Alpha-melanocyte-stimulating hormone-mediated appetite regulation in the central nervous system.

Understanding the complex action mechanism of appetite regulation peptides can significantly impact therapeutic options in the treatment of obesity and other metabolic diseases. Hypothalamic α-melanocyte-stimulating hormone (α-MSH) is an anorexigenic peptide, closely related to the occurrence of obesity, playing a central role in food intake and energy expenditure. In the central nervous system (CNS), α-MSH is cleaved from proopiomelanocortin (POMC) and then released into different hypothalamic regions to act on melanocortin 3/4 receptor (MC3/4R)-expressing neurons, lowering food intake and raising energy expenditure via appetite suppression and sympathetic nervous system. Furthermore, it can increase the transmission of some anorexigenic hormones (e.g., dopamine) and interact with other orexigenic factors (e.g., agouti-related protein, neuropeptide Y) to influence food reward rather than merely feeding behavior. Therefore, α-MSH is a critical node of the hypothalamus in transmitting appetite suppression signals and is a key component of the central appetite-regulating circuits. Herein, we describe the role of α-MSH in appetite suppression in terms of specific receptors, effector neurons, sites of action, and the interaction with other appetite-relative peptides, respectively. We focus on the role of α-MSH in obesity. The status of research on α-MSH-related drugs is also discussed. With the intention of illuminating a new approach for targeting α-MSH in the hypothalamus as a strategy to manage obesity, we hope to further understand the direct or indirect mechanisms by which α-MSH exerts its appetite-regulating effects.