Disease relevance of Mc4r

• These data demonstrate that melanocortin signalling transduced by Mc4r is not an exclusive target of leptin action and that factors resulting from obesity contribute to leptin resistance [1].
• Oxygen consumption of Mc4r-null mice with similar body weights as WT controls was reduced by 20% [2].
• In response to moderately increased dietary fat content, melanocortin-4 receptor-null mutant (MC4R-/-) mice exhibit hyperphagia and accelerated weight gain compared to wild-type mice [3].
• Furthermore, experimental uremic cachexia could be ameliorated by blocking leptin signaling through the hypothalamic MC-4R [4].
• This observation suggests that changes in liver secondary to triglyceride accumulation lead to hyperinsulinemia and increased hepatic FAS expression in Mc4r-/- mice [5].

Psychiatry related information on Mc4r

• Locomotor activity of young nonobese Mc4r-null males was significantly lower than that of WT males; however, locomotion of young nonobese females was normal [2].
• Certain dominant alleles of agouti cause an obesity syndrome when ectopic expression of the peptide aberrantly antagonizes the MC4-R, a related melanocyte-stimulating hormone receptor expressed in hypothalamic circuitry and involved in the regulation of feeding behavior and metabolism [6].
• Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction [7].

High impact information on Mc4r

• Of note, increased food intake, typical of Mc4r null mice, was completely rescued while reduced energy expenditure was unaffected [8].
• Restoration of MC4R expression in the paraventricular hypothalamus (PVH) and a subpopulation of amygdala neurons, using Sim1-Cre transgenic mice, prevented 60% of the obesity [8].
• We conclude that Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis [9].
• Our data identify a novel signaling pathway in the mouse for body weight regulation and support a model in which the primary mechanism by which agouti induces obesity is chronic antagonism of the MC4-R [10].
• Targeted disruption of the melanocortin-4 receptor results in obesity in mice [10].

Chemical compound and disease context of Mc4r

• Interestingly, the 10- to 20-fold increase in liver triglyceride in the outbred strain of Mc4r-/- mice is not always associated with fasting hyperinsulinemia or increased FAS mRNA expression [5].
• To assess the physiological effects of MGRN1 on energy and glucose homeostasis, we generated animals doubly mutant for Mgrn1(md) and A(y), Lep(ob), or a null allele of Mc4r, and diet-induced obesity (DIO) mice segregating for Mgrn1(md) [11].
• Here we demonstrate that cachexia induced by lipopolysaccharide administration and by tumor growth is ameliorated by central MC4-R blockade [12].
• In this study, we used the newly discovered selective MC4R antagonist HS014 for increasing food intake in free-feeding rats and evaluated the effects of the NPY Y1 receptor antagonist 1229U91 and the selective serotonin uptake inhibitor fluoxetine on this increased feeding behavior [13].

Biological context of Mc4r

• Core body temperature of Mc4r-null mice was normal, and they responded normally to cold exposure [2].
• The effect of obesity on energy expenditure was attenuated by 50% in Lep(ob)/Lep(ob) Mc4r+/- and Lep(ob)/Lep(ob) Mc4r-/- mice [14].
• Leptin suppression of insulin and corticosterone in Lep(ob)/Lep(ob) mice were not significantly affected by Mc4r genotype [14].
• The role of MC4Rs in regulating energy balance by leptin was investigated using double heterozygote or homozygous leptin (Lep(ob)) and Mc4r gene mutant mice [14].
• Wild-type mice respond to an increase in the fat content of the diet by rapidly increasing diet-induced thermogenesis and by increasing physical activity, neither of which are observed in MC4R-/- mice [3].

Anatomical context of Mc4r

• AGRP or artificial cerebrospinal fluid was administered daily into the lateral ventricle of adult, male MC4-R knockout and wild-type (WT) mice for 3 d [15].
• Furthermore, co-localization analyses in mice showed co-expression of ALP in cells expressing MC4-R in a number of regions known to be important in the regulation of energy homoeostasis by melanocortins, such as the paraventricular nucleus of hypothalamus and the dorsal motor nucleus of the vagus [16].
• Negative feedback control by body fat content on ARC neuropeptide expression is present in young animals but vanishes with age and is modulated by MC4R deficiency [17].
• The absence of MCR4 blocked leptin's ability to increase UCP1 mRNA in both brown and white adipose tissue, but not its ability to reduce food consumption [18].
• The presence of MC4R in rat adipocytes (RT-PCR and restriction digest) supports the involvement of this receptor subtype in this interaction [19].

Associations of Mc4r with chemical compounds

• Furthermore, ICV infusion of the MC4R agonist significantly reduced ethanol drinking, whereas ICV infusion of AgRP-(83-132) significantly increased ethanol drinking in C57BL/6J mice [20].
• The effect of Mgrn1(md) on circulating insulin concentrations was not due primarily to reductions in fat mass, since the plasma insulin concentrations of Mgrn1(md) mice segregating for either A(y) or Mc4r-null alleles, adjusted for fat mass and plasma glucose, were reduced compared with A(y) and Mc4r mice, respectively [11].
• In addition, it appears that the histamine H(1)-R signaling pathway may be independent or downstream of the POMC/MC-4R signaling [21].
• Mutation of Phe117 to alanine causes a similar increase in agouti KI app at melanocortin receptor 4 [22].
• The data presented here show that GT1-1 cells specifically express a functional MC4-R that couples to GnRH release [23].

Regulatory relationships of Mc4r

• Thus MC4R deficiency augments age-induced NPY expression in the DMN and VMN with no feedback from body fat content [17].
• HF (58% fat) diet promoted transient ( approximately 8 wk) hyperphagia and decreased food efficiency in 11 beta-HSD1-/- mice and decreased melanocortin-4 receptor mRNA expression in control but not 11 beta-HSD1-/- mice [24].

Other interactions of Mc4r

• Obese Mc4r-/-mice do not respond significantly to the inhibitory effects of leptin on feeding, whereas non-obese Mc4r-/- mice do [1].
• In contrast, no significant effects of AGRP were observed in any of these parameters in the MC4-R knockout mice [15].
• Neuropeptide Y Y1 receptor mRNA in rodent brain: distribution and colocalization with melanocortin-4 receptor [25].
• Effects of melanocortin receptor activation and blockade on ethanol intake: a possible role for the melanocortin-4 receptor [20].
• We describe here a novel compound that is highly selective as an agonist at the MC4 receptor but has minimal activity at the MC3 receptor [26].

Analytical, diagnostic and therapeutic context of Mc4r

• In vivo, administration of the melanocortin agonist MTII (10 microg per mouse equivalent to 9.3 nmol) 30 min prior to ischemia (25 min) attenuated mouse heart 2 h reperfusion injury by approximately 40%, an effect prevented by the mixed MC3/4-R antagonist SHU9119 but not by the selective MC4-R antagonist HS204 [27].
• Using the technique of fluorescent in situ hybridization, the gene encoding the melanocortin-4 receptor was localized to chromosome 18 (q21.3) [28].
• Twenty- to 22-week-old male wild-type (WT) C57BL/6J and obese MC4R (-/-) mice (N=5 to 6 per group) were implanted with radiotelemetric transmitters and catheters for measuring mean arterial pressure (MAP) and heart rate 24 hours per day and intravenous infusions [29].
• This ligand possesses novel melanocortin receptor pharmacology, as compared to previously reported peptides, and is potentially useful for in vivo studies to differentiate MC3R vs MC4R physiological roles in animal models, such as primates, where "knockout" animals are not viable options [30].
• In light of previous findings that melanocortins antagonize opiate self-administration, analgesic tolerance, and physical dependence, we hypothesize that decreased melanocortin function, via down-regulation of MC4-R expression, may contribute to the development of these opiate-induced behaviors [7].

References