The precursor protein, proopiomelanocortin (POMC), produces many biologically active peptides via a series of enzymatic steps in a tissue-specific manner, yielding the melanocyte-stimulating hormones (MSHs), corticotrophin (ACTH) and β-endorphin. The MSHs and ACTH bind to the extracellular G-protein coupled melanocortin receptors (MCRs) of which there are five subtypes. The MC3R and MC4R show widespread expression in the central nervous system (CNS), whilst there is low level expression of MC1R and MC5R. In the CNS, cell bodies for POMC are mainly located in the arcuate nucleus of the hypothalamus and the nucleus tractus solitarius of the brainstem. Both of these areas have well defined functions relating to appetite and food intake. Mouse knockouts (ko) for pomc, mc4r and mc3r all show an obese phenotype, as do humans expressing mutations of POMC and MC4R. Recently, human subjects with specific mutations in β-MSH have been found to be obese too, as have mice with engineered β-endorphin deficiency. The CNS POMC system has other functions, including regulation of sexual behaviour, lactation, the reproductive cycle and possibly central cardiovascular control. However, this review will focus on feeding behaviour and link it in with the neuroanatomy of the POMC neurones in the hypothalamus and brainstem.

/pdf/the-role-of-proopiomelanocortin-pomc-neurones-in-feeding-xqzqnyf1ni.pdf

The role of proopiomelanocortin (POMC) neurones in feeding behaviour

Considerable attention has focused on deciphering the hypothalamic pathways that mediate the behavioral and metabolic effects of leptin. We and others have identified several single gene defects that disrupt the molecules in the leptin-melanocortin pathway causing severe obesity in humans. In this review, we consider these human monogenic obesity syndromes and discuss how far the characterization of these patients has informed our understanding of the physiological role of leptin and the melanocortins in the regulation of human body weight and neuroendocrine function.

/pdf/genetics-of-obesity-in-humans-79ve9tpn6m.pdf

Genetics of Obesity in Humans

The melanocortin-4 receptor (MC4R) was cloned in 1993 by degenerate PCR; however, its function was unknown. Subsequent studies suggest that the MC4R might be involved in regulating energy homeostasis. This hypothesis was confirmed in 1997 by a series of seminal studies in mice. In 1998, human genetic studies demonstrated that mutations in the MC4R gene can cause monogenic obesity. We now know that mutations in the MC4R are the most common monogenic form of obesity, with more than 150 distinct mutations reported thus far. This review will summarize the studies on the MC4R, from its cloning and tissue distribution to its physiological roles in regulating energy homeostasis, cachexia, cardiovascular function, glucose and lipid homeostasis, reproduction and sexual function, drug abuse, pain perception, brain inflammation, and anxiety. I will then review the studies on the pharmacology of the receptor, including ligand binding and receptor activation, signaling pathways, as well as its regulation. Finally, the pathophysiology of the MC4R in obesity pathogenesis will be reviewed. Functional studies of the mutant MC4Rs and the therapeutic implications, including small molecules in correcting binding and signaling defect, and their potential as pharmacological chaperones in rescuing intracellularly retained mutants, will be highlighted.

The Melanocortin-4 Receptor: Physiology, Pharmacology, and Pathophysiology

Over the past twenty years a growing number of genes have been described in which loss of function mutations are consistently associated with the development of severe obesity beginning in early childhood. Whilst individually these disorders are rare, cumulatively at least 10% of children with severe obesity have rare chromosomal abnormalities, nonsense mutations, or missense mutations that strongly drive the carrier’s risk of becoming obese. The diagnosis of a genetic obesity syndrome can provide information that has value for the patient and their family and may help them deal with the social stigma that comes with severe obesity in childhood. In some cases, the finding of a genetic cause for a patient’s obesity can lead to specific therapeutic interventions.

The Genetics of Obesity in Humans

The neurotransmitter serotonin (5-hydroxytryptamine) is a well-established modulator of energy balance. Both pharmacological and genetic evidence implicate the serotonin 2C receptor (5-HT(2C)R) as a critical receptor mediator of serotonin's effects on ingestive behavior. Here we characterized the effect of the novel and selective 5-HT(2C)R agonist BVT.X on energy balance in obese and lean mice and report that BVT.X significantly reduces acute food intake without altering locomotor activity or oxygen consumption. In an effort to elucidate the mechanism of this effect, we examined the chemical phenotype of 5-HT(2C)R-expressing neurons in a critical brain region affecting feeding behavior, the arcuate nucleus of the hypothalamus. We show that 5-HT(2C)Rs are coexpressed with neurons containing proopiomelanocortin, known to potently affect appetite, in the arcuate nucleus of the hypothalamus of the mouse. We then demonstrate that prolonged infusion with BVT.X in obese mice significantly increases Pomc mRNA and reduces body weight, percent body fat, and initial food intake. To evaluate the functional importance of melanocortin circuitry in the effect of BVT.X on ingestive behavior, we assessed mice with disrupted melanocortin pathways. We report that mice lacking the melanocortin 4 receptor are not responsive to BVT.X-induced hypophagia, demonstrating that melanocortins acting on melanocortin 4 receptor are a requisite downstream pathway for 5-HT(2C)R agonists to exert effects on food intake. The data presented here not only indicate that the novel 5-HT(2C)R agonist BVT.X warrants further investigation as a treatment for obesity but also elucidate specific neuronal pathways potently affecting energy balance through which 5-HT(2C)R agonists regulate ingestive behavior.

/pdf/serotonin-5-ht2c-receptor-agonist-promotes-hypophagia-via-2fo7id3y7e.pdf

Serotonin 5-HT2C Receptor Agonist Promotes Hypophagia via Downstream Activation of Melanocortin 4 Receptors

alphaMSH has generally been accepted as the endogenous ligand for melanocortin 4 receptor (MC4R), which plays a major role in energy homeostasis. Targeting MC4R to develop antiobesity agents, many investigators have performed a structure-activity relationship (SAR) studies based on alphaMSH structure. In this report, we performed a SAR study using human betaMSH (5 - 22) (DEGPYRMEHFRWGSPPKD, peptide 1) as a lead sequence to develop potent and selective agonists for MC4R and MC3R. The SAR study was begun with a truncation of N terminus of betaMSH (5 - 22) together with acetylation of the N terminus and amidation of the C terminus of the peptide. Introduction of a cyclic disulfide constrain and replacement of L-Phe with D-Phe afforded a super potent agonist (peptide 5). Furthermore truncation at the C terminus generated a small and potent MC4R and MC3R agonist (Ac-YRcyclo[CEHdFRWC]amide, peptide 6), which exhibited no MC5R and greatly reduced MC1R activity. Molecular modeling of Ac-YRcyclo[CEHdFRWC]amide (peptide 6) revealed that Arg2 in the peptide formed a salt bridge with Glu4. Subcutaneous or intracerebroventricular administration of peptide 6 in rats showed potent in vivo efficacy as evidenced by its effects in reducing energy balance, increasing fat use, and decreasing weight gain in both acute and chronic rat metabolic studies. Furthermore, the antiobesity effect by peptide 6 was manifested only in wild-type but not MC4R-deficient mice, indicating that antiobesity effects of the peptide were attributed largely through MC4R but not MC3R agonist activity of the peptide.

A Novel and Selective β-Melanocyte-Stimulating Hormone-Derived Peptide Agonist for Melanocortin 4 Receptor Potently Decreased Food Intake and Body Weight Gain in Diet-Induced Obese Rats

Detection and control of aspartimide formation in the synthesis of cyclic peptides

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A Novel and Selective β-Melanocyte-Stimulating Hormone-Derived Peptide Agonist for Melanocortin 4 Receptor Potently Decreased Food Intake and Body Weight Gain in Diet-Induced Obese Rats

Detection and control of aspartimide formation in the synthesis of cyclic peptides