Leptin-melanocortin pathway plays an essential role in the body weight regulation. Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. The discovery of monogenic obesities with dysfunction of melanocortin-4 receptor (MC4R) greatly contributed to understanding of energy balance regulation. This review presents phenotypical characterization and prevalence of the MC4R gene mutations. Genome-wide association studies revealed that MC4R gene is significantly related not only to monogenic obesities but also to common obesity. An interaction of variants in the MC4R gene with fat mass and obesity associated (FTO) gene significantly increases the risk for obesity, particularly in adolescence. On the other hand, about 15 % of the MC4R gene variants result in a gain of function that protects against obesity and is associated with favorable metabolic profile. Long-term attempts to activate the MC4R have recently been finalized by a discovery of setmelanotide, a novel specific MC4R agonist that is devoid of untoward cardiovascular side-effects. The employment of specific MC4R agonists may open new horizons not only in the treatment of rare monogenic obesities but also in some common obesities where stimulation of MC4R could be achieved.

• MeSH
• alfa-MSH farmakologie   MeSH
• celogenomová asociační studie MeSH
• cílená molekulární terapie MeSH
• látky proti obezitě farmakologie   MeSH
• lidé MeSH
• mutace * MeSH
• obezita farmakoterapie   genetika   metabolismus   MeSH
• receptor melanokortinový typ 4 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• alfa-MSH MeSH
• látky proti obezitě MeSH
• receptor melanokortinový typ 4 MeSH

Maternal obesity predisposes offspring to metabolic dysfunction and Non-Alcoholic Fatty Liver Disease (NAFLD). Melanocortin-4 receptor (Mc4r)-deficient mouse models exhibit obesity during adulthood. Here, we aim to determine the influence of the Mc4r gene on the liver of mice subjected to perinatal diet-induced obesity. Female mice heterozygous for Mc4r fed an obesogenic or a control diet for 5 weeks were mated with heterozygous males, with the same diet continued throughout pregnancy and lactation, generating four offspring groups: control wild type (C_wt), control knockout (C_KO), obese wild type (Ob_wt), and obese knockout (Ob_KO). At 21 days, offspring were genotyped, weaned onto a control diet, and sacrificed at 6 months old. Offspring phenotypic characteristics, plasma biochemical profile, liver histology, and hepatic gene expression were analyzed. Mc4r_ko offspring showed higher body, liver and adipose tissue weights respect to the wild type animals. Histological examination showed mild hepatic steatosis in offspring group C_KO. The expression of hepatic genes involved in regulating inflammation, fibrosis, and immune cell infiltration were upregulated by the absence of the Mc4r gene. These results demonstrate that maternal obesogenic feeding during the perinatal period programs offspring obesity development with involvement of the Mc4r system.

• Klíčová slova
• Non-Alcoholic Fatty Liver Disease, developmental programming, intra-abdominal fat, maternal nutrition, obesity,
• MeSH
• alanintransaminasa krev   MeSH
• aspartátaminotransferasy krev   MeSH
• fyziologie výživy v mateřství * MeSH
• játra metabolismus   MeSH
• krevní glukóza metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované MeSH
• myši obézní MeSH
• myši MeSH
• obezita genetika   MeSH
• perinatální péče MeSH
• receptor melanokortinový typ 4 nedostatek   genetika   MeSH
• regulace genové exprese MeSH
• těhotenství MeSH
• triglyceridy krev   MeSH
• zpožděný efekt prenatální expozice genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alanintransaminasa MeSH
• aspartátaminotransferasy MeSH
• krevní glukóza MeSH
• MC4R protein, mouse MeSH Prohlížeč
• receptor melanokortinový typ 4 MeSH
• triglyceridy MeSH

BACKGROUND: Inactivating mutations of the hypothalamic transcription factor singleminded1 (SIM1) have been shown as a cause of early-onset severe obesity. However, to date, the contribution of SIM1 mutations to the obesity phenotype has only been studied in a few populations. In this study, we screened the functional regions of SIM1 in severely obese children of Slovak and Moravian descent to determine if genetic variants within SIM1 may influence the development of obesity in these populations. METHODS: The SIM1 promoter region, exons and exon-intron boundaries were sequenced in 126 unrelated obese children and adolescents (2-18 years of age) and 41 adult lean controls of Slovak and Moravian origin. Inclusion criteria for the children and adolescents were a body mass index standard deviation score higher than 2 SD for an appropriate age and sex, and obesity onset at less than 5 years of age. The clinical phenotypes of the SIM1 variant carriers were compared with clinical phenotypes of 4 MC4R variant carriers and with 27 unrelated SIM1 and MC4R mutation negative obese controls that were matched for age and gender. RESULTS: Seven previously described SIM1 variants and one novel heterozygous variant p.D134N were identified. The novel variant was predicted to be pathogenic by 7 in silico software analyses and is located at a highly conserved position of the SIM1 protein. The p.D134N variant was found in an 18 year old female proband (BMI 44.2kg/m2; +7.5 SD), and in 3 obese family members. Regardless of early onset severe obesity, the proband and her brother (age 16 years) did not fulfill the criteria of metabolic syndrome. Moreover, the variant carriers had significantly lower preferences for high sugar (p = 0.02) and low fat, low carbohydrate, high protein (p = 0.02) foods compared to the obese controls. CONCLUSIONS: We have identified a novel SIM1 variant, p.D134N, in 4 obese individuals from a single pedigree which is also associated with lower preference for certain foods.

• MeSH
• detekce genetických nosičů MeSH
• dítě MeSH
• fenotyp MeSH
• lidé MeSH
• mladiství MeSH
• mutace MeSH
• nepřímá kalorimetrie MeSH
• obezita etnologie   genetika   MeSH
• předškolní dítě MeSH
• preference v jídle MeSH
• receptor melanokortinový typ 4 genetika   MeSH
• represorové proteiny genetika   MeSH
• rodokmen MeSH
• studie případů a kontrol MeSH
• stupeň závažnosti nemoci MeSH
• transkripční faktory bHLH genetika   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika etnologie   MeSH
• Slovenská republika etnologie   MeSH
• Názvy látek
• receptor melanokortinový typ 4 MeSH
• represorové proteiny MeSH
• SIM1 protein, human MeSH Prohlížeč
• transkripční faktory bHLH MeSH

AIM: The aim of the study was to monitor the importance of laboratory, anthropometric and genetic determination of the presence of risk factors for atherosclerosis, obesity, dyslipidemia and components of the metabolic syndrome in obese children and the response to dietary and regimen interventions in obese children. METHODS: As a part of the study, 353 paediatric patients (46% boys, 54% girls) with obesity and dyslipidemia, aged 8-16 years, participated in a one-month lifestyle intervention programme. The programme involved a reduction of energy intake and supervised exercise programme consisting of 5 exercise units per day, each 50 minutes long. Standard biochemical methods were applied, including Lp-PLA2, as were anthropometric measurements and genetic analyses. RESULTS: During the reduction programme for the children there was a statistically significant decrease in all anthropometric indicators of bodyweight (p<0.001) as well as in lipid parameters and LpLPA2. Carriers of the FTO GG genotype and/or MC4R CC genotype lost significantly more body weight in comparison to non-carriers. CONCLUSION: Child obesity is an important social issue. After regimen interventions, there is weight loss as well as an improvement in biochemical parameters. There are individuals with a genetic predisposition for obesity, as well as individuals with a better response to regimen interventions which could, among other things, be determined by the FTO and MC4R genotypes.

• Klíčová slova
• child obesity, genetic predisposition, regimen intervention, risk factors,
• MeSH
• antropometrie MeSH
• ateroskleróza genetika   MeSH
• dítě MeSH
• dyslipidemie genetika   MeSH
• energetický příjem MeSH
• gen pro FTO MeSH
• genetická predispozice k nemoci * MeSH
• genotyp MeSH
• lidé MeSH
• metabolický syndrom genetika   MeSH
• mladiství MeSH
• obezita dětí a dospívajících genetika   prevence a kontrola   MeSH
• proteiny genetika   MeSH
• receptor melanokortinový typ 4 genetika   MeSH
• rizikové faktory MeSH
• životní styl MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• FTO protein, human MeSH Prohlížeč
• gen pro FTO MeSH
• MC4R protein, human MeSH Prohlížeč
• proteiny MeSH
• receptor melanokortinový typ 4 MeSH

Specific targets for most obesity candidate genes discovered by genomewide association studies remain unknown. Such genes are often highly expressed in the hypothalamus, indicating their role in energy homeostasis. We aimed to evaluate the associations of selected gene variants with adiposity and dietary traits. Anthropometric parameters, fat mass, dietary intake (total energy, fat, protein, carbohydrate, fiber, and calcium) and 10 gene variants (in/near TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R and FTO) were analyzed in 1953 Czech individuals aged 10.0 to 18.0 years (1035 nonoverweight and 918 overweight: body mass index [BMI] ≥90th percentile). Obesity risk alleles of TMEM18 rs7561317, SEC16B rs10913469, and FTO rs9939609 were related to increased body weight and BMI (P < .005). The FTO variant also showed a significant positive association with waist circumference and fat mass (P < .001). Overweight adolescents had a lower total energy intake (P < .001) but a higher percentage of fat (P = .009) and protein intake (P < .001) than the nonoverweight subjects. There was also a lower calcium intake in the overweight group (P < .001). An association with at least one component of dietary intake was found in 3 of 10 studied gene variants. The MC4R rs17782313 was associated negatively with protein (P = .012) and positively associated with fiber (P = .032) intakes. The obesity risk alleles of BDNF rs925946 and FTO rs9939609 were related to a lower calcium intake (P = .001 and .037). The effects of FTO and MC4R variants, however, disappeared after corrections for multiple testing. Our results suggest that the common BDNF variant may influence dietary calcium intake independent of BMI.

• Klíčová slova
• Adolescence, BDNF, Dietary intake, FTO, Obesity, Single nucleotide polymorphism,
• MeSH
• alely MeSH
• dítě MeSH
• energetický příjem * MeSH
• genotyp MeSH
• index tělesné hmotnosti * MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• mladiství MeSH
• mozkový neurotrofický faktor genetika   MeSH
• nadváha MeSH
• obezita etiologie   genetika   MeSH
• receptor melanokortinový typ 4 genetika   MeSH
• stravovací zvyklosti * MeSH
• tělesná hmotnost MeSH
• vápník dietní aplikace a dávkování   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• BDNF protein, human MeSH Prohlížeč
• MC4R protein, human MeSH Prohlížeč
• mozkový neurotrofický faktor MeSH
• receptor melanokortinový typ 4 MeSH
• vápník dietní MeSH

OBJECTIVES: The mutations in gene for the melanocortin-4 receptor (MC4R) are the most common etiology factors of monogenic obesity development. Recently, it has been shown that current life style has a significant impact on the phenotype of MC4R mutation carriers - increases the penetrance of the mutations. We aimed to study the impact of the current age on the time of obesity onset among MC4R mutation carriers. METHODS: DNA analysis of the MC4R gene was performed in 268 unrelated Slovak and Moravian obese children and adolescents 18 years and 28 blood relatives >18 years of the probands with a mutation. RESULTS: Three different previously described heterozygous loss of function MC4R mutations (p.Ser19Alafs*34, p.Ser127Leu, and p.Gly181Asp) were found in 3 <18 years probands, 3 adult probands, and 6 adult obese/overweight family relatives. The age of obesity onset in mutation carriers was 1 year in all probands in the children group and 1-35 years (median 11 years) in adults. The age of the obesity onset significantly correlated (R=0.809, p=0.028) with the current age in all of the MC4R mutation carriers. CONCLUSIONS: The age of obesity onset in the present child generation of MC4R mutation carriers is decreasing compared to the age of onset in their parents' generation. This is in agreement with similarly increasing penetrance of obesity in MC4R mutation carriers and it points out to escalation of obesogenic potential of environment.

• Klíčová slova
• MC4R mutation carriers, adolescents., children, obesity,
• MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• genetické asociační studie MeSH
• heterozygot MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• obezita dětí a dospívajících diagnóza   epidemiologie   genetika   MeSH
• předškolní dítě MeSH
• receptor melanokortinový typ 4 genetika   MeSH
• rizikové faktory MeSH
• studie případů a kontrol MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Slovenská republika epidemiologie   MeSH
• Názvy látek
• MC4R protein, human MeSH Prohlížeč
• receptor melanokortinový typ 4 MeSH

The most common etiology of non-syndromic monogenic obesity are mutations in gene for the Melanocortin-4 receptor (MC485) with variable prevalence in different countries (1.2-6.3 % of obese children). The aim of our study was 1) to search for MC4R mutations in obese children in Slovakia and compare their prevalence with other European countries, and 2) to describe the phenotype of the mutation carriers. DNA analysis by direct Sanger sequencing of the coding exons and intron/exon boundaries of the MC4R gene was performed in 268 unrelated Slovak children and adolescents with body mass index above the 97(th) percentile for age and sex and obesity onset up to 11 years (mean 4.3+/-2.8 years). Two different previously described heterozygous loss of function MC4R variants (i.e. p.Ser19Alafs*34, p.Ser127Leu) were identified in two obese probands, and one obese (p.Ser19Alafs*34), and one lean (p.Ser127Leu) adult family relatives. No loss of function variants were found in lean controls. The prevalence of loss-of-function MC4R variants in obese Slovak children was 0.7 %, what is one of the lowest frequencies in Europe.

• MeSH
• dítě MeSH
• fenotyp MeSH
• genotyp MeSH
• heterozygot MeSH
• lidé MeSH
• mladiství MeSH
• mutační analýza DNA MeSH
• obezita dětí a dospívajících genetika   MeSH
• předškolní dítě MeSH
• receptor melanokortinový typ 4 genetika   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Geografické názvy
• Slovenská republika MeSH
• Názvy látek
• MC4R protein, human MeSH Prohlížeč
• receptor melanokortinový typ 4 MeSH

Although the mutations in MC4R gene became known as the most common genetic cause of human obesity, the effect of rs12970134 A/G near MC4R gene on insulin resistance has been described. The aim of this study was to determine the effect of rs12970134 on obesity, hormone levels, and glucose metabolism in a cohort of women varying in glucose tolerance: 850 normoglycemic women, 423 diagnosed with polycystic ovary syndrome (PCOS), 402 gestational diabetics (GDM), and 250 type 2 diabetic (T2D) women. We did not confirm the explicit effect of rs12970134 on obesity. However, the influence of the A-allele on body adiposity index was observed in a cohort of women diagnosed with PCOS. In normoglycemic women, the A-allele carriership was associated with lower fasting levels of glucose, insulin, C-peptide, and index of insulin resistance. Furthermore, higher levels of growth hormone, leptin and SHBG, and lower levels of fT3, testosterone, and androstenedione were recorded in normoglycemic A-allele carriers. In conclusion, the study presents the evidence of the impact of rs12970134 on complex hypothalamic regulations.

• MeSH
• dospělí MeSH
• genetická predispozice k nemoci epidemiologie   genetika   MeSH
• genetická variace genetika   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• obezita krev   epidemiologie   genetika   MeSH
• receptor melanokortinový typ 4 genetika   MeSH
• rizikové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• MC4R protein, human MeSH Prohlížeč
• receptor melanokortinový typ 4 MeSH

OBJECTIVES: This study aimed to determine whether there is a relationship between common FTO (rs17817449) and MC4R (rs17782313) gene variants and body mass reduction or weight loss after a one-month lifestyle intervention in overweight/obese children. DESIGN AND METHODS: We genotyped 357 unrelated non-diabetic Czech children (age 13.7 ± 4.9 years, average BMI at baseline 30.8 ± 4.6 kg/m(2)). Biochemical and anthropometrical measurements were performed before and after 4 weeks of lifestyle interventions (comprising a reduction in energy intake to the age-matched optimum and a supervised exercise program consisting of 5 exercise units per day, 50 min each). RESULTS: The mean weight loss achieved was 6.2 ± 2.1 kg (P<0.001). Significant associations were found between a BMI decrease and the FTO and MC4R variants. Carriers of the FTO GG genotype and/or MC4R CC genotype lost significantly more body weight compared to noncarriers (P<0.0009 for BMI and P<0.002 for body weight). These differences remained significant following adjustment for sex, age and baseline values (P=0.004 for BMI and P=0.01 for body weight). CONCLUSIONS: FTO and MC4R gene variants modify the impact of an intensive lifestyle intervention on BMI decrease in overweight/obese children. Carriers of the FTO GG genotype and MC4R CC genotype benefit significantly more from the lifestyle intervention.

• MeSH
• dítě MeSH
• energetický příjem MeSH
• frekvence genu MeSH
• gen pro FTO MeSH
• genetická epistáze MeSH
• genetické asociační studie MeSH
• index tělesné hmotnosti MeSH
• lidé MeSH
• mladiství MeSH
• nadváha genetika   terapie   MeSH
• obezita genetika   terapie   MeSH
• polymorfismus genetický MeSH
• programy na snížení hmotnosti MeSH
• proteiny genetika   MeSH
• receptor melanokortinový typ 4 genetika   MeSH
• redukční dieta MeSH
• sekvenční analýza DNA MeSH
• terapie cvičením MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• FTO protein, human MeSH Prohlížeč
• gen pro FTO MeSH
• MC4R protein, human MeSH Prohlížeč
• proteiny MeSH
• receptor melanokortinový typ 4 MeSH

Mutations in genes involved in energy balance regulation within the central nervous system lead to monogenic forms of obesities. Individuals with these mutations are characterized by early-onset obesity and in some cases by endocrine abnormalities. Carriers of leptin gene mutations are able to normalize their body weight after daily subcutaneous leptin administration. Pharmacotherapy targeting the specific-gene deficiencies has not clinically been tested in other monogenic obesities. Mutations in the melanocortin 4 receptor gene (MC4R) represent the most common monogenic cause of human obesity. Several treatment options have been investigated in subjects with MC4R mutations. Few studies showed that an intensive life-style intervention induces similar weight reduction in MC4R mutation carriers in comparison to MC4R mutation noncarriers. However, long-term body weight maintenance is hardly ever achieved in MC4R mutation carriers. Sibutramine, serotonin and noradrenalin reuptake inhibitor, in MC4R mutation carriers induced weight reduction and improved cardiometabolic health risks. This result was also found in our homozygous MC4R mutation carrier. In vitro studies of melanocortin agonists efficiently activate mutated MC4R with impaired endogenous agonist functional response and thus, further research in the development of drugs for MC4R mutations is needed. An administration of intranasal adrenocorticotropic hormone was not shown to be effective in subjects with pro-opiomelanocortin gene mutations. Bariatric surgery has also been performed in few of MC4R mutation carriers. After gastric banding, lower body weight reduction and worse improvement of metabolic complications was found in MC4R mutation carriers versus noncarriers. However, preliminary results suggest that diversionary operations as gastric bypass represent a suitable method also for MC4R mutation carriers. In conclusion, the management of monogenic obesities still remains a challenge.

• MeSH
• bariatrická chirurgie MeSH
• cyklobutany terapeutické užití   MeSH
• dítě MeSH
• energetický metabolismus genetika   MeSH
• heterozygot MeSH
• hmotnostní úbytek genetika   MeSH
• homozygot MeSH
• index tělesné hmotnosti MeSH
• leptin genetika   metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• obezita genetika   terapie   MeSH
• pro-opiomelanokortin agonisté   genetika   metabolismus   MeSH
• receptor melanokortinový typ 4 genetika   metabolismus   MeSH
• tělesná hmotnost MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cyklobutany MeSH
• leptin MeSH
• MC4R protein, human MeSH Prohlížeč
• pro-opiomelanokortin MeSH
• receptor melanokortinový typ 4 MeSH
• sibutramine MeSH Prohlížeč