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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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE199907 | GEO | 2022/11/09

REPOSITORIES: GEO

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Project description:The dramatic increase in myotomal muscle mass in fish is related to their ability to lastingly produce new muscle fibres, a process termed hyperplasia. The molecular and cellular mechanisms underlying fish muscle hyperplasia largely remain unknown. In this study, we aimed to characterize intrinsic properties of myogenic cells originating from fish hyperplasic muscle. For this purpose, we compared in situ proliferation, in vitro cell behavior and transcriptomic profile of myogenic precursors originating from hyperplasic muscle of juvenile trout (JT) and from non-hyperplasic muscle of fasted juvenile trout (FJT) and adult trout (AT). For the first time, we showed that myogenic precursors proliferate in hyperplasic muscle from JTas shown by in vivo BrdU labeling. This proliferative rate was very low in AT and FJT muscle. Transcriptiomic analysis revealed that myogenic cells from FJT and AT displayed close expression profiles with only 64 differentially expressed genes (BH corrected p-val < 0.001). In contrast, 2623 differentially expressed genes were found between myogenic cells from JT and from both FJT and AT. Functional categories related to translation, mitochondrial activity, cell cycle, and myogenic differentiation were inferred from genes up regulated in JT compared to AT and FJT myogenic cells. Conversely, Notch signaling pathway, that signs cell quiescence, was inferred from genes down regulated in JT compared to FJT and AT. In line with our transcriptomic data JT myogenic precursors displayed higher proliferation and differentiation capacities than FJT and AT myogenic precursors. The transcriptomic analysis and examination of cell behavior converge to support the view that myogenic cells extracted from hyperplastic muscle of juvenile trout are intrinsically more potent to form myofibres than myogenic cells extracted from non-hyperplasic muscle. The generation of gene expression profiles in myogenic cell extracted from muscle of juvenile trout may yield insights into the molecular and cellular mechanisms controlling hyperplasia and provides a useful list of potential molecular markers of hyperplasia.

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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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