Weight and Glycemic Control Outcomes of Bariatric Surgery and Pharmacotherapy in Patients With Melanocortin-4 Receptor Deficiency

BackgroundMelanocortin-4 receptor (MC4R) mutations are the most common of the rare monogenic forms of obesity. However, the efficacy of bariatric surgery (BS) and pharmacotherapy on weight and glycemic control in individuals with MC4R deficiency (MC4R-d) is not well-established. We investigated and compared the outcomes of BS and pharmacotherapy in patients with and without MC4R-d.MethodsPertinent details were derived from the electronic database among identified patients who had BS with MC4R-d (study group, SG) and wild-type controls (age- and sex-matched control group, CG). Short- and long-term outcomes were reported for the SG. Short-term outcomes were compared between the two groups.ResultsSeventy patients were screened for MC4R-d. The SG [six individuals (four females, two males); 18 (10–27) years old at BS; 50.3 (41.8–61.9) kg/m2 at BS, three patients with homozygous T162I mutations, two patients with heterozygous T162I mutations, and one patient with heterozygous I170V mutation] had a follow-up duration of up to 10 years. Weight loss, which varied depending on mutation type [17.99 (6.10–22.54) %] was stable for 6 months; heterogeneity of results was observed thereafter. BS was found superior to liraglutide on weight and glycemic control outcomes. At a median follow-up of 6 months, no significant difference was observed on weight loss (20.8% vs. 23.0%, p = 0.65) between the SG and the CG [eight individuals (four females, four males); 19.0 (17.8–36.8) years old at BS, 46.2 (42.0–48.3) kg/m2 at BS or phamacotherapeutic intervention]. Glycemic control in patients with MC4R-d and Type 2 diabetes improved post-BS.ConclusionOur data indicate efficacious short-term but varied long-term weight loss and glycemic control outcomes of BS on patients with MC4R-d, suggesting the importance of ongoing monitoring and complementary therapeutic interventions.

Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors.

Melanocortin-4 receptor and leptin as genes for the selection of superior Madrasin cattle

Background and Aim: The genetic improvement of cattle through livestock section is based on quantitative, qualitative, and molecular characteristics. This study examined polymorphisms of the melanocortin-4 receptor (MC4R) and leptin genes as a reference for the selection of superior breeds in Madrasin cattle. Materials and Methods: The leptin and MC4R genes of Madrasin cattle were amplified using polymerase chain reaction (PCR); then, restriction fragment length polymorphism of the leptin gene was performed using the restriction enzyme BsaA1, at site 2793 with ACGT point position. Results: The leptin gene was divided into three bands, namely, AA with one fragment (522 bp), CG with two fragments (441 bp and 81 bp), and AG with three fragments (522 bp, 441 bp, and 81 bp). The MCR-4 gene was divided into three bands, namely, 493 bp, 318 bp, and 175 bp. Conclusion: The MC4R and leptin genes can act as molecular markers for growth traits in Madrasin cattle and can be used to genetically optimize and improve growth. The GG allele of the MC4R gene and the AA allele of the leptin gene can be used in Madrasin cattle.

SNPs detection in 5’-UTR region of the MC4R gene in Garut sheep

The melanocortin-4 receptor (MC4R) gene has been linked to controlling feeding behavior and body weight. The objective of this study was to detect the polymorphism within the 5’-UTR region of the MC4R gene in Garut sheep. A total of 36 blood samples were isolated and amplified using primers (forward: 5’-TTCGTTTGGGGCAAGTCAAG-3’ and reverse: 5’-GGAAACGCTCACCAACATGT-3’). Two SNPs, g.396C/T and g.399C/G, were discovered in the 5‘UTR region based on sequence alignment (position number based on Genbank acc no. NC_040274). For both SNPs, only two genotypes were found in the samples. Both SNPs had identical allele and genotype frequencies. The C allele (86%, n=26) was higher than the T (g.396C/T) and G allele (g.399C/G) (14%, n=10). The homozygous CC genotype has a higher frequency (72%) in both SNP g.396C/T and g.399C/G, followed by CT and CG genotype (28%), respectively. The Hardy-Weinberg equilibrium analysis resulted in the sample population did not deviate (χ2<5.59). Further analysis could be suggested to provide an overview of this polymorphism effect in Garut sheep’s growth traits.

Association study of rs17782313 polymorphism near MC4R gene with obesity/overweight, BMI, and hedonic hunger among women from Northwestern Iran

BACKGROUND: Obesity, as a medical condition, results from interactions between environmental and genetic factors. The rs17782313 polymorphism, located 188kb downstream of the Melanocortin 4 Receptor (MC4R) gene, is one of the essential candidate genetic markers that has shown the highest association with obesity in different populations. OBJECTIVE: This study aimed to investigate the possible associations of rs17782313 polymorphism near the MC4R gene with obesity/overweight, body mass index (BMI), and hedonic hunger among women from the Iranian Azeri ethnic group. METHODS: Five hundred sixty-three women, composed of 396 patients with obesity/overweight and 167 unrelated healthy controls, were genotyped for the rs17782313 polymorphism by applying the polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) method. RESULTS: This population was in Hardy-Weinberg equilibrium (P = 0.878). The study confirmed a significant association of rs17782313 with obesity, where subjects carrying the C/C genotype had higher odds of obesity (OR = 2.681, P = 0.005, 95%CI:1.340–5.365). Also, C allele carriers have statistically significantly higher BMI scores than those carrying the T allele (P = 0.029). However, no significant associations were found among PFS scores and genotypic/allelic groups of rs17782313 polymorphism (P = 0.368). CONCLUSIONS: Our findings suggest that rs17782313 polymorphism is strongly associated with obesity and BMI but not with hedonic hunger among Northwest Iran women. Moreover, the sequencing data analysis in several homozygous and heterozygous carriers of the C allele led to identifying a novel frameshift variant with TCT deletion (rs534212081) in the 166 upstream of rs17782313, which has not been reported so far.