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An Overfeeding-Induced Obesity Mouse Model Reveals Necessity for Sin3a in Postnatal Peak b-Cell Mass Acquisition

Bartolomé, Alberto; Ravussin, Yann; Yu, Junjie; Ferrante, Anthony W.; Pajvani, Utpal B.

The increase of functional β-cell mass is paramount to maintaining glucose homeostasis in the setting of systemic insulin resistance and/or augmented metabolic load. Understanding compensatory mechanisms that allow β-cell mass adaptation may allow for the discovery of therapeutically actionable control nodes. In this study, we report the rapid and robust β-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 β-cell mass adaptation. β-Cell–specific Sin3a knockout animals showed profound diabetes due to defective acquisition of postnatal β-cell mass. These findings reveal a novel regulatory pathway in β-cell proliferation and validate OIO as a model for discovery of other mechanistic determinants of β-cell adaptation.

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Medicine
Published Here
February 3, 2025