title: FGF1 Mediates Overnutrition-Induced Compensatory β-Cell Differentiation.
abstract: Increased insulin demand resulting from insulin resistance and/or overnutrition induces a compensatory increase in β-cell mass. The physiological factors responsible for the compensation have not been fully characterized. In zebrafish, overnutrition rapidly induces compensatory β-cell differentiation through triggering the release of a paracrine signal from persistently activated β-cells. We identified Fgf1 signaling as a key component of the overnutrition-induced β-cell differentiation signal in a small molecule screen. Fgf1 was confirmed as the overnutrition-induced β-cell differentiation signal, as inactivation of fgf1 abolished the compensatory β-cell differentiation. Furthermore, expression of human FGF1 solely in β-cells in fgf1(-/-) animals rescued the compensatory response, indicating that β-cells can be the source of FGF1. Additionally, constitutive secretion of FGF1 with an exogenous signal peptide increased β-cell number in the absence of overnutrition. These results demonstrate that fgf1 is necessary and FGF1 expression in β-cells is sufficient for the compensatory β-cell differentiation. We further show that FGF1 is secreted during prolonged activation of cultured mammalian β-cells and that endoplasmic reticulum stress acts upstream of FGF1 release. Thus, the recently discovered antidiabetes function of FGF1 may act partially through increasing β-cell differentiation.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Mingyu
authors.identifier: http://orcid.org/0000-0003-1217-2929
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Patrick
authors.initials: P
authors.lastname: Page-McCaw
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN wenbiao.chen@vanderbilt.edu.
authors.forename: Wenbiao
authors.identifier: http://orcid.org/0000-0002-0750-8275
authors.initials: W
authors.lastname: Chen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D044343:Overnutrition / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D029961:Zebrafish Proteins; D016220:Fibroblast Growth Factor 1