Linkage and Association Studies between the Melanocortin Receptors 4 and 5 Genes and Obesity-Related Phenotypes in the Québec Family Study

Chagnon, Yvon C.; Chen, Wenji; Pérusse, Louis; Chagnon, Monique; Nadeau, André; Wilkison, William O.; Bouchard, Claude

doi:10.1007/bf03401705

Cited by 148 publications

(94 citation statements)

References 28 publications

(22 reference statements)

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“…MC5R has been identified in exocrine gland tissue and are involved in glandular secretion (van der Kraan et al 1998). Besides the expression in 3T3-L1 cells, MC5R has also been identified in human adipose tissue and associated with obesity phenotypes (Chagnon et al 1997). …”

Section: Introductionmentioning

confidence: 99%

“…MC4R is widely located throughout the CNS and high levels have been found especially in hypothalamic regions involved in regulation of feeding behaviour and energy expenditure, such as the paraventricular nucleus of the hypothalamus (Mountjoy et al 1994;Mountjoy & Wild 1998). MC4R mRNA has also been identified in human adipose tissue, where it might contribute to the control of energy balance and body weight (Chagnon et al 1997) although this involvement remains controversial. The function of MC5R is poorly understood despite its extensive distribution in the periphery (Bednarek et al 2007).…”

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confidence: 99%

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Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved

Møller

Raun

Jacobsen

et al. 2011

Molecular and Cellular Endocrinology

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The melanocortin receptors (MCRs) belong to the G-protein coupled receptors (family A). So far, 5 different subtypes have been described (MC1R-MC5R) and of these MC2R and MC5R have been proposed to act directly in adipocytes and regulate lipolysis in rodents. Using ACTH and -melanocyte stimulating hormone (-MSH) generated from proopiomelanocortin (POMC), as well as synthetic MSH-analogues to stimulate lipolysis in murine 3T3-L1 adipocytes it is shown that MC2R and MC5R are lipolytic mediators in differentiated 3T3-L1 adipocytes. Involvement of cAMP, phosphorylated extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (PKB), adenosine 5' monophosphateactivated protein kinase (AMPK) and Jun-amino-terminal kinase (JNK) in MCR mediated lipolysis were studied. Interestingly, results obtained in 3T3-L1 cells suggest that lipolysis stimulated by -MSH, NDP--MSH, MT-II, SHU9119and PG-901 is mediated through MC5R in a cAMP independent manner. Finally, we identify essential differences in MCR mediated lipolysis when using 3T3-L1 cells compared to primary adipocytes. INTRODUCTIONThe melanocortin system acts through multiple pathways relevant for the prevention of obesity and obesity-related complications (Cone 1999;Marks et al. 2002;Spiegelman & Flier 2001). The system is acknowledged to have an important function in regulation of satiety and energy expenditure (Yaswen et al. 1999;Spiegelman & Flier 2001;Cheung et al. 1997;Azzara et al. 2002). MC4R knockout mice exhibit a well-described phenotype defined by increased lean body mass and fat mass, hyperphagia and disturbances in the metabolic response to overnutrition (Mountjoy et al. 1994;Huszar et al. 1997;Tschop & Heiman 2001). Furthermore, loss of MC4R function is the most frequent monogenetic alteration in severely obese humans (Krude et al. 1998) and in severe, early onset childhood obesity the frequency of mutations in the MC4R locus is 4-6% (Farooqi et al. 2003). Besides the effect on satiety and energy expenditure, the melanocortin system is believed to influence insulin release and insulin sensitivity (Fan et al. 2000;Huo et al. 2009). The melanocortin peptides and their receptors are also suspected to have a direct lipolytic effect on adipose tissues in rodents (Cho et al. 2005;Boston 1999;Spirovski et al. 1975). However this effect is controversial in humans (Hoch et al. 2007). The effect of melanocortins on adipocytes have by some researchers been explained by neuronal regulation of lipolysis (Brito et al. 2007), since MC4R mRNA has been identified in sympathetic neurons connected to white adipose tissue (WAT), indicating that central MC4R might stimulate lipid mobilization in the periphery (Song et al. 2005). However, studies in differentiated murine 3T3-L1 adipocytes suggest a direct lipolytic effect stimulated by melanocortin peptides ACTH and -MSH (Bradley et al. 2005;Cho et al. 2005), Page 3 of 24 A c c e p t e d M a n u s c r i p t 3 which supports the earlier identification of MC2R and MC5R mRNA in this cell line (Boston & Cone 1996). MC1R...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved

Møller

Raun

Jacobsen

et al. 2011

Molecular and Cellular Endocrinology

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“…10 Mcr5 is not known to be involved in feeding but is expressed in several systemic tissues including muscle and adipose. 11,12 Although a mechanism is unknown, genetic linkage of RFLP markers¯anking the MC5R gene to obesity in French Canadians suggests a possible role for this receptor gene in obesity. 11 …”

Section: Introductionmentioning

confidence: 99%

“…11,12 Although a mechanism is unknown, genetic linkage of RFLP markers¯anking the MC5R gene to obesity in French Canadians suggests a possible role for this receptor gene in obesity. 11 …”

Section: Introductionmentioning

confidence: 99%

Absence of genetic variation in some obesity candidate genes (GLP1R, ASIP, MC4R, MC5R) among Pima Indians

Permana

Tanizawa

et al. 1999

Int J Obes

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OBJECTIVE: To examine the obesity candidate genes glucagon-like-peptide receptor (GLP1R), agouti signaling protein (ASIP) and the melanocortin receptors 4 and 5 (MC4R and MC5R) for DNA polymorphisms in their coding regions. SUBJECTS: Unrelated, non-diabetic Pima Indians (8 to 12 from each extreme of body fat). MEASUREMENTS: DNA sequencing within the coding regions of each gene. RESULT: Only one variant was detected, a silent substitution in exon 6 of GLP1R. CONCLUSION: The exclusion of any common amino-acid polymorphisms (allele frequency ! 0.20). implies that structural variants of these genes do not contribute to variation in the high level of obesity observed among the Pima Indians.

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“…Overview: Melanocortin receptors (provisional nomenclature, see Foord et al, 2005) Rank order of potency (Chagnon et al, 1997;Farooqi and O'Rahilly, 2008). (2-[1-{tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl}-5-chlorophenyl] 2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl (Browning et al, 2000) Melatonin, 2-iodo-melatonin, S20098, GR196429, LY156735 and TAK375 (Kato et al, 2005) are nonselective agonists for MT1 and MT2 receptors.…”

Section: Melanocortinmentioning

confidence: 99%

Ligand-gated Ion Channels

Encyclopedic Reference of Molecular Pharmacology

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Linkage and Association Studies between the Melanocortin Receptors 4 and 5 Genes and Obesity-Related Phenotypes in the Québec Family Study

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

Cited by 148 publications

References 28 publications

Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved

Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved

Absence of genetic variation in some obesity candidate genes (GLP1R, ASIP, MC4R, MC5R) among Pima Indians

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