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

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Montaner, Mireia | Denom, Jessica | Simon, Vincent | Jiang, Wanqing | Holt, Marie | Brierley, Dan | Rouch, Claude | Foppen, Ewout | Kassis, Nadim | Jarriault, David | Khan, Dawood | Eygret, Louise | Mifsud, Francois | Hodson, David | Broichhagen, Johannes | van Oudenhove, Lukas | Fioramonti, Xavier | Gault, Victor | Cota, Daniela | Reimann, Frank | Gribble, Fiona | Migrenne-Li, Stephanie | Trapp, Stefan | Gurden, Hirac | Magnan, Christophe

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Summary 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 demonstrate that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, highlighting the functional implication of the sympathetic nervous system (SNS). Inhibiting GABAA 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. These findings identify a novel top-down neural mechanism engaged by OB GLP-1 signaling to control insulin secretion via the SNS.

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