The increasing prevalence of obesity in many developed countries contributes to major adverse effect on public health.  The search for genetic and environmental factors that contribute to the epidemiology of obesity has led to the discovery of genes that regulate food intake and body weight. Obesity is defined as having very high amount of body fat in relation to lean body mass, or body Mass Index (BMI) 30 or greater. BMI is defined as the ratio of body weight in kilograms to square of height in meters. Obesity can be defined in absolute or relative terms. Assessment of obesity involves using three key measures: body mass index (BMI), if greater than 30, waist circumference, if greater than 40 inches. According to the World Health Organization: Obesity has reached epidemic proportions globally there are more than 1 billion overweight adults, at least 300 million of them obese. The levels of overweight adults worldwide will rise to 2.3 billion by 2015 and more than 700 million of them obese.  An estimated 22 million children under five are estimated to be overweight worldwide. Obesity accounts for 2-6% of total health care costs in several developed countries; some estimates put the figure as high as 7%. The true costs are undoubtedly much greater as not all obesity-related conditions are included in the calculations.

Multiple pathways including peripheral and central hormones and neurotransmitters are involved in regulation of food intake and body weight. Some of the most studied neuroendocrine pathways regulating homeostasis of body weight and energy expenditure involve peripheral hormones such as leptin and insulin and the central neurotransmitters αMSH and AgRP.  αMSH is derived from a large precursor protein pro-opiomelanocortin (POMC) and binds with high affinity to melanocortin receptors (MC-Rs).  Additionally, the endogenous ligand AgRP has been found to bind to MC-Rs with high affinity. Neurons containing αMSH or AgRP are found in high concentration in the hypothalamus of the brain. MC-Rs are also located in these hypothalamic regions. αMSH activates MC-Rs whereas AgRP directly and indirectly inhibits the αMSH mediated stimulation of MC-Rs.

MC-Rs belong to the G protein-coupled receptor (GPCR) superfamily having seven transmembrane-spanning domains. To date, five subtypes of MC-R (MC1R to MC5R) have been identified. Multiple POMC derived peptides are agonists of these receptors with overlapping activity.  MC3R, MC4R and MC5R are mainly located in the central nervous system (CNS) with high concentration in the hypothalamic regions such as the arcuate nucleus and paraventricular nucleus. Multiple lines of evidence indicate that hypothalamic MC4R play a key role in regulating food intake and energy balance whereas MC3R may be more involved in energy regulation.  In humans, mutations of the MC4R have been identified in obese patients and linked to impaired ligand binding and signalling. In animal studies, reduced MC4R stimulation due either to decreased αMSH expression or increased AgRP expression has clearly demonstrated an obese phenotype. Additionally, complete MC4R gene disruption results in an obese phenotype.

The striking characteristics of the MC4R/αMSH/AgRP system suggest that a proper balance between the agonist activity of αMSH and the antagonist/inverse agonist activity of AgRP on the MC4R is critical for proper functioning of the MC4R pathway, resulting in normal energy expenditure and food intake. Although the detailed mechanism regulating stimulatory and inhibitory activity in the pathway is yet to be elucidated, it is reasonable to speculate that an imbalance of αMSH and AgRP exist in obese individuals.