TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy
Elevated or chronic innate immune activation plays a role in the progression of metabolic diseases such as diabetes, yet the influence of innate immune signaling on pancreatic ß-cells is not well characterized. Here we report that TRAF6, an E3 ubiquitin ligase downstream of TLR signaling, maintains ß-cell function during diet-induced obesity. Deletion or inhibition of TRAF6 impairs glucose homeostasis, mitochondrial function, and mitophagy during metabolic stress in both mouse and human islets. The combination of TRAF6 deficiency and palmitate exposure reduces localization of mitophagy machinery, such as BNIP3, to the mitochondria. Interestingly, co-deletion of Parkin restores glucose-stimulated insulin section, mitochondrial bioenergetics, and mitophagy. These findings suggest that Parkin-independent mitophagy mechanisms may be important for maintenance of ß-cell function during metabolic stress. Overall design: RNA-seq profiling of pancreatic islets isolated from either control or beta-cell specific Traf6 KO mice fed a 15-week HFD.