Amylin Receptors In The Locus Coeruleus Mediate Homeostatic And Hedonic Feeding Behavior

Obesity deteriorates both normal physiological activity as well as psychiatric and cognitive functions.Maintaining long-term energy homeostasis is key to prevent and intervene obesity.The central nervous system,which various feeding related peptides act on,is pivotal to regulate energy homeostasis and food intake.Amylin is one of the most important feeding related peptides regulating feeding behavior.Amylin receptors are expressed abundantly in the catecholamine neurons,modulating the releasing of norepinephrine(NE),dopamine,and serotonin.Catecholamine regulates diverse mental and cognitive functions,such as mood,motivation,reward,and memory,thus modulating feeding behavior.Therefore,we propose that amylin receptors in the locus coeruleus(LC)mediate both homeostatic and hedonic feeding behavior.We used immunohistochemistry technique to confirm the expression of amylin receptors in mouse locus coeruleus slices.Then,we combined intra-LC drug administration with in vitro brain slice electrophysiology to examine the neural mechanism underlying the physiological effects of LC amylin receptor activation.Our study found that activation of amylin receptors in the LC increased the firing rate of neurons via ERK signaling pathway in vitro and inhibited food intake and body weight in in vivo animal experiments.Blockade of amylin signaling in the LC abolished hypophagia and reduction in body weight effects induced by systematically administered amylin receptor agonist.Intra-LC injection of amylin receptor agonist decreased the effortbased motivation for food and the reward property of food palatability in progressive ratio task.Open filed test indicated that amylin receptor in the LC could modulate approach-avoidance motivation.Taken together,amylin receptors in the LC modulate homeostatic and hedonic feeding behavior.Amylin and its analogues have great therapeutic potential in the treatment and intervention of obesity.LC-NE system could be an important catecholaminergic therapeutic target for the treatment of obesity.