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

ABSTRACT: 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.

SUBMITTER: Bartolome A

PROVIDER: S-EPMC9630089 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Bartolomé Alberto A Ravussin Yann Y Yu Junjie J Ferrante Anthony W AW Pajvani Utpal B UB

Diabetes 20221101 11

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 seq ...[more]

PMID: 35944274

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Project description:Pancreatic β-cells have the key homeostatic function of releasing insulin to keep blood glucose in the normal range. It is not fully understood how β-cell mass is determined. Ablation of a nuclear receptor, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII), in mouse pancreatic β-cells results in glucose intolerance and 50% fewer β-cells during the postnatal period. By testing islets isolated from these mice and cultured β-cells with loss and gain of COUP-TFII function, we found that COUP-TFII induces β-catenin thus upregulating target genes like cyclin D1. Beta-cell expansion triggered by glucagon-like peptide 1 (GLP-1) is known to be mediated by β-catenin controlling cyclin D1. We show that in the absence of COUP-TFII, exendin-4, an agonist of the GLP-1 receptor, does not fully induce cyclin D1 expression, while overexpression of β-catenin induces cyclin D1. A marked decrease in cyclin D1 expression is detected in islets isolated from transgenic mice lacking both GLP-1 receptor and gastric inhibitory peptide receptor. COUP-TFII is therefore required for GLP-1 activation of the β-catenin-dependent pathway in pancreatic β-cells to increase β-cell number. To understand the molecular mechanisms by which COUP-TFII controls β-cell mass, we determined the RNA profile of COUP-TFII knockdown β-cells using Affymetrix oligonucleotide microarrays. Computational analysis identified clusters of genes shared by different gene regulatory Networks that are up or down regulated namely genes involved in Wnt/β-catenin signaling, insulin signaling and lipid/carbohydrate metabolism. We determined the RNA profile of COUP-TFII knockdown β-cells (832/13 INS-1 cells transfected with COUP-TFII specific siRNA) with respect to control cells (832/13 INS-1 cells transfected with scrambled siRNA) using Affymetrix expression analysis technical manual 701025Rev.5 (Affymetrix, Santa Clara, California, USA). Briefly, 1 mg of total cellular mRNA was reverse transcribed into cDNA (SuperScript Choice System Invitrogen, Carlsbad, CA) using oligo-dT primers and a T7 RNA polymerase promoter site. The cDNA was in vitro transcribed and biotin-labeled for microarray analysis using the Affymetrix IVT labeling kit. The concentration of labelled cRNA was measured using a NanoDrop ND-1000 spectrophotometer. Labeled cRNA was fragmented in a fragmentation buffer for 35 min at 94°C. The quality of labeled and fragmented cRNA was analyzed using the Agilent bioanalyzer 2100 (Van Lommel et al, 2006). Fragmented cRNA was hybridized to the rat 230 2.0 array (Affymetrix) during 16h at 45°C. Arrays were washed and stained in a fluidics station (Affymetrix) and scanned using the Affymetrix 3000 GeneScanner.

Dataset Information

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

Publications

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

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