Fasting hijacks proximal tubule circadian control mechanisms to regulate glucose reabsorption via the Nrf1/Sglt2 pathway in mice

Xiaoyue Pan (), Cyrus Mowdawalla, Samantha Bagnato, Jeffrey Pessin, Volker Vallon () and M. Mahmood Hussain ()
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Xiaoyue Pan: New York University Grossman Long Island School of Medicine, Department of Foundations of Medicine
Cyrus Mowdawalla: New York University Grossman Long Island School of Medicine, Department of Foundations of Medicine
Samantha Bagnato: New York University Grossman Long Island School of Medicine, Department of Foundations of Medicine
Jeffrey Pessin: Albert Einstein College of Medicine, Einstein-Mount Sinai Diabetes Research Center and Fleischer Institute of Diabetes and Metabolism
Volker Vallon: University of California San Diego, Division of Nephrology and Hypertension, Department of Medicine
M. Mahmood Hussain: New York University Grossman Long Island School of Medicine, Department of Foundations of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The kidneys contribute to glucose homeostasis by gluconeogenesis and glucose reabsorption. Herein, we identified previously unknown fasting-induced, glucagon-mediated inhibitory effect of the circadian clock gene basic helix-loop-helix ARNT like 1 (Bmal1) on the expression of the main proximal tubule glucose transporter solute carrier family 5 member 2 (Sglt2) in mice. During fasting, glucagon induces Bmal1, which increases expression of nuclear receptor subfamily 1, group D, member 1 (Rev-erbα). Rev-erbα represses nuclear respiratory factor 1, a transcriptional activator of Sglt2, and diminishes Sglt2 expression and thereby kidney glucose reabsorption capacity. During refeeding (lower glucagon) this process is attenuated, thereby inducing glucose reabsorption. The physiological role of this mechanism appears to ensure optimal temporal retrieval of filtered glucose during fasting/refeeding. Thus, this study demonstrates that during fasting and refeeding, glucagon regulates renal glucose reabsorption by utilizing the local cellular circadian machinery.

Date: 2025
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DOI: 10.1038/s41467-025-65402-x

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