts exercise-induced improvement in muscular glucose metabolism by inhibiting the BMAL1 transcriptional activity in high-fat diet-fed mice

May 14, 2026Journal of physiology and biochemistry

Too much Chrono weakens exercise's benefits on muscle sugar use by blocking BMAL1 activity in mice on a high-fat diet

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Abstract

Aerobic exercise improves systemic insulin sensitivity in normal mice but not in those with Chrono overexpression.

Exercise did not reduce adipose mass, dyslipidemia, or insulin resistance in Chrono overexpression mice on a high-fat diet.
In Chrono overexpression mice, exercise reduced CHRONO expression and CHRONO-BMAL1 binding less than in wild-type mice.
Exercise increased levels of a protein involved in glucose transport (GLUT4) in Chrono overexpression mice but failed to enhance its movement to the cell membrane.
Chrono overexpression inhibited the transcriptional activation of genes related to glycolysis and glycogen metabolism following aerobic exercise.
The findings suggest that dissociation of the CHRONO-BMAL1 complex is necessary for exercise-induced improvements in glucose metabolism.

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Aerobic exercise improves systemic insulin sensitivity by modulating muscle glucose metabolism. The CHRONO/BMAL1 pathway constitutes a core component of the endogenous molecular clock and participates in glucose metabolic regulation; however, whether it mediates exercise-induced metabolic benefits under high-fat diet (HFD) conditions remains unclear. We therefore investigated the role of this pathway in conferring protective effects of aerobic exercise against HFD-induced glucose metabolic dysfunction in skeletal muscle, by subjecting wild-type (WT) and inducible muscle-specific Chrono overexpression (Chrono IMOE) mice to an HFD with or without 12-week exercise. Unlike in WT mice, exercise failed to ameliorate adipose mass, dyslipidemia, and insulin resistance in HFD-fed Chrono IMOE mice. Mechanistically, in skeletal muscle of Chrono IMOE mice, Chrono overexpression suppressed exercise-induced reductions in CHRONO expression and CHRONO-BMAL1 binding, as well as the increase in BMAL1 levels. Consequently, despite elevated p-TBC1D1and GLUT4 expression, exercise failed to promote GLUT4 sarcolemmal colocalization or upregulate gene expression of key enzymes for glycolysis and glycogen metabolism in skeletal muscle of Chrono IMOE mice. These findings demonstrate that preventing CHRONO‑BMAL1 dissociation via muscle-specific Chrono overexpression abrogates exercise-induced GLUT4 membrane trafficking, transcriptional activation of glycolytic/glycogen metabolic genes, and systemic insulin sensitivity improvements in HFD-fed mice, establishing CHRONO‑BMAL1 dissociation as a required step for these exercise adaptations. Ser237

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Chrono overexpression blunts exercise-induced improvement in muscular glucose metabolism by inhibiting the BMAL1 transcriptional activity in high-fat diet-fed mice

Abstract

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