The locus coeruleus contributes to the anorectic, nausea, and autonomic physiological effects of glucagon-like peptide-1

Increasing the therapeutic potential and reducing the side effects of U.S. Food and Drug Administration-approved glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat obesity require complete characterization of the central mechanisms that mediate both the food intake-suppressive and illness-like effects of GLP-1R signaling. Our studies, in the rat, demonstrate that GLP-1Rs in the locus coeruleus (LC) are pharmacologically and physiologically relevant for food intake control. Furthermore, agonism of LC GLP-1Rs induces illness-like behaviors, and antagonism of LC GLP-1Rs can attenuate GLP-1R-mediated nausea. Electrophysiological and behavioral pharmacology data support a role for LC GLP-1Rs expressed on presynaptic glutamatergic terminals in the control of feeding and malaise. Collectively, our work establishes the LC as a site of action for GLP-1 signaling and extends our understanding of the GLP-1 signaling mechanism necessary for the development of improved obesity pharmacotherapies. Publication Link

LC GLP-1R activation contributes to food intake control via enhanced glutamate signaling.

(A) RNAscope analysis did not reveal Glp1r mRNA expression in LC NE neuron (DBH) soma. (B) LC NE neurons express N-methyl-d-aspartate (NMDA) receptors (Grin1A). (C) LC NE neurons express AMPA receptors (GluA1). (D) Pretreatment with an NMDA/AMPA antagonist cocktail [GluR antag; MK-801, 0.05 μg/CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), 0.3 μg] attenuated the food intake-suppressive effects of LC Ex-4 (0.05 μg) at 3 and 6 hours after administration (n = 20). (E) MK-801/CNQX attenuated the food intake suppressive effects of LC Ex-4 at 24 hours (n = 20). (F) Twenty-four-hour body weight reduction by LC Ex-4 was not significantly affected by MK-801/CNQX pretreatment (n = 20).