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• W2016011885 abstract "The CNS melanocortin pathway plays an important role in the control of body weight. Two papers in this issue of Cell Metabolism, Lee et al., 2006Lee Y.S. Challis B.G. Thompson D.A. Yeo G.S.H. Keogh J.M. Madonna M.E. Wraight V. Sims M. Vatin V. Meyre D. et al.Cell Metab. 2006; 3 (this issue): 135-140Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar and Biebermann et al., 2006Biebermann H. Castañeda T.R. van Landeghem F. von Deimling A. Escher F. Brabant G. Hebebrand J. Hinney A. Tschöp M.H. Grüters A. et al.Cell Metab. 2006; 3 (this issue): 141-146Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, suggest that β MSH—a product of POMC processing—plays an unanticipated role in this pathway in humans. The CNS melanocortin pathway plays an important role in the control of body weight. Two papers in this issue of Cell Metabolism, Lee et al., 2006Lee Y.S. Challis B.G. Thompson D.A. Yeo G.S.H. Keogh J.M. Madonna M.E. Wraight V. Sims M. Vatin V. Meyre D. et al.Cell Metab. 2006; 3 (this issue): 135-140Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar and Biebermann et al., 2006Biebermann H. Castañeda T.R. van Landeghem F. von Deimling A. Escher F. Brabant G. Hebebrand J. Hinney A. Tschöp M.H. Grüters A. et al.Cell Metab. 2006; 3 (this issue): 141-146Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, suggest that β MSH—a product of POMC processing—plays an unanticipated role in this pathway in humans. “The proper study of mankind is man” A. Pope, Essay on Man (1733–1734) Considerable evidence supports a strong genetic basis for human predisposition to obesity. This includes twin and adoption studies (Maes et al., 1997Maes H.H. Neale M.C. Eaves L.J. Behav. Genet. 1997; 27: 325-351Crossref PubMed Scopus (1156) Google Scholar), as well as identification of statistically linked genetic intervals or alleles of specific candidate genes. In seeming contradistinction to such data, the prevalence of obesity is increasing rapidly in many parts of the world, at a pace that cannot possibly be accounted for by changes in allele frequencies of relevant genes in these populations (Flegal et al., 2002Flegal K.M. Carroll M.D. Ogden C.L. Johnson C.L. JAMA. 2002; 288: 1723-1727Crossref PubMed Scopus (5355) Google Scholar). The most likely explanation for these outwardly disparate observations is that humans segregating for alleles selected by evolution to enhance energy storage and reproductive efficiency have, by virtue of more recently selected enhancements in higher cortical function, succeeded in creating an environment in which such metabolic efficiency is actually a disadvantage. The search for genetic factors takes a step forward in this issue of Cell Metabolism, with two papers demonstrating that β MSH, a small peptide cleaved from proopiomelanocortin (POMC) in humans, but not in rodents, plays a role in the control of body weight in humans. Rodent studies identified the melanocortin pathway as an important component in the control of body weight. The melanocortin pathway conveys primarily anorexigenic signals in the hypothalamus and brain stem via receptors (MC4R, MC3R) that mediate the effects of ligands generated by the posttranslational processing of POMC by proconvertases (PC1 + PC2) and other peptidases. Modifiers of the action of the POMC-derived ligands at these receptors include attractin, (ATRN), mahogunin (MGRN1), AgRP, and ASP. The critical role of the melanocortin system in the control of energy homeostasis is reflected in the obesity of animals and/or humans with null or hypomorphic alleles of POMC, MC4R, MC3R, or the relevant proconvertase processing enzymes (Cone, 2005Cone R.D. Nat. Neurosci. 2005; 8: 571-578Crossref PubMed Scopus (1171) Google Scholar). The causal relationship of inactivating POMC mutations to obesity was identified first in humans (Krude et al., 1998Krude H. Biebermann H. Luck W. Horn R. Brabant G. Gruters A. Nat. Genet. 1998; 19: 155-157Crossref PubMed Scopus (1384) Google Scholar); mice with knockouts of Pomc were created subsequently to enable mechanistic studies. Based upon the phenotypes of humans and mice with these mutations, and the absence in rodents of an endonuclease site that allows PC2 to cleave the 18 aa β MSH from its POMC precursor, it was generally assumed that the obesity associated with hetero- or homozygosity for inactivating mutations of POMC was due to lack of α MSH, a potent MC3/4R agonist and suppressor of food intake (Figure 1). Two papers in this issue of Cell Metabolism suggest that this inference was wrong, or at least incomplete. Humans heterozygous for a rare Y5C variant in β MSH (Tyr221CyS in POMC) (demonstrated in vitro to display significantly reduced binding and activation of MC4R) are shown here to be at increased risk of obesity. POMC is expressed in the hypothalamus, pituitary, and skin (including hair follicle) where posttranslational processing of the 241 aa protein (in humans) by proconvertases 1, 2 (acting as endopeptidases at adjacent combinations of dibasic amino acids Lys and Arg) (Seidah and Chretien, 1994Seidah N.G. Chretien M. Methods Enzymol. 1994; 244: 175-188Crossref PubMed Scopus (85) Google Scholar) generates ACTH, melanocortins, and β endorphins in organ-specific fashion (Figure 1). The levels of these endopeptidases decrease with fasting and increase with administration of leptin, accounting for some of the changes seen in POMC production in these circumstances. The specific effects of α MSH (a 13 aa cleavage product of ACTH precursor in the hypothalamus and hair follicle) on energy homeostasis and skin/hair pigment (via MC1R) are widely acknowledged. α MSH is a potent anorectic peptide acting through MC4R and, possibly MC3R, in the regions of the brain receiving POMC neuron projections. γ MSH (from the N-terminal fragment of POMC) acts via MC3R to influence blood pressure and natriuresis. The physiological role of β MSH (an 18 aa product of C-terminal β LPH) is less clear. β MSH is anorexigenic when applied ICV to rats, but this endopeptide is not synthesized to any significant extent in rodent hypothalamus due to the fact that the mouse and rat lack a canonical endopeptidase site at amino acids 215/216 of POMC (http://www.pir.uniprot.org/); this is the site before the amino terminus of β MSH in humans. In the brain, POMC is most highly expressed in the arcuate nucleus of the hypothalamus and the solitary tract (NTS) of the brain stem. The arcuate POMC neurons send projections widely throughout the brain including the paraventricular nucleus (PVN), lateral hypothalamus, amygdala, and reticular nucleus. These neurons have the molecular machinery to integrate signals from leptin, NPY, melanocortins, serotonin, CCK, Ghrelin, PPY, and circulating nutrients (e.g., glucose) (Cone, 2005Cone R.D. Nat. Neurosci. 2005; 8: 571-578Crossref PubMed Scopus (1171) Google Scholar). Codominant mutations of MC4R may account for about 5% of early-onset, severe obesity in humans, and KO mice show similar genetics and phenotypes (Farooqi et al., 2003Farooqi I.S. Keogh J.M. Yeo G.S. Lank E.J. Cheetham T. O'Rahilly S. N. Engl. J. Med. 2003; 348: 1085-1095Crossref PubMed Scopus (1271) Google Scholar). It has been generally assumed that the metabolic phenotypes in both humans and rodents are due primarily to reduced α MSH signaling. In humans and mice, homozygosity for effectively null alleles of POMC results in severe obesity, adrenal insufficiency, and lightened skin/hair pigmentation, while heterozygosity appears to moderately increase obesity proneness in both mice and humans without causing adrenal insufficiency or pigment changes. Notably, interruption of the melanocortinergic system at either POMC or MC4R results not only in obesity due to both increased energy intake and reduced energy expenditure, but also increased linear growth, lean body mass, and bone mineral density (Farooqi et al., 2003Farooqi I.S. Keogh J.M. Yeo G.S. Lank E.J. Cheetham T. O'Rahilly S. N. Engl. J. Med. 2003; 348: 1085-1095Crossref PubMed Scopus (1271) Google Scholar). In Mc4r−/− mice, the primary mechanism for obesity (of relatively late onset compared to affected humans) is increased energy intake. However, female mice show evidence of reduced energy expenditure, and males show reduced locomotor activity (Ste Marie et al., 2000Ste Marie L. Miura G.I. Marsh D.J. Yagaloff K. Palmiter R.D. Proc. Natl. Acad. Sci. USA. 2000; 97: 12339-12344Crossref PubMed Scopus (312) Google Scholar). It is not clear that effects on energy expenditure/physical activity play a significant role in humans with hypomorphic MC4R alleles. The six Tyr221Cys β MSH heterozygotes studied by Lee et al., 2006Lee Y.S. Challis B.G. Thompson D.A. Yeo G.S.H. Keogh J.M. Madonna M.E. Wraight V. Sims M. Vatin V. Meyre D. et al.Cell Metab. 2006; 3 (this issue): 135-140Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar in a clinical research center showed marked increases in energy intake but no decrease in resting metabolic rate. In the two families reported by Biebermann et al., 2006Biebermann H. Castañeda T.R. van Landeghem F. von Deimling A. Escher F. Brabant G. Hebebrand J. Hinney A. Tschöp M.H. Grüters A. et al.Cell Metab. 2006; 3 (this issue): 141-146Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, the proband children have the highest BMI deviations in the family, but the severity of obesity in affected older family members is less. The same reduction in severity of obesity with age has been reported in humans with hypomorphic MC4R alleles. Challis et al., 2002Challis B.G. Pritchard L.E. Creemers J.W. Delplanque J. Keogh J.M. Luan J. Wareham N.J. Yeo G.S. Bhattacharyya S. Froguel P. et al.Hum. Mol. Genet. 2002; 11: 1997-2004Crossref PubMed Scopus (226) Google Scholar described a human subject in whom obesity was associated with a mutation producing a fusion protein of β MSH/β endorphin. It was not clear whether the obesity in this individual reflected a dominant-negative effect of the fusion protein on α MSH activity at MC3/4R and/or an effect of β MSH hypofunction (Challis et al., 2002Challis B.G. Pritchard L.E. Creemers J.W. Delplanque J. Keogh J.M. Luan J. Wareham N.J. Yeo G.S. Bhattacharyya S. Froguel P. et al.Hum. Mol. Genet. 2002; 11: 1997-2004Crossref PubMed Scopus (226) Google Scholar). The two papers in the current issue of Cell Metabolism suggest that β MSH itself plays a role in the control of energy homeostasis in humans. Interestingly, the phenotype of the affected children included accelerated linear growth and increased fat-free mass also seen, as noted above, in POMC- and MC4R-deficient humans and mice. None of the previously reported POMC mutations would be predicted to preserve β MSH synthesis while eliminating α MSH. Hence, one might expect individuals with the nominally β-MSH-only inactivation described in these two papers to display less severe obesity than individuals heterozygous for a POMC allele affecting both α and β MSH quantity and/or function. Clearly, the (presumed) preservation of α MSH synthesis in the reported β MSH hypomorphs does not “rescue” the obese phenotype. A related question is: Why in obligate POMC null heterozygotes, is the degree of obesity not equal to or greater than that of the β MSH-only subjects? The greater effect of the Try221Cys β MSH mutation suggests, contrary to the in vitro evidence against a dominant-negative effect of this mutation, that just such a phenomenon may be occurring in vivo, possibly due to further processing of the aberrant peptides created by the mutation. A mouse with a humanized Pomc gene segregating for this mutation could help to answer some of these questions. Finally, MC3R mediates lordosis responses in rodent females, and MC4R activation stimulates erectile function in male rodents and humans. Strikingly absent from reports on the phenotypes of individuals with MC3R, MC4R, and POMC mutations is mention of possible effects on these aspects of neurophysiology. Clearly, mutation-specific effects on these phenotypes would be of considerable interest. What is the take home message from these papers? That, in the study of the molecular physiology of human energy homeostasis (and most other human phenotypes for that matter), the circumspect analysis of carefully selected human subjects can reveal processes/mechanisms not discoverable (or even present) in an experimental animal. In the instance discussed here, one missing endopeptidase site (in rodents) apparently alters important aspects of the molecular physiology of a critical pathway in the control of energy homeostasis. Alexander Pope – an acerbic investigator of the human condition – got it right. So did these investigators." @default.
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• W2016011885 title "The molecular genetics of the melanocortin pathway and energy homeostasis" @default.
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