Abstract
Intracerebroventricular administration of the protein hormone fibroblast growth factor 19 (FGF19) to the hindbrain produces potent antidiabetic effects in hyperglycemic mice that are likely mediated through a vagal parasympathetic mechanism. FGF19 increases the synaptic excitability of parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) from hyperglycemic, but not normoglycemic, mice but the source of this synaptic input is unknown. Neurons in the area postrema (AP) and nucleus tractus solitarius (NTS) express high levels of FGF receptors and exert glutamatergic control over the DMV. This study tested the hypothesis that FGF19 increases glutamate release in the DMV by increasing the activity of glutamatergic AP and NTS neurons in hyperglycemic mice. Glutamate photoactivation experiments confirmed that FGF19 increases synaptic glutamate release from AP and NTS neurons that connect to the DMV in hyperglycemic, but not normoglycemic mice. Contrary to expectations, FGF19 produced a mixed effect on intrinsic membrane properties in the NTS with a trend towards inhibition, suggesting that another mechanism was responsible for the observed effects on glutamate release in the DMV. Consistent with the hypothesis, FGF19 increased action potential-dependent glutamate release in the NTS in hyperglycemic mice only. Finally, glutamate photoactivation experiments confirmed that FGF19 increases the activity of glutamatergic AP neurons that project to the NTS in hyperglycemic mice. Together, these results support the hypothesis that FGF19 increases glutamate release from AP and NTS neurons that project to the DMV in hyperglycemic mice. FGF19 therefore modifies the local vago-vagal reflex circuitry at several points. Additionally, since the AP and NTS communicate with several other metabolic regulatory nuclei in the brain, FGF19 in the hindbrain may alter neuroendocrine and behavioral aspects of metabolism, in addition to changes in parasympathetic output.
Highlights
Fibroblast growth factor 19 (FGF19) is an ileal-derived protein hormone that produces potent, anti-diabetic, and anti-obesogenic effects
The averaged fold-change of all cells in this group was 1.96. These data suggest that FGF19 increases the excitability of glutamatergic area postrema (AP) neurons that project to the nucleus tractus solitarius (NTS) in hyperglycemic mice. These results indicate that FGF19 increases glutamatergic transmission at multiple points in dorsal vagal complex (DVC) circuitry in hyperglycemic, but not normoglycemic mice, which implies a mechanistic understanding of FGF19 activity in the hindbrain
We found previously that FGF19 decreased blood glucose in hyperglycemic mice through actions in the dorsal hindbrain, and this effect was abrogated by co-administration of a peripheral muscarinic receptor blocker [6], suggesting a parasympathetic mechanism
Summary
Fibroblast growth factor 19 (FGF19) is an ileal-derived protein hormone that produces potent, anti-diabetic, and anti-obesogenic effects. Lateral ventricle administration of FGF19 increases metabolic rate [1], while 3rd ventricular administration was found to decrease food intake, lower insulin resistance, improve glucose tolerance, and reduce blood glucose concentrations in rodent models of diabetes and obesity [2,3,4,5]. These findings suggest a hypothalamic mechanism since FGF19 was found to suppress AGRP/NPY activity [4] and decrease plasma ACTH [2]. The DVC, especially the AP and NTS, contains multiple FGF receptors (FGFR) as well as ß-klotho, an obligate co-receptor [26,27,28], suggesting that neuronal activity in the DVC may regulate metabolic homeostatic mechanisms in response to endogenous FGF signaling
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