Upregulation of Xbp1 in NPY/AgRP neurons reverses diet-induced obesity and ameliorates leptin and insulin resistance.

The molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes are not fully understood. In this study, we show that induction of the unfolded protein response transcription factor, spliced X-box binding protein 1 (Xbp1s), in Agouti-Related Peptide (AgRP) neurons alone, is sufficient to not only protect against but also significantly reverse diet-induced obesity (DIO) as well as improve leptin and insulin sensitivity, despite activation of endoplasmic reticulum stress. We also demonstrate that constitutive expression of Xbp1s in AgRP neurons contributes to improved insulin sensitivity and glucose tolerance. Together, our results identify critical molecular mechanisms linking ER stress in arcuate AgRP neurons to acute leptin and insulin resistance as well as liver glucose metabolism in DIO and diabetes.