A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α 2 -adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABA A receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.Glucagon-like peptide-1 (GLP-1) is an insulinotropic 1,2 incretin derived from preproglucagon (PPG), which was first identified in the intestine 3 . Since its discovery in the periphery, the presence of PPG, GLP-1 and its receptor GLP-1R has also been reported in the central nervous system. GLP-1 is notably produced by hindbrain PPG neurons, mainly in the nucleus tractus solitarius (NTS) and the medullary intermediate reticular nucleus (IRT) 4 . In mice, GLP-1R are found in several areas including the circumventricular organs, the amygdala and hypothalamic nuclei 5 . Neural circuits driven by GLP-1 and GLP-1R in the NTS and hypothalamus has been shown to contribute to many aspects of