The melanocortin pathway and control of appetite-progress and therapeutic implications

Abstract

The initial discovery thatob/obmice become obese because of a recessive mutation of the leptin gene has been crucial to discover the melanocortin pathway to control appetite. In the melanocortin pathway, the fed state is signaled by abundance of circulating hormones such as leptin and insulin, which bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH). The α-MSH released by POMC neurons then signals to decrease energy intake by binding to melanocortin-4 receptor (MC4R) expressed by MC4R neurons to the paraventricular nucleus (PVN). Conversely, in the ‘starved state’ activity of agouti-related neuropeptide (AgRP) and of neuropeptide Y (NPY)-expressing neurons is increased by decreased levels of circulating leptin and insulin and by the orexigenic hormone ghrelin to promote food intake. This initial understanding of the melanocortin pathway has recently been implemented by the description of the complex neuronal circuit that controls the activity of POMC, AgRP/NPY and MC4R neurons and downstream signaling by these neurons. This review summarizes the progress done on the melanocortin pathway and describes how obesity alters this pathway to disrupt energy homeostasis. We also describe progress on how leptin and insulin receptors signal in POMC neurons, how MC4R signals and how altered expression and traffic of MC4R change the acute signaling and desensitization properties of the receptor. We also describe how the discovery of the melanocortin pathway has led to the use of melanocortin agonists to treat obesity derived from genetic disorders.

Melanocortin-4 receptor antagonist TCMCB07 ameliorates cancer- and chronic kidney disease–associated cachexia

“…While MC3R neurons likely contribute to behavioral adaptation to fasting and nutrient partitioning, MC4R neurons are involved in feeding behavior, adaptive thermogenesis, and glucose homeostasis (10). Therefore, this system provides a logical target for developing drugs for treating cachexia, obesity, and diabetes (8,(11)(12)(13)(14). The pathophysiological processes of many illnesses increase the melanocortin tone that suppresses appetite and anabolism, leading to anorexia and body weight loss, with inflammation as an essential driver (15).…”

Genetic architecture underlying changes in carotenoid accumulation during the evolution of the Blind Mexican cavefish,Astyanax mexicanus

“…Tinaja and Molino cavefish consume more than surface fish in the laboratory and this difference is associated with mutations in melanocortin receptor 4 (MC4R) (Aspiras et al, 2015). MC4R is a G protein-coupled receptor expressed in the hypothalamus that integrates leptin and insulin signals to modulate appetite (Baldini & Phelan, 2019). Human variation at the MC4R locus is associated obesity, anorexia, and one study found a human SNP in MC4R associated with lutein levels in the serum (Borel et al, 2014).…”

Diagnostic and therapeutic odyssey of two patients with compound heterozygous leptin receptor deficiency

“…POMC is then processed via prohormone convertase 1 into the αmelanocyte-stimulating hormone (α-MSH), which activates the melanocortin 4 receptor (MC4R). This finally mediates a feeling of satiety, reduces food intake, and enhances energy expenditure [10][11][12]. In summary, the disease-causing variants in the LEPR gene found in the two patients interrupt the leptin-melanocortin signalling pathway and lead to severe early-onset obesity, pronounced hyperphagia, and permanent food-seeking behaviour.…”