A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion

Alexandre Picard; Josselin Soyer; Xavier Berney; David Tarussio; Simon Quenneville; Maxime Jan; Eric Grouzmann; Frédéric Burdet; Mark Ibberson; Bernard Thorens

doi:10.1016/j.celrep.2016.10.041

Cell Reports (Nov 2016)

A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion

Alexandre Picard,
Josselin Soyer,
Xavier Berney,
David Tarussio,
Simon Quenneville,
Maxime Jan,
Eric Grouzmann,
Frédéric Burdet,
Mark Ibberson,
Bernard Thorens

Affiliations

Alexandre Picard: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland
Josselin Soyer: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland
Xavier Berney: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland
David Tarussio: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland
Simon Quenneville: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland
Maxime Jan: Vital-IT, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Eric Grouzmann: Service de Biomédicine, Laboratoire des Catécholamines et Peptides, Centre Hospitalier Universitaire Vaudois CHUV, 1011 Lausanne, Switzerland
Frédéric Burdet: Vital-IT, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Mark Ibberson: Vital-IT, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Bernard Thorens: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland

DOI: https://doi.org/10.1016/j.celrep.2016.10.041
Journal volume & issue: Vol. 17, no. 7
pp. 1795 – 1806

Abstract

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The counterregulatory response to hypoglycemia, which restores normal blood glucose levels to ensure sufficient provision of glucose to the brain, is critical for survival. To discover underlying brain regulatory systems, we performed a genetic screen in recombinant inbred mice for quantitative trait loci (QTL) controlling glucagon secretion in response to neuroglucopenia. We identified a QTL on the distal part of chromosome 7 and combined this genetic information with transcriptomic analysis of hypothalami. This revealed Fgf15 as the strongest candidate to control the glucagon response. Fgf15 was expressed by neurons of the dorsomedial hypothalamus and the perifornical area. Intracerebroventricular injection of FGF19, the human ortholog of Fgf15, reduced activation by neuroglucopenia of dorsal vagal complex neurons, of the parasympathetic nerve, and lowered glucagon secretion. In contrast, silencing Fgf15 in the dorsomedial hypothalamus increased neuroglucopenia-induced glucagon secretion. These data identify hypothalamic Fgf15 as a regulator of glucagon secretion.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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