Central nervous system pathways targeted by amylin in the regulation of food intake

Abstract

Amylin is a peptide hormone co-released with insulin from pancreatic β-cells during a meal and primarily serves to promote satiation. While the caudal hindbrain was originally implicated as a major site of action in this regard, it is becoming increasingly clear that amylin recruits numerous central nervous system pathways to exert multifaceted effects on food intake. In this Review, we discuss the evidence derived from preclinical studies showing that amylin and the related peptide salmon calcitonin (sCT) directly or indirectly target genetically distinct neurons in the caudal hindbrain (nucleus tractus solitarius and area postrema), rostral hindbrain (lateral parabrachial nucleus), midbrain (lateral dorsal tegmentum and ventral tegmental area) and hypothalamus (arcuate nucleus and parasubthalamic nucleus) via activation of amylin and/or calcitonin receptors. Given that the stable amylin analogue cagrilintide is under clinical development for the treatment of obesity, it is important to determine whether this drug recruits overlapping or distinct central nervous system pathways to that of amylin and sCT with implications for minimising any aversive effects it potentially causes. Such insight will also be important to understand how amylin and sCT analogues synergize with other molecules as part of dual or triple agonist therapies for obesity, especially the glucagon-like peptide 1 receptor (GLP-1R) agonist semaglutide, which has been shown to synergistically lower body weight with cagrilintide (CagriSema) in clinical trials.