Chop/Ddit3 depletion in β-cells alleviates ER stress and corrects hepatic steatosis

Type 2 diabetes ( T2D ) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia and insulin resistance ( IR ). During the early phase of T2D, insulin synthesis and secretion by pancreatic β cells is enhanced, which can lead to proinsulin ( ProIns ) misfolding that aggravates endoplasmic reticulum ( ER ) homeostasis in β cells. Moreover, increased insulin in the circulation may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in β cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germline Chop gene deletion preserved β cells in high fat diet (HFD) fed mice and in leptin receptor-deficient db/db mice. In the current study, we further investigated whether targeting Chop/Ddit3 specifically in murine β cells confers therapeutic benefits. First, we show that Chop deletion in β cells alleviates β cell ER stress and delays glucose-stimulated insulin secretion ( GSIS ) in HFD fed mice. Second, importantly, β cell-specific Chop deletion prevented liver steatosis and hepatomegaly in aged HFD fed mice without affecting basal glucose homeostasis. Third, we provide the first mechanistic evidence that ER remodeling secondary to Chop deletion modulates glucose-induced islet Ca2+ oscillations. Finally, using state-of-the-art GLP1-conjugated Chop AntiSense Oligonucleotides (GLP1- Chop ASO), we demonstrated that the Chop deletion induced GSIS change is a long term complex event in β cells. In summary, our results demonstrate that Chop depletion in β cells is a new therapeutic strategy to alleviate dysregulated insulin secretion and the consequently fatty liver disease in T2D.