The locus coeruleus calcitonin receptor can Be engaged by amylin and calcitonin gene-related peptide to suppress feeding without inducing nausea.

Efforts to fully characterize the diversity of mechanisms underlying energy balance control have led to the identification of atypical sites of action for metabolic signals. The locus coeruleus (LC), a major noradrenergic nucleus of the brain, has recently been shown to regulate aspects of food intake and energy expenditure. We use complementary pharmacological, behavioral, immunohistochemical, and genetic approaches in both rats and mice to demonstrate the role of LC calcitonin receptors (CTR) in feeding behavior. LC neurons robustly express CTRs that can be pharmacologically and chemogenetically activated to potently inhibit food intake and body weight without inducing nausea or changes in autonomic physiology including heart rate, body temperature, and gastric emptying. We next examined the ability of amylin and calcitonin gene-related peptide (CGRP), two endogenous anorectic peptides that signal through the CTR, to modulate feeding through signaling in the LC. RNAscope analysis revealed that LC CTRs are in fact capable of responding to amylin and CGRP, as they co-express RAMP1, and microinjections of either peptide to the LC induces anorexia without nausea. Together, these findings identify LC CTRs as a previously unrecognized neural substrate through which amylin and CGRP signaling suppress feeding, with direct relevance to the mechanisms underlying emerging amylin-based obesity therapeutics.