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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.

No MeSH data available.


Related in: MedlinePlus

Fgf19 and the Control of Glucagon Secretion(A) Glycemia of mice injected i.c.v. with aCSF or FGF19 60 min before i.p. injection (0 min) of 2DG (600 mg/kg) (n = 7).(B) Plasma glucagon 30 min after i.p. injection of saline or 2DG in mice that were treated 60 min before with i.c.v. injection of aCSF or FGF19 (n = 7).(C–E) Plasma insulin (C), corticosterone (D), and epinephrine (E) 30 min after i.p. injection of saline or 2DG in mice that were treated 60 min before with i.c.v. injection of aCSF or FGF19 (n = 9–10) (E).(F) Hypothalamic expression of Fgf15 in C57Bl6/J mice fed a NC or a HFD for 4 weeks (n = 6–8).(G) Glycemia in NC and HFD fed mice before and 30 min after i.p. injection of 2DG (n = 6–8).(H) Plasma glucagon in NC and HFD fed mice in the basal state and 30 min after 2DG injection (n = 6–8).Data are mean ± SEM. ∗p ≤ 0.05 and ∗∗∗p ≤ 0.001. Two-way ANOVA followed by Bonferroni post hoc test (A–E, G, and H). Student’s t test (F).
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fig3: Fgf19 and the Control of Glucagon Secretion(A) Glycemia of mice injected i.c.v. with aCSF or FGF19 60 min before i.p. injection (0 min) of 2DG (600 mg/kg) (n = 7).(B) Plasma glucagon 30 min after i.p. injection of saline or 2DG in mice that were treated 60 min before with i.c.v. injection of aCSF or FGF19 (n = 7).(C–E) Plasma insulin (C), corticosterone (D), and epinephrine (E) 30 min after i.p. injection of saline or 2DG in mice that were treated 60 min before with i.c.v. injection of aCSF or FGF19 (n = 9–10) (E).(F) Hypothalamic expression of Fgf15 in C57Bl6/J mice fed a NC or a HFD for 4 weeks (n = 6–8).(G) Glycemia in NC and HFD fed mice before and 30 min after i.p. injection of 2DG (n = 6–8).(H) Plasma glucagon in NC and HFD fed mice in the basal state and 30 min after 2DG injection (n = 6–8).Data are mean ± SEM. ∗p ≤ 0.05 and ∗∗∗p ≤ 0.001. Two-way ANOVA followed by Bonferroni post hoc test (A–E, G, and H). Student’s t test (F).

Mentions: To verify that Fgf15 could regulate glucagon secretion through a central mechanism of action, we injected C57BL/6 mice i.c.v. with FGF19 (the human ortholog of Fgf15, which shows high stability in vivo and activates the same receptors; Owen et al., 2015) or an artificial cerebrospinal fluid (aCSF). Sixty min later, the mice received an i.p. injection of saline or 2DG. The glycemia was not modified by i.c.v. injections of aCSF or FGF19 (Figure 3A; t = 0) and was similarly increased 30 min after i.p. 2DG injection in both groups of mice (Figure 3A). The plasma glucagon level in i.p. saline injected mice was unaffected by previous i.c.v. FGF19 injection (Figure 3B). However, following 2DG-induced neuroglucopenia, the glucagon response was markedly lower in mice previously treated with i.c.v. FGF19 (Figure 3B). In these experiments, secretion of insulin, corticosterone, and epinephrine 30 min after i.p. saline or 2DG injections was not affected by previous i.c.v. FGF19 injection (Figures 3C–3E).


A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion
Fgf19 and the Control of Glucagon Secretion(A) Glycemia of mice injected i.c.v. with aCSF or FGF19 60 min before i.p. injection (0 min) of 2DG (600 mg/kg) (n = 7).(B) Plasma glucagon 30 min after i.p. injection of saline or 2DG in mice that were treated 60 min before with i.c.v. injection of aCSF or FGF19 (n = 7).(C–E) Plasma insulin (C), corticosterone (D), and epinephrine (E) 30 min after i.p. injection of saline or 2DG in mice that were treated 60 min before with i.c.v. injection of aCSF or FGF19 (n = 9–10) (E).(F) Hypothalamic expression of Fgf15 in C57Bl6/J mice fed a NC or a HFD for 4 weeks (n = 6–8).(G) Glycemia in NC and HFD fed mice before and 30 min after i.p. injection of 2DG (n = 6–8).(H) Plasma glucagon in NC and HFD fed mice in the basal state and 30 min after 2DG injection (n = 6–8).Data are mean ± SEM. ∗p ≤ 0.05 and ∗∗∗p ≤ 0.001. Two-way ANOVA followed by Bonferroni post hoc test (A–E, G, and H). Student’s t test (F).
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fig3: Fgf19 and the Control of Glucagon Secretion(A) Glycemia of mice injected i.c.v. with aCSF or FGF19 60 min before i.p. injection (0 min) of 2DG (600 mg/kg) (n = 7).(B) Plasma glucagon 30 min after i.p. injection of saline or 2DG in mice that were treated 60 min before with i.c.v. injection of aCSF or FGF19 (n = 7).(C–E) Plasma insulin (C), corticosterone (D), and epinephrine (E) 30 min after i.p. injection of saline or 2DG in mice that were treated 60 min before with i.c.v. injection of aCSF or FGF19 (n = 9–10) (E).(F) Hypothalamic expression of Fgf15 in C57Bl6/J mice fed a NC or a HFD for 4 weeks (n = 6–8).(G) Glycemia in NC and HFD fed mice before and 30 min after i.p. injection of 2DG (n = 6–8).(H) Plasma glucagon in NC and HFD fed mice in the basal state and 30 min after 2DG injection (n = 6–8).Data are mean ± SEM. ∗p ≤ 0.05 and ∗∗∗p ≤ 0.001. Two-way ANOVA followed by Bonferroni post hoc test (A–E, G, and H). Student’s t test (F).
Mentions: To verify that Fgf15 could regulate glucagon secretion through a central mechanism of action, we injected C57BL/6 mice i.c.v. with FGF19 (the human ortholog of Fgf15, which shows high stability in vivo and activates the same receptors; Owen et al., 2015) or an artificial cerebrospinal fluid (aCSF). Sixty min later, the mice received an i.p. injection of saline or 2DG. The glycemia was not modified by i.c.v. injections of aCSF or FGF19 (Figure 3A; t = 0) and was similarly increased 30 min after i.p. 2DG injection in both groups of mice (Figure 3A). The plasma glucagon level in i.p. saline injected mice was unaffected by previous i.c.v. FGF19 injection (Figure 3B). However, following 2DG-induced neuroglucopenia, the glucagon response was markedly lower in mice previously treated with i.c.v. FGF19 (Figure 3B). In these experiments, secretion of insulin, corticosterone, and epinephrine 30 min after i.p. saline or 2DG injections was not affected by previous i.c.v. FGF19 injection (Figures 3C–3E).

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