What is the Origin of MC4 Receptor?

The receptor was designated as the fourth subtype within the Melanocortin receptor family, which is known to bind melanocortin peptides derived from the precursor protein Pro-opiomelanocortin (POMC). Its crucial function in energy balance was conclusively established through genetic studies that identified loss-of-function mutations in the MC4R gene as the most common monogenic cause of severe human obesity. This discovery solidified its role as a key therapeutic target for the pharmacological management of weight.

What is the Mechanism of MC4 Receptor?

The MC4R is subject to tonic inhibition by the Agouti-related peptide (AgRP) and is activated by the potent α-MSH, which is produced by POMC neurons in the arcuate nucleus of the hypothalamus. When α-MSH binds to the MC4R, it activates a downstream intracellular signaling cascade involving adenylyl cyclase and cyclic AMP (cAMP). This signaling effectively suppresses food intake and promotes energy expenditure. Conversely, the competitive blockade by AgRP leads to increased feeding. The precise balance of these opposing signals at the MC4R integrates information from peripheral hormones like leptin and insulin to maintain overall energy balance.

MC4 Receptor

Meaning

The Melanocortin 4 Receptor (MC4R) is a G protein-coupled receptor predominantly expressed in the central nervous system, particularly within the hypothalamic nuclei, and it serves a pivotal role in the precise regulation of energy homeostasis, appetite, and total body weight. Activation of this receptor by its endogenous agonist, alpha-melanocyte-stimulating hormone (α-MSH), transmits a potent signal for satiety and simultaneously promotes an increase in energy expenditure. The MC4R pathway is recognized as a critical component of the leptin-melanocortin system, the major neuroendocrine circuit governing long-term body weight regulation.