Endocrine Abstracts

Amylin is a pancreatic gut hormone co-released with insulin in response to a meal. Amylin signaling has drawn a large amount of interest these past years due to its potential as an anti-obesity treatment. Amylin binds to an heterodimeric receptor (AMY1-3) composed of the calcitonin receptor (CTR) and the receptor activity modifying proteins (RAMP1-3). These receptors are located in multiples brain areas involved in the homeostatic and hedonic control of energy homeostasis. The distribution and the localization of these receptors subtype may be important in mediating amylin’s specific effects. Amylin’s main binding site is located in the area postrema where its activates noradrenergic neurons to produce its anorectic effect by decreasing meal size. The signal is then propagated to the nucleus of the solitary tract and lateral parabrachial nucleus (LPBN) and transmitted to forebrain areas such as central amygdala and bed nucleus of the stria terminalis. In the LPBN, amylin signaling mainly activates non-aversive non-CGRP (calcitonin-gene related peptide) neurons while the AMY agonist salmon calcitonin, which also binds the CTR alone, activates CGRP neurons leading to malaise and nausea. Amylin also act in the mediobasal hypothalamus where it sensitize leptin action. Cagrilintide is a long acting, dual amylin and calcitonin receptor agonist (DACRA) that induces weight loss in people living with obesity. The combination of cagrilintide and the long-acting glucagon-like peptide 1 receptor (GLP-1R) agonist, semaglutide (CagriSema) is currently in clinical development for treatment of obesity and type-2-diabetes. Our current work aim to identify the exact neuronal pathways and molecular identity of the neurons activated by these drugs.

Key learning points: - Amylin is a pancreatic peptide secreted in response to a meal; it controls eating and energy homeostasis.

- Amylin acts through a variety of receptor composed of the calcitonin receptor and the receptor activity modifying protein 1-3.

- Amylin primary sites of action are located in the area postrema and the arcuate nucleus of the hypothalamus.

- Amylin receptor agonist promote an aversive through NTS-LPBN neuronal pathway.

- The amylin receptor agonist, cagrilintide, acts in concert with semaglutide to decrease body weight at lower dose than each compound alone.