Linkage and association studies between the melanocortin receptors 4 and 5 genes and obesity-related phenotypes in the Québec Family Study.

Abstract

BACKGROUND:

The agouti yellow mouse shows adult onset of moderate obesity and diabetes. A depressed basal lipolytic rate in adipocytes or a decreased adrenergic tone arising from antagonizing alpha-melanocyte-stimulating hormone (MSH) activation of melanocortin receptors (MCR) could be at the origin of the obesity phenotype.

MATERIAL AND METHODS:

MCR 4 and 5 (MC4R, MC5R) genes were studied in the Québec Family Study. Sequence variations were detected by Southern blot probing of restricted genomic DNA, and mRNA tissue expression was detected by RT-PCR. Subjects with a wide range of weight were used for single-point sib-pair linkage studies (maximum of 289 sibships from 124 nuclear families). Analysis of variance across genotypes in unrelated males (n = 143) and females (n = 156) was also undertaken. Body mass index (BMI), sum of six skin-folds (SF6), fat mass (FM), percent body fat (%FAT), respiratory quotient (RQ), resting metabolic rate (RMR), fasting glucose and insulin, and glucose and insulin area during an oral glucose tolerance test were analyzed.

RESULTS:

MC4R showed polymorphism with NcoI, and MC5R, with PstI and PvuII, with a heterozygosity of 0.38, 0.10, and 0.20, respectively. Linkages were observed between MC5R and BMI (p = 0.001), SF6 (p = 0.005), FM (p = 0.001), and RMR (p = 0.002), whereas associations were observed in females between MC5R and BMI (p = 0.003), and between MC4R and FM (p = 0.002) and %FAT (p = 0.004). After correction for multiple tests, these p values are lowered by one tenth. MC4R and MC5R mRNAs have been detected in brain, adipose tissue, and skeletal muscle.

CONCLUSIONS:

MC4R and MC5R exhibit evidence of linkage or association with obesity phenotypes, but this evidence is strongest for MC5R.

• Authors: Y C Chagnon, W J Chen, L Pérusse, M Chagnon, A Nadeau, W O Wilkison, C Bouchard
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 3 Issue 10 Pg. 663-73 (Oct 1997) ISSN: 1076-1551 [Print] England
• PMID: 9392003 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Insulin
• Receptor, Melanocortin, Type 4
• Receptors, Corticotropin
• Receptors, Melanocortin
• Receptors, Peptide
• melanocortin 5 receptor
• Glucose

Topics

• Adolescent
• Adult
• Aged
• Analysis of Variance
• Energy Metabolism
• Female
• Genetic Linkage
• Glucose (metabolism)
• Homeostasis
• Humans
• Insulin (metabolism)
• Male
• Middle Aged
• Obesity (genetics)
• Polymorphism, Restriction Fragment Length
• Quebec
• Receptor, Melanocortin, Type 4
• Receptors, Corticotropin (genetics)
• Receptors, Melanocortin
• Receptors, Peptide (genetics)
• Tissue Distribution