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

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

OBJECTIVE: Obesity represents a low-grade inflammatory disease and appears a risk factor for insulin resistance, but little is known on whether this may contribute to the development of autoimmune inflammatory diseases. The aim of this work was to study the early-life diet-induced obesity in Lewis rats which are known to be highly susceptible to autoimmunity. METHODS: Obesity was induced by reduced litter size (4 pups per litter) followed by high-fat diet (SHF rats). Control rats (8 pups per litter) were fed with standard diet (CN rats). Oral glucose tolerance test (3 g glucose per kg b.w.) was performed by intra-gastric tube in conscious rats after 12 h fast. Adipocyte size was assessed by light microscope after collagenase digestion. Hypothalamic arcuate (ARC) and paraventricular nuclei (PVN) were isolated by the punching technique. Target mRNAs were quantified by real-time PCR with the use of TaqMan probes and primers. Serum hormones (leptin, ghrelin, adiponectin, visfatin and insulin) were assayed by specific RIAs . RESULTS: During the experimental period SHF rats had the same body weight gain and caloric intake as CN rats. At the age of 8 weeks SHF rats showed increased epididymal fat mass and adipocyte volume, impaired glucose tolerance, normal basal fasting insulin, visfatin, and ghrelin level, but decreased adiponectin and high leptin level. In the ARC, the SHF rats showed increased expression of mRNA for orexigenic neuropeptide Y (NPY), agouti-related protein (AgRP) and anorexigenic pro-inflammatory cytokine IL-6. In the PVN, the SHF rats showed increased expression of mRNA for anorexigenic melanocortin 4 receptor (MC4R) and IL-6. CONCLUSION: Overexpression of orexigenic NPY and AgRP in the ARC indicates leptin resistance in SHF rats. The increased expression of MC4R in PVN points to the activation of melanocortin anorexigenic system which, along with increased hypothalamic IL-6, might prevent the animals from overfeeding. Higher adiposity in these rats results from the high fat-diet composition and not from increased caloric intake. Furthermore, enhanced leptin production appears the main factor indicating the predisposition to autoimmunity in these overfed rats.

• MeSH
• adiponektin krev   MeSH
• adipozita MeSH
• AgRP protein genetika   metabolismus   MeSH
• analýza rozptylu MeSH
• bílá tuková tkáň cytologie   MeSH
• bílé tukové buňky MeSH
• dietní tuky aplikace a dávkování   MeSH
• energetický příjem MeSH
• exprese genu MeSH
• ghrelin krev   MeSH
• interleukin-6 genetika   metabolismus   MeSH
• inzulin krev   MeSH
• krysa rodu Rattus MeSH
• leptin krev   MeSH
• messenger RNA metabolismus   MeSH
• neuropeptid Y genetika   metabolismus   MeSH
• nikotinamidfosforibosyltransferasa krev   MeSH
• nucleus arcuatus hypothalami metabolismus   MeSH
• nucleus paraventricularis hypothalami metabolismus   MeSH
• obezita genetika   metabolismus   MeSH
• plocha pod křivkou MeSH
• porucha glukózové tolerance MeSH
• potkani inbrední LEW MeSH
• receptor melanokortinový typ 4 genetika   metabolismus   MeSH
• regulace chuti k jídlu fyziologie   MeSH
• stárnutí MeSH
• stravovací zvyklosti MeSH
• tělesná hmotnost MeSH
• velikost buňky MeSH
• velikost vrhu MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adiponektin MeSH
• AgRP protein MeSH
• dietní tuky MeSH
• ghrelin MeSH
• interleukin-6 MeSH
• inzulin MeSH
• leptin MeSH
• messenger RNA MeSH
• neuropeptid Y MeSH
• nikotinamidfosforibosyltransferasa MeSH
• receptor melanokortinový typ 4 MeSH