Deficiency of endothelial sirtuin1 in mice stimulates skeletal muscle insulin sensitivity by modifying the secretome

Qiuxia Li (), Quanjiang Zhang, Young-Rae Kim, Ravinder Reddy Gaddam, Julia S. Jacobs, Markus M. Bachschmid, Tsneem Younis, Zhiyong Zhu, Leonid Zingman, Barry London, Adam J. Rauckhorst, Eric B. Taylor, Andrew W. Norris, Ajit Vikram and Kaikobad Irani ()
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Qiuxia Li: University of Iowa Carver College of Medicine
Quanjiang Zhang: University of Iowa Carver College of Medicine
Young-Rae Kim: University of Iowa Carver College of Medicine
Ravinder Reddy Gaddam: University of Iowa Carver College of Medicine
Julia S. Jacobs: University of Iowa Carver College of Medicine
Markus M. Bachschmid: Boston University School of Medicine
Tsneem Younis: University of Iowa Carver College of Medicine
Zhiyong Zhu: University of Iowa Carver College of Medicine
Leonid Zingman: University of Iowa Carver College of Medicine
Barry London: University of Iowa Carver College of Medicine
Adam J. Rauckhorst: University of Iowa Carver College of Medicine
Eric B. Taylor: University of Iowa Carver College of Medicine
Andrew W. Norris: University of Iowa Carver College of Medicine
Ajit Vikram: University of Iowa Carver College of Medicine
Kaikobad Irani: University of Iowa Carver College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Downregulation of endothelial Sirtuin1 (Sirt1) in insulin resistant states contributes to vascular dysfunction. Furthermore, Sirt1 deficiency in skeletal myocytes promotes insulin resistance. Here, we show that deletion of endothelial Sirt1, while impairing endothelial function, paradoxically improves skeletal muscle insulin sensitivity. Compared to wild-type mice, male mice lacking endothelial Sirt1 (E-Sirt1-KO) preferentially utilize glucose over fat, and have higher insulin sensitivity, glucose uptake, and Akt signaling in fast-twitch skeletal muscle. Enhanced insulin sensitivity of E-Sirt1-KO mice is transferrable to wild-type mice via the systemic circulation. Endothelial Sirt1 deficiency, by inhibiting autophagy and activating nuclear factor-kappa B signaling, augments expression and secretion of thymosin beta-4 (Tβ4) that promotes insulin signaling in skeletal myotubes. Thus, unlike in skeletal myocytes, Sirt1 deficiency in the endothelium promotes glucose homeostasis by stimulating skeletal muscle insulin sensitivity through a blood-borne mechanism, and augmented secretion of Tβ4 by Sirt1-deficient endothelial cells boosts insulin signaling in skeletal muscle cells.

Date: 2023
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DOI: 10.1038/s41467-023-41351-1

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