Agouti and Agouti-Related Protein

The common term agouti refers to several rodent species of the genus asyprocta that look similar to guinea pigs and inhabit areas of Central America, the West Indies, and northern South America. The gene (called the agouti gene) that is responsible for the [Page 20]pecific hair-color in these rodents (dark hairs that are lighter at the tip) also makes these animals fat. A similar gene is also found in various other mammals including humans. Its human homologue (version) is located on chromosome 20 and encodes for the agouti-related protein, consists of 132-amino-acids and is 81 percent identical to the one found in the agouti. The agouti-related protein (or agouti-related peptide, AgRP) is produced by a collection of neurons called the arcuate nucleus in the hypothalamus region of the brain.

In 1997, two independent sets of researchers discovered AgRP and showed that it stimulates appetite and is a putative cause of obesity. Understanding the role AgRP plays in weight gain holds the promise of enabling researchers to probe the metabolic processes that lead to obesity and discover therapeutics to treat this health disorder.

AgRP is critical to the mechanism by which the brain controls eating behavior. The arcuate nucleus of the brain has two sets of neurons. One set, the AgRP/NPY (neuropeptide-Y) neurons, produces AgRP. The other set, the POMC neurons, produces proopiomelanocortin (POMC), a precursor to the melanocortin (MC) family of hormones that includes adrenocorticotropin (ACTH) and the alpha-, beta-, and gamma-melanocyte-stimulating hormones (MSH-α, β, and γ). Currently, there are five known receptors of melanocortins, MC1R through MC5R, that are agonized (activated) by them and antagonized (deactivated) by AgRP. In humans, MC1R is expressed in melanocytes; MC2R in the adrenal and adipose (fat) tissue; MC3R in the brain, placenta, and pancreas; and MC4R in the brain, muscle, and adipose tissue. MC5R is expressed ubiquitously in most tissues. Together, the MC receptors control lipogenesis (fat storage), lipolysis (fat burning), and food intake, as well as skin pigmentation, thermogenesis, sexual behavior, memory, and antiinflammatory and antipyretic effects. MC3R and MC4R, found in the brain, are known to control energy expenditure.

The presence of endogenous agonists (melanocortins) and antagonist (AgRP) acting on the same receptor system suggests tight control of energy metabolism by the brain. Central to the brain's control of eating behavior is the protein hormone leptin produced in adipose (fat) tissue. When animals overeat or the body accumulates more fat, more leptin is produced. High levels of circulating leptins in the body decrease AgRP release and increase production of ACTH and MSH-α. In turn, this activates the MC receptors (especially MC3R and MC4R), which results in an increase in metabolism and energy utilization, and a decrease in appetite. Conversely, fasting results in loss of adipose tissue and low leptin levels, which inhibits the activity of POMC neurons, thereby reducing energy usage and increasing appetite. The mechanism via deactivating melanocortin receptors is, however, not the only way in which AgRP is believed to prevent breakdown of fatty tissue. Some recent studies have indicated that AgRP can have similar effects through alternate physiological routes (calcium signaling channels in fat cells) as well.

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