Evidence for a Gut-Brain Axis Used by Glucagon-like Peptide-1 to Elicit Hyperglycaemia in Fish

Abstract

In mammals, glucagon-like peptide-1 (GLP-1) produces changes in glucose and energy homeostasis through a gut-pancreas-brain axis. In fish, the effects of GLP-1 are opposed to those described in other vertebrates, such as stimulation of hyperglycaemia and the lack of an effect of incretin. In the present study conducted in a teleost fish such as the rainbow trout, we present evidence of a gut-brain axis used by GLP-1 to exert its actions on glucose and energy homeostasis. We have assessed the effects of GLP-1 on glucose metabolism in the liver as well as the glucose-sensing potential in the hypothalamus and hindbrain. We confirm that peripheral GLP-1 administration elicits sustained hyperglycaemia, whereas, for the first time in a vertebrate species, we report that central GLP-1 treatment increases plasma glucose levels. We have observed (using capsaicin) that at least part of the action of GLP-1 on glucose homeostasis was mediated by vagal and splanchnic afferents. GLP-1 has a direct effect in parameters involved in glucose sensing in the hindbrain, whereas, in the hypothalamus, changes occurred indirectly through hyperglycaemia. Moreover, in the hindbrain, GLP-1 altered the expression of peptides involved in the control of food intake. We have elaborated a model for the actions of GLP-1 in fish in which this peptide uses a mammalian-like ancestral gut-brain axis to elicit the regulation of glucose homeostasis in different manner than the model described in mammals. Finally, it is worth noting that the hyperglycaemia induced by this peptide and the lack of incretin function could be related to the glucose intolerance observed in carnivorous teleost fish species such as the rainbow trout.