An overfeeding-induced obesity mouse model reveals necessity for Sin3a in postnatal peak ß cell mass acquisition

The increase of functional ß cell mass is paramount to maintain glucose homeostasis in the setting of systemic insulin resistance and/or augmented metabolic load. Understanding compensatory mechanisms that allow ß cell mass adaptation may allow discovery of therapeutically actionable control nodes. In this study, we report the rapid and robust ß cell hyperplasic effect in a mouse model of overfeeding-induced obesity (OIO) based on direct gastric caloric infusion. By performing RNA sequencing in islets isolated from OIO mice, we identified Sin3a as a novel transcriptional regulator of ß cell mass adaptation. ß cell-specific Sin3a knockout animals showed profound diabetes, due to defective acquisition of postnatal ß cell mass. These findings reveal a novel regulatory pathway in ß cell proliferation, and validate OIO as a model for discovery of other mechanistic determinants to ß cell adaptation. Overall design: RNA-seq of pancreatic islets from a mouse model of overfeeding.