The
melanocortin system is an important treatment target towards improving both adiposity (excessive body fat) and adiposopathy (dysfunctional body fat).
Melanocortin agonism can be achieved by increasing CNS
leptin and/or
insulin activity, which is dependent upon peripheral
leptin/
insulin production, transport across the blood-brain barrier (potentially relevant to inhaled/nasal
insulin), and effects upon CNS target receptors.
Melanocortin agonism may also be achieved through inhibiting inverse agonists of
melanocortin receptors (such as inhibition of agouti-related
peptide), and directly through selective
melanocortin receptor ligands such as
piperazine,
piperidine, pyridazinone, tetrahydropyran,
thiadiazole and diazole derivatives. While the development of most (but not all)
neuropeptide Y inhibitors as monotherapy interventions have demonstrated limited efficacy thus far, it is possible that the combination of a
neuropeptide Y inhibitor with a selective
melanocortin receptor ligand may provide improved
weight loss over that of either agent alone. In general,
melanocortin system agonism promotes
weight loss through decreasing appetite, increasing sympathetic nervous system activity, and modulating thyroid-releasing
hormone,
corticotropin-releasing hormone,
brain-derived neurotrophic factor,
melanin-concentrating hormone and
orexin. Of particular interest, given the development of
cannabinoid receptor antagonists as
weight loss agents, is the fact that receptors in the
endocannabinoid system are also affected by the
melanocortin system. It will only be through the conduct of human clinical trials that
melanocortin agonists will be proven to reduce adiposity to a meaningful degree, and, as importantly, be proven to improve adiposopathy, and thus effectively treat excessive fat-related
metabolic diseases.