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Melanocortin-4 receptor (MC4R) plays important roles in regulation of multiple physiological processes, and interaction of MC4R and melanocortin receptor accessory protein 2 (MRAP2) is suggested to play pivotal role in energy balance of vertebrates. Topmouth culter ( Show less

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor that plays major roles in the central control of energy balance. Loss-of-function mutations of MC4R constitute the most common monogenic cause of early-onset extreme obesity in humans, whereas gain-of-function mutations appear to be protective. In particular, two relatively frequent alleles carrying the non-synonymous coding mutations V103I or I251L are associated with lower risks of obesity and type-2 diabetes. Although V103I and I251L MC4Rs showed more efficient signalling in transfected cells, their specific effects in live animals remain unexplored. Here, we investigated whether the introduction of V103I and I251L mutations into the mouse MC4R leads to a lean phenotype and provides protection against an obesogenic diet. Using CRISPR/Cas9, we generated two novel strains of mice carrying single-nucleotide mutations into the mouse Mc4r which are identical to those present in V103I and I251L MCR4 human alleles, and studied their phenotypic outcomes in mice fed with normal chow or a high-fat diet. In particular, we measured body weight progression, food intake and adiposity. In addition, we analysed glucose homeostasis through glucose and insulin tolerance tests. We found that homozygous V103I females displayed shorter longitudinal length and decreased abdominal white fat, whereas homozygous I251L females were also shorter and leaner due to decreased weight in all white fat pads examined. Homozygous Mc4r Our results demonstrate that mice carrying V103I and I251L MC4R mutations displayed gain-of-function phenotypes that were more evident in females. However, hypermorphic MC4R mutants were as susceptible as their control littermates to the obesogenic and diabetogenic effects elicited by a long-term hypercaloric diet, highlighting the importance of healthy feeding habits even under favourable genetic conditions. Show less

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the melanocortin 4 receptor (MC4R), gene which are associated with risk of obesity. Since obesity is an established risk factor of cancer, several studies have examined the association between SNPs near the MC4R gene and cancer risk, but the findings are inconsistent. The present study aimed to perform a meta-analysis to clarify the association between SNPs near MC4R and cancer risk. The PubMed and Embase databases were searched for potentially eligible publications. All studies that evaluated the association between MC4R rs17782313 SNP (or its proxy rs12970134) and cancer risk were included. The pooled odds ratios with 95% confidence intervals (CIs) were calculated using the random-effects model. And subgroup analysis by cancer type (colorectal cancer, endometrial cancer and breast cancer) was conducted for further investigate the association. A total of 6 eligible studies (6517 cases and 16,886 controls) were included in the present meta-analysis. The results indicated that MC4R rs17782313 SNP was moderately associated with cancer risk (odds ratio = 1.12, 95% CI = 1.01-1.24). However, the subgroup analysis between different cancer types shows that rs17782313 is only associated with colorectal cancer but not the endometrial cancer and breast cancer. Risk factor in colorectal cancer was both significantly associated with rs17782313 with and without adjustment for body mass index; while the risk factor of the endometrial cancer and breast cancer were both not associated with the rs17782313 with and without adjustment for body mass index. There was no publication bias for the association between MC4R rs17782313 and cancer risk. The present meta-analysis confirmed the moderate association between MC4R rs17782313 and cancer risk. Show less

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lep Show less

Proopiomelanocortin (POMC) is a neuropeptide precursor produced in the anterior and intermediate pituitary lobes, the hypothalamic arcuate nucleus (ARC), and solitary tract nucleus. Alpha-melanocyte-stimulating hormone (α-MSH) is a cell type specific POMC derivative that is essential for regulating feeding, and energy homeostasis. However, the molecular mechanism underlying POMC/α-MSH secretion remains unclear. Ca Show less

There is a lack of information available on the anorexic action of fusarenon-x (FX), which is a sesquiterpenoid mycotoxin. In this study, we investigated the changes in the hypothalamus and small intestine related to appetite after oral FX exposure. The time-course change of food intake after oral FX exposure (0.5, 1.0, and 2.5 mg/kg bw) in B6C3F1 mice showed that 2.5 mg/kg bw of FX significantly suppressed food intake during 3-6 h compared to the control. Furthermore, the total food intake for 24 h was lower in the group exposed to FX than in the control. The FX exposure (2.5 mg/kg bw for 3 h) significantly increased mRNA levels of anorexic hormones (pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcription (CART)) without changing the mRNA levels of orexigenic hormones. In addition, FX exposure indicated significantly higher mRNA levels of possible downstream targets of anorexic POMC neurons, such as the melanocortin 4 receptor (MC4R), brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB), in the hypothalamus compared to the control. FX exposure also significantly increased the mRNA level of inflammatory cytokines (tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)) and activated nuclear factor-kappa B (NF-κB), which is a regulatory factor for POMC in the hypothalamus. In the intestine, FX exposure did not affect the mRNA level of anorexic peptide YY but significantly elevated that of anorexic cholecystokinin (CCK) and regulatory factors for CCK (calcium-sensing receptor (CaSR), the transient receptor potential ankyrin-1 channel (TRPA1), and transient receptor potential cation channel subfamily M member 5 (TRPM5)). These results suggest that FX sequentially induces inflammatory cytokine expression, NF-κB activation, and POMC expression in the hypothalamus. FX also induces CCK expression in the intestine possibly via induction of CaSR, TRPM5, and TRPA1 expression. These changes will eventually lead to the anorexic action of FX. Show less

Melanocortins are peptides that share a common central pharmacophor. Melanin pigmentation of interfollicular epidermis and hair via MC1R remains the key physiologic function of the naturally occurring melanocortin peptides in skin. Moreover, the melanocortins are crucially involved in the ultraviolet light-induced tanning response. Under pathophysiologic conditions, melanocortin peptides induce cutaneous hyperpigmentation, likewise via the MC1R axis, e.g. in patients with Addison's disease, ectopic precursor pro-opiomelanocortin (POMC) syndrome and in those with abnormally elevated melanocortin blood levels. Translational research on α‑MSH (melanocyte-stimulating hormones) and their antagonists has further revealed a variety of other biological activities beyond pigmentation. They include cytoprotection, antioxidative effects, regulation of collagen metabolism and fibrosis, sebum production, and cutaneous wound healing. These findings have also promoted the development of novel therapies in clinical dermatology including the exploitation of afamelanotide. In 2015, this agent became the first in-class synthetic α‑MSH analogue to be approved in dermatology for the treatment of erythropoetic protoporphyria. In addition to afamelanotide, setmelanotide has recently emerged as a highly selective MC4R agonist useful for the treatment of distinct forms of genetically determined obesity, e.g., POMC deficiency. Future perspectives in dermatology reside in treatment of other difficult-to-treat skin diseases with α‑MSH analogues, either with topical or systemic formulations. Moreover, synthetic melanocortin peptide derivatives lacking the central pharmacophor but with maintained anti-inflammatory effects could become a promising strategy for the design of new therapies in dermatology. Show less

BACKGROUND The mechanism by which sleeve gastrectomy (SG) improves glycometabolism has remained unclear so far. Increasing evidence has demonstrated that bone is a regulator of glucose metabolism, and osteoblast-derived forkhead box O1 (FoxO1) and lipocalin-2 (LCN2) are regulators of energy metabolism. The aim of this study was to investigate whether the FOXO1/LCN2 signaling pathway is involved in the anti-diabetic effect of SG. MATERIAL AND METHODS Insulin resistance was induced in Wistar rats, which were then intraperitoneally injected with streptozotocin to induce a type 2 diabetic state. Levels of fasting blood glucose, serum insulin, HbA1c, and LCN2 were analyzed at corresponding time points after SG and sham surgeries. The expressions of FOXO1, LCN2, and the melanocortin 4 receptor (MC4R) in bone and hypothalamus were detected by immunofluorescence. FOXO1 siRNA was applied to downregulate FOXO1 expression in osteoblasts of rats. The influence of FOXO1 gene on expression of LCN2 was investigated in cultured osteoblasts by western blot and PCR. RESULTS Glucose metabolism in the SG group was significantly improved. The LCN2 expression in bone in the SG group was higher than that in the sham group, whereas FOXO1 expression in the SG group was lower than that in the sham group. The binding rate of LCN2 and MC4R in the hypothalamus was also higher in the SG group compared with that in the sham group. The downregulation of FOXO1 expression in osteoblasts was accompanied by upregulation of LCN2 expression. CONCLUSIONS These results suggest that the FOXO1/LCN2 signaling pathway participates in the anti-diabetic effect of SG. Show less

There is a critical need to find safe therapeutics to treat an increasingly obese population and diseases associated with an imbalance in energy homeostasis. The melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) ligands have long been the focus to help scientists understand energy homeostasis and the regulation of feeding behavior. Herein, we use a nanomolar macrocyclic melanocortin receptor agonist ligand MDE6-5-2c (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro) to examine metabolic and energy hemostasis profiles upon intrathecal (IT) administration directly into the spinal cord as compared to intracerebroventricular (ICV) administration directly into the brain. Overall, central ICV administration of MDE6-5-2c resulted in decreased food intake, in a dose-dependent manner, and decreased respiratory exchange ratio (RER). Comparison of IT versus ICV routes of MDE6-5-2c administration resulted in MDE6-5-2c possessing a longer duration of action on both feeding behavior and RER via IT. The C-peptide, ghrelin, GIP, leptin, IL-6, and resistin plasma hormones and biomarkers were compared using IT versus ICV MDE6-5-2c routes of administration. Plasma resistin levels were decreased upon ICV treatment of MDE6-5-2c, as compared to ICV vehicle control treatment. Intrathecal treatment resulted in significantly decreased inflammatory cytokine interleukin-6 (IL-6) levels compared to ICV administration. Investigation of the nonselective MC3R and MC4R macrocyclic agonist MDE6-5-2c molecule revealed differences in food intake, RER, and plasma biomarker profiles based upon ICV or IT routes of administration and characterize this novel molecular chemotype as a molecular probe to study the melanocortin system Show less

Melanocortins are neuropeptides exerting versatile functions in the nervous system. Melanocortin 4 receptor (MC4R) is primarily expressed in the brain and is thought to be a major mediator for melanocortin. Brain-derived neurotrophic factor (BDNF) may be a crucial downstream molecule of MC4R activation, to yield neurite outgrowth, neuroregenerative, anorexigenic and other actions. In this study, we stimulated Neuro2a murine neuronal cells with an α-melanocyte stimulating hormone (α-MSH) analog, [Nle(4), D-Phe(7)]melanocyte-stimulating hormone (NDP-MSH). In Neuro2a cells, NDP-MSH promoted neurite outgrowth. Upon NDP-MSH administration, BDNF expression was greatly enhanced. Furthermore, this effect was effectively reversed by the MC4R antagonist, JKC-363. We found that NDP-MSH treatment activated the ERK cascade and its downstream kinase MSK1 (mitogen- and stress-activated protein kinase-1). Antagonism of the MSK1 cascade by a specific inhibitor or overexpression of a defective MSK1 mutant interrupted the phosphorylation of the transcription factor cAMP-response element binding protein (CREB), blocking BDNF upregulation. In addition, MSK1 activation triggered an epigenetic alteration in histone H3 (Ser10), facilitating the expression of the BDNF gene. Taken together, our results showed that MSK1 kinase positively activates MC4R-induced BDNF expression via modulating the phosphorylation of CREB and histone H3 in Neuro2a neuronal cells. Show less

Diabetes is mostly assessed by the fasting glucose level. Several studies reported that serum fasting glucose levels and cardiovascular disease are associated with MC4R. A total of 4294 subjects participated in this study. There were 1810 subjects with cardiovascular disease among the 4294 subjects. We used multivariate linear regression models and multiple logistic regression analysis. Individuals with the TC/CC genotype had a 1.29-fold higher risk of diabetes than did those with the TT genotype when adjusting for age, sex, and BMI (OR, 1.29; 95% CI, 1.04-1.60). For healthy subjects, the association was significant in women (OR, 1.99; 95% CI, 1.01-3.93). Men with the TC/CC genotype had a 1.21-fold higher risk of cardiovascular disease than did those with the TT genotype when adjusting for age, sex, and BMI (OR, 1.21; 95% CI, 1.04-1.41). The relationship between MC4R and cardiovascular disease was stronger in lean men (OR, 1.40; 95% CI, 1.12-1.74, p = 0.0028) than in overweight men. This study suggests that the rs17782313 SNP in MC4R is related to diabetes and the SNP is also associated with cardiovascular disease in lean men. Show less

Monogenic non-syndromic obesity is characterized by severe early-onset obesity with abnormal eating behaviour and endocrine disorders. Genes contributing to these rare forms of obesity are mainly located in the leptin/melanocortin pathway, with typically an autosomal additive inheritance of obesity. The normal function of this hypothalamic pathway is essential for the control of energy balance. Genetic variants are involved in 5-30 % of severe early-onset obesity depending on explored populations. Compared to other genes in the pathway especially leptin (LEP), leptin receptor (LEPR), pro-opiomelanocortin (POMC) and prohormone convertase subtilisin/kexin type 1 (PCSK1), Melanocortin 4 receptor (MC4R)-linked obesity is characterized by obesity of variable severity with no notable endocrine phenotypes. Managing patients with monogenic non-syndromic obesity is clinically challenging since they display complex phenotypes and the obesity is often morbid and refractory to classical treatments. Until recent years, there has been a lack of effective and targeted pharmaceutical molecules except for leptin therapy that was available for leptin deficiency. The picture has changed and new promising molecules acting on the leptin-melanocortin pathway such as setmelanotide -a new MC4R agonist- are now emerging as novel targeted therapeutic opportunities. Show less

Recent decades have seen a marked increase in the prevalence of obesity and its associated comorbidities. This increase correlates with greater access to calorie-dense food that is often consumed later in the active phase of the day. Studies in high-fat diet-induced obese (DIO) mice indicate that restricting food access to their active (dark) phase is sufficient to reduce obesity. However, the specific mechanisms mediating these beneficial metabolic effects of dark restricted feeding (DRF) remain unknown. We examined the impact of DRF on the response to peripheral signals regulating the central melanocortin system of DIO mice and on Mc4r The body weight loss following DRF has an acute onset that is sustained over time. This effect is contributed by a reduction on food intake that requires a functional central melanocortin system. Specifically, DRF impacts the circadian expression of melanocortin system genes in the arcuate nucleus of the hypothalamus (ARC). Consistent with this, DRF significantly increases the effectiveness of the fasting-feeding signals ghrelin and leptin that interact with the melanocortin system to regulate energy balance. Importantly, DRF did not reduce or prevent obesity in Mc4r Taken together, our data reveal a critical role of brain melanocortin signaling in mediating the beneficial effects of timed feeding on metabolic control, supporting potential meaningful benefits in combining timed feeding with pharmacological targeting of the melanocortin signaling for the treatment of obesity. Show less

Little is known about the correlation between the melanocortin 4 receptor gene (MC4R) single nucleotide polymorphisms (SNPs) and the risk of obesity. This research sought to test the MC4R rs17782313, rs476828 and rs12970134 SNPs, their haplotypes and gene-environment interactions on the risk of obesity in the Maonan ethnic group, an isolated minority in China. A case-control study comprised of 1836 participants (obesity group, 858; and control group, 978) was conducted. Genotypes of the three SNPs were determined by the next-generation sequencing (NGS) technology. The genotypic frequencies of the three SNPs were different between the obesity and control groups (P <  0.05 for all). The minor allelic frequency of the MC4R rs17782313C, rs476828C and rs12970134A was higher in obesity than in control groups (13.8% vs. 8.3%, P <  0.001, 17.1% vs. 10.9%, P <  0.001; and 15.5% vs. 11.5%, P <  0.001; respectively). Additionally, the dominant model of rs17782313 and rs476828 SNPs revealed an increased morbidity function on the risk of obesity (P <  0.05). A correlation between SNP-environment and the risk of obesity was also observed. The rs17782313C-rs476828C-rs12970134A haplotype was associated with high risk of obesity (OR = 1.796, 95% CI = 1.447-2.229), whereas the rs17782313T-rs476828T-rs12970134G and rs17782313T-rs476828T-rs12970134A haplotypes were associated with low risk of obesity (OR = 0.699, 95% CI = 0.586-0.834 and OR = 0.620, 95% CI = 0.416-0.925; respectively). The interactions between haplotype and waist circumference on the risk of obesity were also noted. We discovered that the MC4R rs17782313, rs476828 and rs12970134 SNPs and their haplotypes were associated with the risk of obesity in the Chinese Maonan population. Show less

The role of sphingosine 1-phosphate (S1P) and its sphingosine-1-phosphate receptors (S1PRs) in non-alcoholic steatohepatitis (NASH) is unclear. We aimed to analyze the role of S1P/S1PRs in a Melanocortin-4 receptor (Mc4r)-deficient NASH murine model using FTY720, the functional antagonist of S1PR1, S1PR3, S1PR4, and S1PR5, and JTE-013, the antagonist of S1PR2. We observed that, compared to that in the control, the mRNA of S1pr1 tended to decrease, whereas those of S1pr2 and S1pr3 significantly increased in Mc4r-knockout (KO) mice subjected to a Western diet (WD). While the fat area did not differ, fibrosis progression differed significantly between control mice and mice in which liver S1PRs were blocked. Lipidomic and metabolomic analysis of liver tissues showed that JTE-013-administered mice showed elevation of S-adenosyl-l-methionine level, which can induce aberrant methylation due to reduction in glycine N-methyltransferase (GNMT) and elevation in diacylglycerol (DG) and triacylglycerol (TG) levels, leading to increased susceptibility to hepatocellular carcinoma (HCC). These phenotypes are similar to those of Gnmt-KO mice, suggesting that blocking the S1P/S1PR2 axis triggers aberrant methylation, which may increase DG and TG, and hepatocarcinogenesis. Our observations that the S1P/S1PR2 axis averts HCC occurrence may assist in HCC prevention in NASH. Show less

The association with obesity of a common variant near the melanocortin-4 receptor (MC4R) gene (rs17782313) has been indicated in various studies. Adherence to dietary quality indices also have shown to have potential favorable effects on obesity-related health outcomes. However, no study has examined the interaction between rs17782313 and the Dietary Approach to Stop Hypertension (DASH) score and the Mediterranean Dietary Score (MDS) on cardio-metabolic risk factors and hypothalamic hormones. Therefore, the purpose of the current study was to examine whether adherence to these dietary quality indices modifies the association of the MC4R rs17782313 polymorphism with cardio-metabolic risk factors and hypothalamic hormones among obese adults. Two hundred eighty-eight healthy obese adults were recruited in this cross-sectional study. Diet quality indices, including DASH score and MDS, were calculated from a validated 147-item food frequency questionnaire (FFQ). MC4R s17782313 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). An ANCOVA multivariate interaction model was used to assess the gene-diet interaction. Significant interactions were detected between DASH score and MC4R rs17782313 genotypes on systolic blood pressure (SBP), atherogenic index of plasma (AIP), and serum glucose and triglyceride (TG) among the female group (p MC4R rs17782313 interacts with healthy dietary pattern (DASH score and MDS) to influence cardio-metabolic risk factors and hypothalamic hormones in obese individuals. Prospective cohort studies are needed to further assess these findings. Show less

When the nerve tissue is injured, endogenous agonist of melanocortin type 4 (MC4) receptor, α-MSH, exerts tonic pronociceptive action in the central nervous system, contributing to sustaining the neuropathic pain state and counteracting the analgesic effects of exogenous opioids. With the intent of enhancing opioid analgesia in neuropathy by blocking the MC4 activation, so-called parent compounds (opioid agonist, MC4 antagonist) were joined together using various linkers to create novel bifunctional hybrid compounds. Analgesic action of four hybrids was tested after intrathecal (i.t.) administration in mouse models of acute and neuropathic pain (chronic constriction injury model, CCI). Under nerve injury conditions, one of the hybrids, UW3, induced analgesia in 1500 times lower i.t. dose than the opioid parent (ED50: 0.0002 nmol for the hybrid, 0.3 nmol for the opioid parent) and in an over 16000 times lower dose than the MC4 parent (ED50: 3.33 nmol) as measured by the von Frey test. Two selected hybrids were tested for analgesic properties in CCI mice after intravenous (i.v.) and intraperitoneal (i.p.) administration. Opioid receptor antagonists and MC4 receptor agonists diminished the analgesic action of these two hybrids studied, though the extent of this effect differed between the hybrids; this suggests that linker is of key importance here. Further results indicate a significant advantage of hybrid compounds over the physical mixture of individual pharmacophores in their analgesic effect. All this evidence justifies the idea of synthesizing a bifunctional opioid agonist-linker-MC4 antagonist compound, as such structure may bring important benefits in neuropathic pain treatment. Show less

Obesity plays a pivotal role in the development of metabolic syndrome-excessive body fat, spikes in blood glucose levels and hypertension-and ultimately leads to cardiovascular diseases and type 2 diabetes (T2D), if left unattended. The present study aimed to investigate the associated risk of T2D with obesity risk alleles of fat mass and obesity-associated (FTO) and melanocortin 4 receptor (MC4R) genes. The study includes 400 subjects (300 T2D diabetic cases and 100 healthy controls). Genetic analysis was done by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. The findings of the study show no significant increase in odds of diabetes associated with the prevalence of FTO and MC4R minor alleles. Rare allele frequencies for "A" of FTO rs9939609 were 0.34 and 0.30 in cases and controls, respectively. Rare allele frequencies for A of MC4R rs12970134 were found to be more common in controls (0.45) than cases (0.41), but the difference was insignificant (p 0.246); however, an increase in body weight with the presence of allele "A" of the FTO gene (p value < 0.001) was found, indicating indirect involvement in the development of T2D. In addition, these were also correlated with the demographic/lifestyle and clinico-pathological parameters between T2D cases and controls. We found that T2D patients with a history of smoking and high consumption of alcohol, fast foods and sweetened beverages are at high risk of T2D compared to healthy controls (p  < 0.01*). The present study concludes that there is no direct association of rs9939609 of the FTO gene with the occurrence of diabetes in the Indian population, but its role in T2D development cannot be overlooked altogether. Furthermore, we conclude that the rs9939609 of FTO carries a potential risk of obesity and because of this FTO rs9939609 T > A is widely considered an obesity-associated allele/single-nucleotide polymorphism (SNP). Show less

In humans and mice, melanocortin receptor 4 (MC4R) and melanocortin receptor accessory protein 2 (MRAP2) can form a complex and control energy balance, thus regulating body weight and obesity. In pigs, a missense variant (p.Asp298Asn) of MC4R has been suggested to be associated with growth and fatness; however, the effect of Asp298Asn substitution on MC4R function is controversial, limiting its application in animal breeding. Here we examined the effect of this polymorphism on MC4R constitutive activity, cell surface expression and signaling, and its interaction with MRAP2 in pigs. We found that: (i) both pig MC4R Show less

The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders). Therefore, this review aims to elucidate the role of bariatric surgery in the treatment of genetic obesity. In monogenic non-syndromic obesity, an underlying genetic defect seems to be the most important factor determining the efficacy of bariatric surgery. In syndromic obesity, bariatric surgery result data are scarce, and even though some promising follow-up results have been reported, caution is required as patients with more severe behavioral and developmental disorders might have poorer outcomes. There is limited evidence in support of bariatric surgery as a treatment option for genetic obesity disorders; hence, no strong statements can be made regarding the efficacy and safety of these procedures for these patients. However, considering that patients with genetic obesity often present with life-threatening obesity-related comorbidities, we believe that bariatric surgery could be considered a last-resort treatment option in selected patients. Show less

The leptin melanocortin signaling pathway is playing a pivotal role for body weight regulation. Genetic defects within this cascade are leading to severe hyperphagia and early onset obesity. In most cases, due to persistent hyperphagia the affected patients are not able to stabilize body weight for a longer period of time with conservative treatment strategies based on lifestyle interventions. Therefore, it is of importance to implement alternative treatment options for these patients. This review provides an overview about the published pharmacological treatment attempts in respect to monogenic forms of obesity and summarizes recent research progress about the role of MC4R signaling and POMC derivatives for body weight regulation. Show less

Cachexia is a debilitating, life-threatening condition whose pathology includes reduced food intake accompanied by hypermetabolism, leading to a catabolic state. The hypothalamic melanocortin system is a critical regulator of metabolic rate with effects being mediated through the melanocortin-4 receptor (MC4R). MC4R activation is also critical to the initiation and maintenance of cachexia. A major problem in the design of anti-cachexia drugs has been the need to cross the blood-brain barrier to access the metabolic rate-controlling centres in the hypothalamus. The overwhelming majority of anti-cachexia drugs are only effective when administered intracerebroventricularly. TCMCB07 is a cyclic nonapeptide peptide MC4R antagonist with parenteral anti-cachexia activity in both small and large animal models. This suggests it can cross the blood-brain barrier. The aim of this study was to examine potential transport mechanisms of TCMCB07 furthering its preclinical development for subsequent studies in humans. In vitro studies were performed in transporter-transfected cells to study whether or not TCMCB07 was an inhibitor as well as substrate for OATP1A2, OATP1B1, OATP1B3, OATP2B1, OCT2, OAT1, OAT3, MATE1, MATE2-K, P-gp (MDR1), and BCRP. In vivo mass balance studies were also performed in mice to evaluate the absorption and disposition of TCMCB07 after oral and intravenous bolus administrations. TCMCB07 inhibited the uptake of prototypical substrates in cells transfected with OATP1A2 (IC OATP1A2 is the transporter responsible for the oral absorption of TCMCB07 in the intestine and for its pharmacologic response in the brain. Show less

Melanocortin 4 receptor (MC4R) deficiency, caused by mutations in MC4R, is the most common cause of monogenic forms of obesity. However, these mutations have often been identified in small-scale, case-focused studies. Here, we assess the penetrance of previously reported MC4R mutations at a population level. Furthermore, we examine why some carriers of pathogenic mutations remain of normal weight, to gain insight into the mechanisms that control body weight. We identified 59 known obesity-increasing mutations in MC4R from the Human Gene Mutation Database (HGMD) and Clinvar. We assessed their penetrance and effect on obesity (body mass index [BMI] ≥ 30 kg/m2) in >450,000 individuals (age 40-69 years) of the UK Biobank, a population-based cohort study. Of these 59 mutations, only 11 had moderate-to-high penetrance and increased the odds of obesity by more than 2-fold. We subsequently focused on these 11 mutations and examined differences between carriers of normal weight and carriers with obesity. Twenty-eight of the 182 carriers of these 11 mutations were of normal weight. Body composition of carriers of normal weight was similar to noncarriers of normal weight, whereas among individuals with obesity, carriers had a somewhat higher BMI than noncarriers (1.44 ± 0.07 standard deviation scores [SDSs] ± standard error [SE] versus 1.29 ± 0.001, P = 0.03), because of greater lean mass (1.44 ± 0.09 versus 1.15 ± 0.002, P = 0.002). Carriers of normal weight more often reported that, already at age 10 years, their body size was below average or average (72%) compared with carriers with obesity (48%) (P = 0.01). To assess the polygenic contribution to body weight in carriers of normal weight and carriers with obesity, we calculated a genome-wide polygenic risk score for BMI (PRSBMI). The PRSBMI of carriers of normal weight (PRSBMI = -0.64 ± 0.18) was significantly lower than of carriers with obesity (0.40 ± 0.11; P = 1.7 × 10-6), and tended to be lower than that of noncarriers of normal weight (-0.29 ± 0.003; P = 0.05). Among carriers, those with a low PRSBMI (bottom quartile) have an approximately 5-kg/m2 lower BMI (approximately 14 kg of body weight for a 1.7-m-tall person) than those with a high PRS (top quartile). Because the UK Biobank population is healthier than the general population in the United Kingdom, penetrance may have been somewhat underestimated. We showed that large-scale data are needed to validate the impact of mutations observed in small-scale and case-focused studies. Furthermore, we observed that despite the key role of MC4R in obesity, the effects of pathogenic MC4R mutations may be countered, at least in part, by a low polygenic risk potentially representing other innate mechanisms implicated in body weight regulation. Show less

Melanocortin-4-receptor (MC4R) gene codes for a G-protein-coupled receptor that is highly expressed in the hypothalamus and involved in the regulation of appetite. Single-nucleotide polymorphisms (SNPs) in the MC4R gene region have been associated with obesity, type 2-diabetes (T2D) and with antipsychotic-induced weight gain. Of these, rs17066842 (G>A) in the MC4R promoter region is the top variant associated with obesity and diabetes. In this study, we investigated the effect of rs17066842 on MC4R expression at various glucose concentrations using reporter gene expression in the SH-SY5Y cell line and regulation of MC4R expression in human cerebral organoids. We observed that higher glucose concentrations significantly reduced MC4R mRNA expression in SH-SY5Y cells. In addition, at high glucose concentrations, the luciferase reporter plasmid containing the MC4R promoter insert with the G-allele of rs170066842 showed significantly reduced activity compared to the A-allele carrying plasmid. The immediate early gene product, early growth-response 1 (EGR-1), was identified to bind to the sequence containing the G-allele at rs17066842 but not to the A-allele-containing sequence. Interestingly, in human induced pluripotent stem cell (hiPSC)-derived cerebral organoids, we observed increased MC4R expression in response to high glucose exposure. These opposite observations might suggest that glucose regulation is complex and may be cell-specific. This study provides evidence that rs17066842 regulates MC4R gene expression through binding of EGR-1 and that this process is influenced by glucose concentration. Show less

Introduction: Obesity is considered a serious public health problem. Efforts have been directed to search for candidate genes such as LEP, LEPR, and MC4R involved in the leptin-melanocortin system. The neuroendocrine regulation of these genes on energy intake and balance influences the pathogenesis of this disease. Contradictory results regarding the association of these genes with obesity raise the need for new research. Objective: To analyze the association between obesity and LEP rs2167270, LEPR rs1137101, and MC4R rs17782313 polymorphisms and the clinical and biochemical variables in obese adults from Barranquilla, Colombia. Materials and methods: We analyzed 111 obese adults and 155 non-obese individuals as controls. The polymorphisms were determined by real-time PCR. Besides, anthropometric measures, blood pressure, and biochemical tests were evaluated. Results: No statistical differences were found in allele and genotype frequencies of gene polymorphisms between groups. The CC genotype of MC4R rs17782313 polymorphism was associated with increased systolic blood pressure and T allele and TT genotype, with decreased HDL cholesterol in obese adults. The effect of the other polymorphisms on these variables was not evidenced. Conclusions: LEP rs2167270, LEPR rs1137101, and MC4R rs17782313 polymorphisms were not associated with obesity in the population under study. MC4R rs17782313 polymorphisms were associated with an increase in systolic blood pressure and a decrease in HDL cholesterol. Show less

Although epidemiological studies have shown that obesity is associated with increased incidence of hypertension during pregnancy, the mechanisms linking these two comorbidities are not as well studied. Previous investigations detected lower levels of the anti-hypertensive and pregnancy-related factor, placental growth factor (PlGF), in obese hypertensive pregnancies. Therefore, we examined whether obese hypertensive pregnant rats have reduced PlGF and whether increasing its levels by administering recombinant human (rh)PlGF reduces their blood pressure. We utilized a genetic model of obesity characterized to be heavier, hypertensive and fertile, namely rats having heterozygous deficiency of the melanocortin-4 receptor (MC4R-def). MC4R-def obese rats had lower circulating levels of PlGF than wild-type lean controls at gestational day 19. Also, assessment of the PlGF receptor, Flt-1, in the vasculature showed that its levels were reduced in aorta and kidney glomeruli but increased in small mesenteric arteries. Chronic intraperitoneal administration of rhPlGF from gestational day 13-19 significantly increased circulating PlGF levels in both obese and lean rats, but reduced blood pressure only in the obese pregnant group. The rhPlGF treatment did not alter maternal body and fat masses or circulating levels of the adipokines, leptin and adiponectin. In addition, this treatment did not impact average foetal weights but increased placental weights regardless of obese or lean pregnancy. PlGF is reduced in MC4R-def obese hypertensive pregnant rats, which is similar to findings in obese hypertensive pregnant women, while increasing its levels with exogenous rhPlGF reduces their blood pressure. Show less

The melanocortin-4 receptor (MC4R) plays a critical role in the regulation of energy homeostasis in both mammals and fish. Several fish MC4Rs recently characterized have high constitutive activities, potentially associated with food intake and growth rate. In the present study, we systematically investigated the effects of four human MC4R (hMC4R) antagonists, including agouti-related peptide (AgRP), Ipsen 5i, ML00253764, and MCL0020, on the cAMP and ERK1/2 signaling of two fish MC4Rs: spotted scat (Scatophagus argus) MC4R (saMC4R) and grass carp (Ctenopharyngodon idella) MC4R (ciMC4R), with hMC4R as a control. We showed that both saMC4R and ciMC4R were constitutively active with significantly increased basal cAMP levels. AgRP acted as an inverse agonist in cAMP signaling pathway in both fish MC4Rs whereas MCL0020 functioned as an inverse agonist for ciMC4R but a weak neutral antagonist for saMC4R. Ipsen 5i and MCL0020 behaved as neutral allosteric modulators in the cAMP signaling of fish MC4Rs. The saMC4R and ciMC4R had similar basal pERK1/2 levels as hMC4R and the pERK1/2 levels of the two fish MC4Rs were significantly increased upon stimulation with all four ligands. In summary, our studies demonstrated the existence of biased signaling in fish MC4R. We also showed dramatic pharmacological differences of human and fish MC4Rs with synthetic ligands. Our data provided novel insights and led to a better understanding of fish MC4R pharmacology. Show less