Sirt6 deficiency in mast cells promotes adipose fibroinflammation in obesity through galectin-3 signaling.

Mast cells (MCs) play a key role in obesity and insulin resistance, though the mechanisms driving adipose dysfunction remain unclear. We find that Sirt6 expression in MCs decreases with obesity in both male mice and humans. Selective depletion of Sirt6 in MCs worsens inflammation, fibrosis, and metabolic dysfunction in diet-induced obesity. Adoptive transfer of MC-deficient KitW-sh/W-sh mice with Sirt6-deficient MCs leads to greater weight gain on a high-fat diet compared to transfer with wild-type MCs; however, this effect is absent when the transferred MCs lack both Sirt6 and galectin-3. Mechanistically, Sirt6 deacetylates H3K9 at the Lgals3 promoter, inhibiting galectin-3 production and protecting against M1 macrophage polarization and adipose tissue fibrosis. Single-cell RNA sequencing reveals a fibroinflammatory MC subpopulation dominating in the adipose tissue of Sirt6 knockout mice. Targeting Sirt6 activation or galectin-3 inhibition in MCs may represent a therapeutic approach for obesity-associated adipose fibroinflammation and insulin resistance.