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

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posted on 2022-08-09, 21:01 authored by Alberto Bartolome, Yann Ravusin, Junjie Yu, Anthony W. Ferrante Jr., Utpal B. Pajvani

The increase of functional β 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 β cell mass adaptation may allow 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 to β cell adaptation.

Funding

This work was supported by NIH R01DK103818 and R01DK132661 (UBP), a Russell Berrie Foundation Award (AB) and an American Diabetes Association Grant 1-17-PMF-025 (AB).

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