Melanocortin-4 Receptor in Energy Homeostasis and Obesity Pathogenesis

Hinney, Anke; Volckmar, Anna‐Lena; Knoll, Nadja

doi:10.1016/b978-0-12-386933-3.00005-4

Cited by 144 publications

(101 citation statements)

References 174 publications

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“…The patient was not discarded for MC4R sequencing because other brother and daughter relatives also affected with mental retardation never revealed overweight or obesity phenotypes. Genotypephenotype correlation is in accordance with the literature findings indicating that mutation p.R7H has reduced function (Hinney et al, 2013). The genetic basis of the familial mental deficiency has not been identified to date.…”

Section: Pedigree a Mc4r Pr7h Mutationsupporting

confidence: 90%

“…Currently, the clinical genotype-phenotype relationships in adult MC4R mutation carriers constitute an essential objective to define and corroborate the severity of each functional alteration (Hinney et al, 2003(Hinney et al, , 2006Lubrano-Berthelier et al, 2006;Wang & Tao, 2011). To date, more than 150 different MC4R mutations, mostly leading to a reduced function, have been detected in obese individuals (Hinney et al, 2013). On the other hand, independent genome-wide association studies (GWAS) have shown obesogenic effects of several single nucleotide polymorphisms located downstream of the MC4R gene Scherag et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Novel Variants in theMC4RandLEPRGenes among Severely Obese Children from the Iberian Population

Albuquerque

Estévez

Beato-Víbora

et al. 2014

Annals of Human Genetics

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SummaryWe screened for mutations in the MC4R and LEPR genes and investigated the genotype-phenotype correlation in obese individuals belonging to families with evident hereditary patterns of severe and early-onset obesity among the Iberian population.A total of 202 unrelated and severely obese patients since childhood, were enrolled in the study. Bidirectional sequencing of the MC4R gene was carried out in all patients; the LEPR gene was sequenced in 15 individuals based on additional clinical signals. Segregation analysis and/or genotype-phenotype description was performed for subjects with the new mutations and with presumably functional variants.

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Section: Pedigree a Mc4r Pr7h Mutationsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Novel Variants in theMC4RandLEPRGenes among Severely Obese Children from the Iberian Population

Albuquerque

Estévez

Beato-Víbora

et al. 2014

Annals of Human Genetics

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“…The melanocortin 4 receptor (MC4R) is a key regulator of energy homeostasis, inducing energy expenditure and decreasing food intake. MC4R is a G protein-coupled receptor which is activated by a-MSH and blocked by Agouti-related peptide (Hinney et al 2013). MC4R has been associated with key components of nutrient absorption, lipid metabolism, energy expenditure, thermogenesis, adiposity, insulin secretion, food intake, and appetite (Adan et al 2006).…”

Section: Introductionmentioning

confidence: 99%

“…There are 166 SNPs or mutations of MC4R reported thus far, mainly in obese subjects (Frayling et al 2007;Hinney et al 2013). The functional MC4R mutations (missense, frameshift, nonsense, or deletion) are associated with severe childhood obesity (Hinney et al 2013).…”

Section: Introductionmentioning

confidence: 99%

“…In a systematic review of 61 studies (involving 80,957 obese and 220,223 controls), rs17782313 polymorphism was significantly associated with obesity risk (OR 1.18, 95 % CI 1.15-1.21, p = 0.001) (Xi et al 2012). The effects of MC4R and rs17782313 polymorphisms on eating behavior were recently reviewed by Valette et al (2012) and Hinney et al 2013 These large population-based studies focused on body mass phenotype and indicated a relationship between rs17782313 and obesity. In addition, there are mechanistic insights that suggest the genetic variation rs17782313 may influence 'reward' mechanisms, particularly in females.…”

Section: Introductionmentioning

confidence: 99%

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Association of melanocortin 4 receptor gene variation with satiation and gastric emptying in overweight and obese adults

et al. 2014

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Melanocortin 4 receptor (MC4R) has a major role in energy homeostasis. The rs17782313 polymorphism, mapped 188 kb downstream from MC4R, has been associated with satiety, higher body mass index (BMI) and total calorie intake in adults. To assess the association of rs17782313 with gastric functions, satiation, or satiety, we studied 178 predominantly Caucasian overweight and obese people: 120 females, 58 males; mean BMI 33.4 ± 5.3 kg/m 2 (SD); age 37.7 ± 11.2 years. Quantitative traits assessed were gastric emptying (GE) of solids and liquids; fasting and postprandial gastric volume; satiation by maximum tolerated volume and 4 symptoms by 100-mm visual analog scales (VAS); and satiety by ad libitum buffet meal. Associations of genotype and quantitative traits were assessed by analysis of covariance (using gender and BMI as covariates), based on a dominant [TC (n = 72) -CC (n = 12) vs. TT (n = 94)] genetic model. rs17782313(C) was associated with postprandial satiation symptoms (median D total VAS 26.5 mm, p = 0.036), reduced proportion of solid GE at 2 h (median D 6.7 %, p = 0.008) and 4 h (median D 3.2 %, p = 0.006), and longer t (median D 6 min, p = 0.034). Associations of rs17782313 with obesity may be explained by reduced satiation and GE. The role of MC4R mechanisms in satiation and gastric function deserves further study.

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Design of cyclized selective melanotropins

Cai

Hruby

2016

Biopolymers

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This paper describes the development of cyclic peptides for G protein coupled receptors to enable structure-function knowledge and the design of novel therapeutics. One important property of cyclic peptides is that they tend to be resistant to the digestion, enabling them to survive in the human digestive tract. This trait makes them very important as drug leads or as scaffolds which, in theory, can be engineered to incorporate a peptide domain of medicinal value. This is especially important for delivery of peptides that would be destroyed without such implementation. The melanocortin system is the focus of this article, and includes melanotropin ligands and melanocortin receptors (MCRs). We examine two strategies to constrain the melanotropin peptide backbone. The first is based on global constraint of peptides by cyclization using various kinds of linkers. In the second approach we describe the use of a natural cyclized template, the cyclotide, to graft the melanotropin phamacophore, -His-Phe-Arg-Trp-, to obtain selective drug leads. In these examples the conserved melanocyte stimulating hormone (MSH) pharmacophore is examined and the modified peptides were synthesized by solid phase methodology. Biological studies confirmed the production of selective, potent and in some cases orally available ligands.

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Melanocortin-4 Receptor in Energy Homeostasis and Obesity Pathogenesis

Cited by 144 publications

References 174 publications

Novel Variants in theMC4RandLEPRGenes among Severely Obese Children from the Iberian Population

Novel Variants in theMC4RandLEPRGenes among Severely Obese Children from the Iberian Population

Association of melanocortin 4 receptor gene variation with satiation and gastric emptying in overweight and obese adults

Design of cyclized selective melanotropins

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