PEPTIDES IN ENERGY BALANCE AND OBESITY
by CAB International 2009

Melanocortins
The melanocortinergic signalling system in the brain is an important member of the family of catabolic central pathways, as supported by solid genetic and pharmacological evidence. It has been shown that leptin exerts its action partly by activation of the melanocortin system in the brain.

Melanocortins are a family of peptides, including a-MSH (Melanotan 2) and corticotropin, which are cleaved from POMC precursors. In the mammalian brain, POMC is expressed by neurones of the ARC, adjacent to NPY-producing cells, and by the neurones of the NST. These neurones release a-MSH from axon terminals, where it can bind and activate melanocortin receptors (MCR) on postsynaptic membrane surfaces.

Among the five MCR subtypes identified, MC4R is strongly implicated in food intake and possibly in energy expenditure, with knocking out of this receptor subtype causing hyperphagia and obesity in mice, central administration of an MC4R agonist producing anorexia, whereas administration of an antagonist of MC4R stimulates feeding. MC4R is a seven-transmembrane G protein-coupled receptor (GPCR) encoded by a single exon gene localized on chromosome 18q22. MC4R is highly expressed in PVN, which contains POMC and AgRP fibres. MC4R is stimulated by a-MSH and antagonized by AgRP, which is the endogenous antagonist of the melanocortin system.

Mice with targeted disruption of the POMC gene are obese. In humans, MC4R mutations have been reported as the most common single genetic cause of obesity in some populations, being responsible for about 4% of early-onset obesity. Mutations in MC4R result in a distinct obesity syndrome that is inherited in a codominant manner. Mutations leading to complete loss of function are associated with a more severe phenotype. The correlation between the signaling properties of these mutant receptors and energy intake emphasizes the key role of this receptor in the control of eating behavior in humans.

MC4R activity affects meal size and meal choice but not meal frequency, with the type of diet affecting the efficacy of MC4R agonists to reduce food intake. The central sites involved in the different aspects of feeding behavior that are affected by MC4R signaling are being unravelled. The PVN plays an important role in food intake per se, whereas melanocortin signaling in the lateral hypothalamus is associated with the response to a high fat diet. MC4R signaling in the brainstem has been shown to affect meal size. Further genetic, behavioral and brain region-specific studies need to clarify how the MC4R agonists affect feeding behavior in order to determine which obese individuals would benefit most from treatment with these drugs. Application of MCR agonists in humans has already revealed side effects, such as penile erection, which may complicate introduction of these drugs in the treatment of obesity.

The role of the CNS-MCR system in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake has been established. Pharmacological inhibition of MCR in rats and genetic disruption of MCR4 in mice promote lipid uptake, triglyceride synthesis and fat accumulation in white adipose tissue directly and potently, while increased CNS-MCR signaling triggers lipid mobilization. These effects have been shown to be independent of food intake and precede changes in adiposity. In addition, decreased CNS-MCR signaling promotes increased insulin sensitivity and glucose uptake in white adipose tissue, while decreasing glucose utilization in muscle and brown adipose tissue. Interestingly, this CNS control of peripheral nutrient partitioning depends on functionality of the SNS and is enhanced by synergistic effects on liver triglyceride synthesis. The reported findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization, as reflected by the respiratory quotient, which is increased with chronic MCR blockade in rodents and in humans with loss-of-function mutations in MC4R. Transgenic mice over-expressing MSH show reduced weight gain and adiposity, improved glucose tolerance and insulin sensitivity. These results are observed in diverse backgrounds such as lean and genetically obese mice. Additional studies are necessary to determine if MSH over-expression might protect against more common forms of obesity such as diet-induced obesity and the associated metabolic changes. Long-term melanocortinergic activation has been targeted as a potential strategy for antiobesity and/or antidiabetic therapy.

Conclusion
There is a great effort to develop agonists and antagonists of peptide receptors that have been associated specifically with energy homeostasis. As described above, the MCR system represents an attractive target. A natural agonist, a-MSH (Melanotan 2) reduces food intake, with mice lacking POMC, the precursor of a-MSH, being obese. This suggests that specific agonists for MC4R might become useful obesity agents. MC3R has been suggested to play a role in nutrient partitioning. Although agonists of the MC3R would not be expected to produce dramatic weight loss, they may favor a more beneficial partitioning of nutrients.The development of dual MC4 and MC3 receptor agonists has been addressed in order to reduce weight dramatically, as well as improve the metabolic co-morbidities of obesity significantly.