Regulators of appetite in mammals—old and new players

Appetite regulation is a complex yet vital concept, with several pathways conserved throughout evolution that are still to be fully understood. Appetite, or the drive to search for and consume food, is driven by the integration of different food and environmental cues, as well as internal state. It is dynamically managed by intricate systems that can be broadly categorized into homeostatic (driven by physiological energy needs) and hedonic feeding (driven by pleasure and reward). This review compiles and analyzes recently described and unconventional mechanisms of appetite control in mammals, detailing their underlying molecular pathways and neural circuit integration, and implications for drug discovery. The hypothalamus plays a vital role in this, serving as the main hub for appetite control, integrating peripheral hormonal and neural signals to maintain energy balance and where several pathways converge. Beyond the established hypothalamic Arcuate Nucleus (ARC) circuit, key regulators examined include neuropeptides like Orexin A, Oxyntomodulin, PACAP, and Galanin, alongside key receptor systems such as the Melanocortin-3 receptor (MC3R), the Endocannabinoid (ECS) and the Endorphin Systems. We also explore the roles of the NUCB2/nesfatin-1 pathway and amino acid transporters (SLCs). These examinations resulted in a blurred vision of the distinction between homeostatic and hedonic regulation, with pathways converging on the hypothalamus as well as the mesolimbic reward system. Understanding this interconnected regulatory network is vital for improving therapies for disorders such as obesity, anorexia nervosa, and binge-eating disorder. This comprehensive knowledge paves the way for the development of targeted, precision medicine, or the implementation of multi-target compounds.