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

View Article: PubMed Central - PubMed

ABSTRACT

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.

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A Locus on Chromosome 7 Controls Neuroglucopenia-Induced Glucagon Secretion(A) Distribution of the glucagon ratio (2DG/NaCl) phenotype in the 36 BXD strains (n¬†= 4‚Äď14 for each strain).(B) Basal and neuroglucopenia-stimulated glucagonemia in the 36 BXD mouse strains. Each circle is the mean glucagonemia for each strain.(C) Scatterplot representing the absence of correlation between the glucagon ratio (2DG/NaCl) phenotype and the total pancreatic glucagon content in BXD mice.(D) Whole genome significant QTL on distal chromosome 7. The red line indicates the whole genome significative threshold (p ‚ȧ 0.05). The blue line indicates the whole genome suggestive threshold (p ‚ȧ 0.63).(E) Localization of the locus between with a LRS peak on marker rs2304086585.
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fig1: A Locus on Chromosome 7 Controls Neuroglucopenia-Induced Glucagon Secretion(A) Distribution of the glucagon ratio (2DG/NaCl) phenotype in the 36 BXD strains (n¬†= 4‚Äď14 for each strain).(B) Basal and neuroglucopenia-stimulated glucagonemia in the 36 BXD mouse strains. Each circle is the mean glucagonemia for each strain.(C) Scatterplot representing the absence of correlation between the glucagon ratio (2DG/NaCl) phenotype and the total pancreatic glucagon content in BXD mice.(D) Whole genome significant QTL on distal chromosome 7. The red line indicates the whole genome significative threshold (p ‚ȧ 0.05). The blue line indicates the whole genome suggestive threshold (p ‚ȧ 0.63).(E) Localization of the locus between with a LRS peak on marker rs2304086585.

Mentions: We searched for genomic intervals associated with glucagon secretion induced by 2DG-induced neuroglucopenia in a panel of 36 BXD mouse strains. Groups of male mice were generated for each BXD strain and used when they reached 10 weeks of age. In a first experimental session, mice were injected intraperitoneally (i.p.) with a saline solution and blood was collected 30 min later for plasma preparation and storage. Two weeks later, the mice received an i.p. injection of 2DG and blood was collected and plasma prepared. Glucagon levels were measured by radioimmunoassay at the same time for all mice and the ratio between plasma glucagon after 2DG and NaCl injections was calculated. This trait varies by 3-fold between BXD strains (Figure 1A) with the lowest response (1.5-fold) detected in BXD49 and the highest (4.7-fold) in BXD50. This trait was due to differences in stimulated plasma glucagon levels rather than to differences in basal glucagonemia (Figure 1B); it was not correlated to differences in total pancreatic glucagon content across all the BXD strains (Figure 1C). This suggests that the variability in the secretion response results from differences in hypoglycemia detection and signaling to pancreatic alpha cells rather than from differences in pancreatic glucagon stores.


A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion
A Locus on Chromosome 7 Controls Neuroglucopenia-Induced Glucagon Secretion(A) Distribution of the glucagon ratio (2DG/NaCl) phenotype in the 36 BXD strains (n¬†= 4‚Äď14 for each strain).(B) Basal and neuroglucopenia-stimulated glucagonemia in the 36 BXD mouse strains. Each circle is the mean glucagonemia for each strain.(C) Scatterplot representing the absence of correlation between the glucagon ratio (2DG/NaCl) phenotype and the total pancreatic glucagon content in BXD mice.(D) Whole genome significant QTL on distal chromosome 7. The red line indicates the whole genome significative threshold (p ‚ȧ 0.05). The blue line indicates the whole genome suggestive threshold (p ‚ȧ 0.63).(E) Localization of the locus between with a LRS peak on marker rs2304086585.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120348&req=5

fig1: A Locus on Chromosome 7 Controls Neuroglucopenia-Induced Glucagon Secretion(A) Distribution of the glucagon ratio (2DG/NaCl) phenotype in the 36 BXD strains (n¬†= 4‚Äď14 for each strain).(B) Basal and neuroglucopenia-stimulated glucagonemia in the 36 BXD mouse strains. Each circle is the mean glucagonemia for each strain.(C) Scatterplot representing the absence of correlation between the glucagon ratio (2DG/NaCl) phenotype and the total pancreatic glucagon content in BXD mice.(D) Whole genome significant QTL on distal chromosome 7. The red line indicates the whole genome significative threshold (p ‚ȧ 0.05). The blue line indicates the whole genome suggestive threshold (p ‚ȧ 0.63).(E) Localization of the locus between with a LRS peak on marker rs2304086585.
Mentions: We searched for genomic intervals associated with glucagon secretion induced by 2DG-induced neuroglucopenia in a panel of 36 BXD mouse strains. Groups of male mice were generated for each BXD strain and used when they reached 10 weeks of age. In a first experimental session, mice were injected intraperitoneally (i.p.) with a saline solution and blood was collected 30 min later for plasma preparation and storage. Two weeks later, the mice received an i.p. injection of 2DG and blood was collected and plasma prepared. Glucagon levels were measured by radioimmunoassay at the same time for all mice and the ratio between plasma glucagon after 2DG and NaCl injections was calculated. This trait varies by 3-fold between BXD strains (Figure 1A) with the lowest response (1.5-fold) detected in BXD49 and the highest (4.7-fold) in BXD50. This trait was due to differences in stimulated plasma glucagon levels rather than to differences in basal glucagonemia (Figure 1B); it was not correlated to differences in total pancreatic glucagon content across all the BXD strains (Figure 1C). This suggests that the variability in the secretion response results from differences in hypoglycemia detection and signaling to pancreatic alpha cells rather than from differences in pancreatic glucagon stores.

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus