A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion.
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.
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Alexandre
A
Picard
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Josselin
J
Soyer
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Xavier
X
Berney
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
David
D
Tarussio
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Simon
S
Quenneville
Vital-IT, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
Maxime
M
Jan
Service de Biomédicine, Laboratoire des Catécholamines et Peptides, Centre Hospitalier Universitaire Vaudois CHUV, 1011 Lausanne, Switzerland.
Eric
E
Grouzmann
Vital-IT, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
Frédéric
F
Burdet
Vital-IT, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
Mark
M
Ibberson
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address: bernard.thorens@unil.ch.
Bernard
B
Thorens
D000375:Aging; D000818:Animals; D033481:Chromosomes, Mammalian / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D020868:Gene Silencing / Q000187:drug effects; D005820:Genetic Testing; D016678:Genome; D005934:Glucagon / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics
C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; D005934:Glucagon; D003847:Deoxyglucose
FGF15; FGF19; QTL mapping; autonomic nervous system; dorsal vagal complex; genetic screen; glucagon secretion; glucose sensing; hypothalamus; neuroglucopenia