Review maps old and new neuropeptide and receptor systems regulating mammalian appetite

Appetite regulation is a complex, evolutionarily conserved process driven by integrated food, environmental, and internal cues. It's broadly categorized into homeostatic (energy needs) and hedonic feeding (pleasure/reward). The hypothalamus serves as the main hub, integrating peripheral signals to maintain energy balance. Despite established pathways like the Arcuate Nucleus (ARC) circuit, a full understanding of all regulatory mechanisms remains elusive, hindering effective therapies for disorders like obesity and anorexia nervosa.

This review compiled and analyzed recently described and unconventional mechanisms of appetite control in mammals. Researchers detailed their underlying molecular pathways and neural circuit integration, assessing implications for drug discovery. The scope extended beyond the established hypothalamic ARC circuit to include specific neuropeptides, receptor systems, and other pathways. The analysis aimed to synthesize current knowledge and identify convergences between homeostatic and hedonic regulation.

The review identified several key regulators beyond traditional pathways, including neuropeptides like Orexin A, Oxyntomodulin, PACAP, and Galanin. Key receptor systems examined were the Melanocortin-3 receptor (MC3R), the Endocannabinoid (ECS), and the Endorphin Systems. Additionally, the NUCB2/nesfatin-1 pathway and amino acid transporters (SLCs) were explored for their roles in appetite control.

These examinations revealed a blurred distinction between homeostatic and hedonic regulation, with pathways converging on both the hypothalamus and the mesolimbic reward system. This interconnected network highlights the intricate integration of physiological energy needs and reward-driven feeding behaviors, suggesting a more unified regulatory system than previously compartmentalized.