Involution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway

Xiaofan Yu, Gabrielle Benitez, Peter Tszki Wei, Sofia V. Krylova, Ziyi Song, Li Liu, Meifan Zhang, Alus M. Xiaoli, Henna Wei, Fenfen Chen, Simone Sidoli, Fajun Yang, Kosaku Shinoda, Jeffrey E. Pessin and Daorong Feng ()
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Xiaofan Yu: Albert Einstein College of Medicine
Gabrielle Benitez: Albert Einstein College of Medicine
Peter Tszki Wei: Cornell University
Sofia V. Krylova: Albert Einstein College of Medicine
Ziyi Song: Guangxi University
Li Liu: Albert Einstein College of Medicine
Meifan Zhang: Rutgers University
Alus M. Xiaoli: Albert Einstein College of Medicine
Henna Wei: Albert Einstein College of Medicine
Fenfen Chen: Southwest Forestry University
Simone Sidoli: Albert Einstein College of Medicine
Fajun Yang: Albert Einstein College of Medicine
Kosaku Shinoda: Albert Einstein College of Medicine
Jeffrey E. Pessin: Albert Einstein College of Medicine
Daorong Feng: Albert Einstein College of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Aging, chronic high-fat diet feeding, or housing at thermoneutrality induces brown adipose tissue (BAT) involution, a process characterized by reduction of BAT mass and function with increased lipid droplet size. Single nuclei RNA sequencing of aged mice identifies a specific brown adipocyte population of Ucp1-low cells that are pyroptotic and display a reduction in the longevity gene syntaxin 4 (Stx4a). Similar to aged brown adipocytes, Ucp1-STX4KO mice display loss of brown adipose tissue mass and thermogenic dysfunction concomitant with increased pyroptosis. Restoration of STX4 expression or suppression of pyroptosis activation protects against the decline in both mass and thermogenic activity in the aged and Ucp1-STX4KO mice. Mechanistically, STX4 deficiency reduces oxidative phosphorylation, glucose uptake, and glycolysis leading to reduced ATP levels, a known triggering signal for pyroptosis. Together, these data demonstrate an understanding of rapid brown adipocyte involution and that physiologic aging and thermogenic dysfunction result from pyroptotic signaling activation.

Date: 2024
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DOI: 10.1038/s41467-024-46944-y

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