📋 Browse Articles

MC4R represents a key player involved in melanocortin-mediated control of energy balance. Recently identified near MC4R variant rs17782313 (T > C) can serve as a contributing factor for obese phenotype but its association with obesity has never been sought in a sample of the Pakistani population. The role of genetic variants as causal factors varies across populations. Association studies in a specific population can help us to distinguish global from local gene-gene and gene-environment interactions. This is the first study that investigated the association of rs17782313 with obesity and various obesity-linked anthropometric, metabolic, physical, and behavioural traits in Pakistani subjects including 306 OW/OB (overweight and obese) and 300 NW (normal weight) individuals. The comparison of various aforementioned obesity-linked continuous and categorical variables between OW/OB and NW subjects revealed that almost all variables were found significantly aberrant ( Show less

The melanocortin-4 receptor (MC4R) belongs to the G protein-coupled receptor (GPCR) family and plays an essential role in the control of energy homeostasis. Here, we identified a novel MC4R-interacting protein, glucose-regulated protein 78 (GRP78), from a pulldown assay using hypothalamic protein extracts and the third intracellular loop of MC4R. We found that MC4R interacted with GRP78 in both the cytosol and at the cell surface and that this interaction increased when MC4R was internalized in the presence of the agonist melanotan-II (MTII). Downregulation of GRP78 using a short interfering RNA approach attenuated MTII-mediated receptor internalization. Reduction in GRP78 expression during tunicamycin-induced endoplasmic reticulum stress also suppressed MTII-mediated internalization of MC4R and cAMP-mediated transcriptional activity. Furthermore, lentiviral-mediated short hairpin RNA knockdown of endogenous GRP78 in the paraventricular nucleus (PVN) of the hypothalamus resulted in an increase in body weight in mice fed a high-fat diet. These results suggest that GRP78 in the PVN binds to MC4R and may have a chaperone-like role in the regulation of MC4R trafficking and signaling. Show less

Elucidating the genetic basis of adaptation to the local environment can improve our understanding of how the diversity of life has evolved. In this study, we used a dense SNP array to identify candidate loci potentially underlying fine-scale local adaptation within a large Atlantic salmon (Salmo salar) population. By combining outlier, gene-environment association and haplotype homozygosity analyses, we identified multiple regions of the genome with strong evidence for diversifying selection. Several of these candidate regions had previously been identified in other studies, demonstrating that the same loci could be adaptively important in Atlantic salmon at subdrainage, regional and continental scales. Notably, we identified signals consistent with local selection around genes associated with variation in sexual maturation, energy homeostasis and immune defence. These included the large-effect age-at-maturity gene vgll3, the known obesity gene mc4r, and major histocompatibility complex II. Most strikingly, we confirmed a genomic region on Ssa09 that was extremely differentiated among subpopulations and that is also a candidate for local selection over the global range of Atlantic salmon. This region colocalized with a haplotype strongly associated with spawning ecotype in sockeye salmon (Oncorhynchus nerka), with circumstantial evidence that the same gene (six6) may be the selective target in both cases. The phenotypic effect of this region in Atlantic salmon remains cryptic, although allelic variation is related to upstream catchment area and covaries with timing of the return spawning migration. Our results further inform management of Atlantic salmon and open multiple avenues for future research. Show less

Screening 92,445 subjects in the Geisinger-Regeneron DiscovEHR cohort, we identified 5 patients heterozygous for nonsense mutations causing early terminations at Glu307 or Leu328 on the C-terminus of melanocortin 4 receptor (MC4R). Two Q307Ter carriers are severely obese (BMI > 40), while one is overweight (BMI > 25). One L328Ter carrier is overweight and the other is lean. Pedigree analysis for two Q307Ter carriers shows segregation of the variant with higher BMI. Functionally, MC4R(Q307Ter) eliminated receptor surface expression and signaling, while MC4R(L328Ter) functioned like the wild-type receptor. MC4R(Q307Ter) is therefore a loss of function (LOF) variant and the region between the two truncation sites identified in our patients is critical to MC4R function. Truncating MC4R at various C-terminal positions between these two variant sites, we find that cysteine318 sits at a critical junction for receptor trafficking and function. We show that MC4R is lipid modified at cysteine318 and cysteine319. Therefore, truncation early in the MC4R C-terminus results in haploinsufficiency in humans while truncation after the first lipid-modification site is well tolerated. MC4R haploinsufficiency clearly segregates with higher BMI; however, severe obesity is not fully penetrant even in MC4R LOF carriers, suggesting critical roles for environmental and lifestyle factors in MC4R monogenic obesity. Show less

In the last decade, over 175 genetic loci have robustly been associated to levels of major circulating blood lipids. Most loci are specific to one or two lipids, whereas some (SUGP1, ZPR1, TRIB1, HERPUD1, and FADS1) are associated to all. While exposing the polygenic architecture of circulating lipids and the underpinnings of dyslipidaemia, these genome-wide association studies (GWAS) have provided further evidence of the critical role that lipids play in coronary heart disease (CHD) risk, as indicated by the 2.7-fold enrichment for macrophage gene expression in atherosclerotic plaques and the association of 25 loci (such as PCSK9, APOB, ABCG5-G8, KCNK5, LPL, HMGCR, NPC1L1, CETP, TRIB1, ABO, PMAIP1-MC4R, and LDLR) with CHD. These GWAS also confirmed known and commonly used therapeutic targets, including HMGCR (statins), PCSK9 (antibodies), and NPC1L1 (ezetimibe). As we head into the post-GWAS era, we offer suggestions for how to move forward beyond genetic risk loci, towards refining the biology behind the associations and identifying causal genes and therapeutic targets. Deep phenotyping through lipidomics and metabolomics will refine and increase the resolution to find causal and druggable targets, and studies aimed at demonstrating gene transcriptional and regulatory effects of lipid associated loci will further aid in identifying these targets. Thus, we argue the need for deeply phenotyped, large genetic association studies to reduce costs and failures and increase the efficiency of the drug discovery pipeline. We conjecture that in the next decade a paradigm shift will tip the balance towards a data-driven approach to therapeutic target development and the application of precision medicine where human genomics takes centre stage. Show less

Maternal smoking is a risk factor for progeny obesity. We have previously shown, in a rat model of neonatal tobacco smoke exposure, a mild increase in food intake and a considerable increase in visceral adiposity in the adult offspring. Males also had secondary hyperthyroidism, while females had only higher T4. Since brown adipose tissue (BAT) hypofunction is related to obesity, here we tested the hypothesis that higher levels of thyroid hormones are not functional in BAT, suggesting a lower metabolic rate. We evaluated autonomic nerve activity in BAT and its function in adult rats that were exposed to tobacco smoke during lactation. At birth, litters were adjusted to 3 male and 3 female pups/litter. From postnatal day (PND) 3 to 21, Wistar lactating rats and their pups were divided into SE group, smoke-exposed in a cigarette smoking machine (4 times/day) and C group, exposed to filtered air. Offspring were sacrificed at PND180. Adult SE rats of both genders had lower interscapular BAT autonomic nervous system activity, with higher BAT mass but no change in morphology. BAT UCP1 and CPT1a protein levels were decreased in the SE groups of both genders. Male SE rats had lower β3-AR, TRα1, and TRβ1 expression while females showed lower PGC1α expression. BAT Dio2 mRNA and hypothalamic POMC and MC4R levels were similar between groups. Hypothalamic pAMPK level was higher in SE males and lower in SE females. Thus, neonatal cigarette smoke exposure induces lower BAT thermogenic capacity, which can be obesogenic at adulthood. Show less

Genetic and environmental factors contribute to the incidence of metabolic syndrome (MetS). This study aimed to review all findings of studies conducted in framework of the Tehran lipid and glucose study (TLGS) regarding the association of dietary factors with cardio-metabolic risk factors. All English-language studies were searched using PubMed and Scopus databases from 2000 to 2017. Finally, 105 relevant papers were included in this review. Whole grains, legumes, nuts and healthy dietary patterns (DPs) reduced risk of MetS, while white rice, salty/sweet snacks increased this. The western DP had a significant interaction with APOC3, APOA1 and MC4R polymorphisms in relation to MetS. After 6.5 years of follow-up, odds of reaching menarche ≤ 12 years was significantly higher in girls with higher intakes of milk, calcium, magnesium, and phosphorous. Among children and adolescents, higher adherence to the dietary approaches to stop hypertension (DASH)-style diet decreased the risk of abdominal obesity, whereas increased adherence to the western DP could contribute to general and abdominal obesity. A three-year follow-up of adult participants showed that higher intakes of phytochemical-rich foods were inversely related to development of insulin resistance. Higher adherence to the healthy DPs was associated with the reduced risk of hyperlipidemia and hypertention. Nutrition interventions postponed rise in the prevalence of MetS. The DASH diet resulted in weight reduction compared to control diet. Higher adherence to healthy food choices was associated with reduced odds of MetS, abdominal obesity, dyslipidemia and hypertension. The western DP accentuated the association of polymorphisms with MetS. Show less

Obesity is a global and severe health problem. Due to genetic heterogeneity, the identification of genetic defects in patients with obesity can be time consuming and costly. Therefore, we developed a custom diagnostic targeted next-generation sequencing (NGS)-based analysis to simultaneously identify mutations in 52 obesity-related genes. The aim of this study was to assess the diagnostic yield of this approach in patients with suspected genetic obesity. DNA of 1230 patients with obesity (median BMI adults 43.6 kg/m In 48 patients pathogenic mutations confirming the clinical diagnosis were detected. The majority of these were observed in the NGS-based gene panel analysis in patients with obesity led to a definitive diagnosis of a genetic obesity disorder in 3.9% of obese probands, and a possible diagnosis in an additional 5.4% of obese probands. The highest yield was achieved in a selected paediatric subgroup, establishing a definitive diagnosis in 12 out of 164 children with severe early onset obesity (7.3%). These findings give a realistic insight in the diagnostic yield of genetic testing for patients with obesity and could help these patients to receive (future) personalised treatment. Show less

Melanocortin-3 receptor (MC3R), melanocortin-4 receptor (MC4R), and a recently identified melanocortin-2 receptor accessory protein 2 (MRAP2), are highly expressed in hypothalamus and coordinately regulate energy homeostasis, but the single cellular transcriptome of melanocortin system remains unknown. Several infrequent MRAP2 variants are reported from severe obese human patients but the mechanisms on how they affect melanocortin signaling are unclear. First, we performed in silico analysis of mouse hypothalamus RNA sequencing datasets at single-cell resolution from two independent studies. Next, we inspected the three-dimensional conformational alteration of three mutations on MRAP2 protein. Finally, the influence of MRAP2 variants on MC3R and MC4R signaling was analyzed in vitro. (1) We confirmed the actual co-expression of Mrap2 with Mc3r and Mc4r, and demonstrated more broad distribution of Mrap2-positive neuronal populations than Mc3r or Mc4r in mouse hypothalamus. (2) Compared with wild-type MRAP2, MRAP2 This is the first dedicated description of single-cell transcriptome signature of Mrap2, Mc3r, and Mc4r in the central nerve system and the first evidence describing the unique dimer formation, conformational change, and pharmacological effect of MRAP2 mutations on MC3R signaling. Show less

The obesity epidemic is well recognized as a significant global health issue. A better understanding of the energy homeostasis mechanisms could help to identify promising anti-obesity therapeutic strategies. It is well established that the hypothalamus plays a pivotal role governing energy balance. The hypothalamus consists of tightly interconnected and specialized neurons that permit the sensing and integration of several peripheral inputs, including metabolic and hormonal signals for an appropriate physiological response. Current evidence shows that thyroid hormones (THs) constitute one of the key endocrine factors governing the regulation and the integration of metabolic homeostasis at the hypothalamic level. THs modulate numerous genes involved in the central control of metabolism, as Show less

The United Arab Emirates (UAE) is one of the countries most threatened with obesity. Here we investigated associations between hundreds of single-nucleotide polymorphisms (SNPs) and the following obesity indicators: body mass index (BMI), waist circumference (WC), and height. We also investigated the associations between obesity-related genes with type 2 diabetes mellitus (T2DM). We tested 87, 58, and 586 SNPs in a previous genome-wide significance level for associations with BMI (n = 880), WC (n = 455), and height (n = 897), respectively. For each trait, we used normally transformed Z scores and tested them with SNPs using linear regression models that incorporated age and gender as covariates. The weighted polygenic risk scores for significant SNPs for each trait were tested with the corresponding Z scores using linear regression models with the same covariates. We further tested 145 obesity loci with T2DM (464 cases, 415 controls) using a logistic regression model including age, gender, and BMI Z scores as covariates. The Mean BMI was 29.39 kg/m In this first study of Arab descendants, we confirmed several known obesity (FTO, USP37, and RFX7), height (NSD1, MFAP2), and T2DM (TCF7L2, MC4R) associations; and report novel associations, like KCNK3 and RARB for T2DM. Show less

The central melanocortin system is a well-established neuronal pathway involved in regulating energy metabolism. Pro-opiomelanocortin (POMC) neurons, agouti gene-related protein (AgRP) neurons, and their downstream cells expressing the melanocortin-3 (MC3R) and melanocortin-4 receptors (MC4R) are three key components of the central melanocortin pathway. This chapter focuses on the Pomc gene and the POMC neural system. First, I summarize the established role of this system in inhibiting food intake. Second, in light of new cutting-edge techniques, our understanding of how POMC neurons function to regulate energy homeostasis has been refined during the last few years. I describe some recent advances and discuss bidirectional effects of POMC neurons on feeding. Finally, the physiological significance beyond energy metabolism, in particular for reward and sex, is also discussed. Show less

It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and κ opioid receptor-induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli. Show less

Cardiovascular disease (CVD) is the leading cause of death in the United States and globally. There is significant evidence implicating genetic and dietary factors in the development and progression of CVD and its risk factors. Nutritional genomics is a comparatively new field of science that focuses on the relationship of individual genetic variation with response to nutrition. The purpose of this review is to summarize recent progress, in the field of nutritional genomics as it relates to cardiovascular disease. Evidence from recent studies has shown significant effects of gene-diet interactions on CVD biomarkers and the development and progression of CVD. The cardiovascular effects of gene-nutrient interactions with respect to macronutrients and genes such as The identification of individual genetic variation influencing diet-related CVD risk is important and may inform future nutritional intervention studies. Although there is ample scientific evidence indicating that the genetic susceptibility to CVD can be modified by diet, we are still not at a stage where this information is easily translated into dietary plans. Thus, there is a need for better approaches to achieve precision in dietary data collection and streamline computational approaches for meaningful and effective nutritional interventions. Show less

Antagonist ligands of the melanocortin-3 and -4 receptors (MC3R, MC4R), including agouti-related protein (AGRP), are postulated to be targets for the treatment of diseases of negative energy balance. Previous studies reported the macrocyclic MC3R/MC4R antagonist c[Pro Show less

Hypothalamic In the current experimental study, 24 female rats were randomly and equally allocated into nulliparous and primiparous groups and then were divided into two subgroups of PCOS and control. PCOS was induced by exposure to continuous light. Sex-related hormones were evaluated by radioimmunoassay or immunoradiometric assay. Expressions of Number of tertiary follicles and their size and number of atretic follicles in the PCOS subgroups were more than those in the controls (P<0.05) whereas the number of secondary follicles and corpus luteum in the PCOS subgroups were lower than those in the controls (P<0.05). Antrum and total diameters of tertiary follicles in the PCOS subgroups were greater and granulosa layer diameter was lower than those in the controls (P<0.05). The Overexpression of Show less

Like most homeostatic systems, adiposity in mammals is defended between upper and lower boundary conditions. While leptin and melanocortin-4 receptor (MC4R) signaling are required for defending energy set point, mechanisms controlling upper and lower homeostatic boundaries are less well understood. In contrast to the MC4R, deletion of the MC3R does not produce measurable hyperphagia or hypometabolism under normal conditions. However, we demonstrate that MC3R is required bidirectionally for controlling responses to external homeostatic challenges, such as caloric restriction or calorie-rich diet. MC3R is also required for regulated excursion from set point, or rheostasis, during pregnancy. Further, we demonstrate a molecular mechanism: MC3R provides regulatory inputs to melanocortin signaling, acting presynaptically on agouti-related protein neurons to regulate γ-aminobutyric acid release onto anorexigenic MC4R neurons, exerting boundary control on the activity of MC4R neurons. Thus, the MC3R is a critical regulator of boundary controls on melanocortin signaling, providing rheostatic control on energy storage. Show less

The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap). Macrocyclic peptides were synthesized with one, two, or three residues of the Arg-Phe-Phe sequence substituted with the corresponding d-isomer(s), generating a 14 compound library. While l-to-d inversions of the Arg-Phe-Phe sequence in a 20-residue AGRP-derived ligand previously resulted in agonist activity at the MC1R, MC3R, MC4R, and MC5R, only the MC1R was consistently stimulated by the macrocyclic ligands in the present study, with varying ligand potencies and efficacies observed at the MC1R. A general trend of increased MC4R antagonist potency was observed for Dap-containing compounds, while MC5R inverse agonist activity was observed for select ligands. It was observed that stereochemical modification of the Arg-Phe-Phe active tripeptide sequence was insufficient to convert melanocortin antagonist into agonists. Overall, these observations are important in the design of melanocortin ligands possessing potent and selective agonist and antagonist activities. Show less

A better understanding of the role of appetite regulation in obesity and metabolic disorders requires consideration of both genetic and developmental influences on appetite. Previously we detected genetic differences in responses to nutritional programming (e.g., the permanent influence that nutrition in early life has on the physiological and metabolic states in adults) on a presumed measure of appetite (feeding rate) in the swordtail fish Xiphophorus multilineatus. In this study we validate that feeding rate is a good measure of appetite, by first demonstrating that it is repeatable and correlated with food consumed when controlling for body size. Second, we detected a significant positive correlation between juvenile growth rates and feeding rates measured in adult males, when growth has ceased. In addition, feeding rates explained significant variation in the size of the nuchal hump, a fat deposit that develops after sexual maturity. Finally, we show that the feeding rates of "courter" males were significantly greater than "sneaker" males, alternative reproductive tactics that are influenced by variation in the Mc4r gene on the Y-chromosome. Our results suggest that examining feeding rate in X. multilineatus could provide valuable insights into how nutritional programming influences appetite independently from food intake, as well as insights into the mechanisms that produce the correlation between delayed maturation and faster growth rates of the courter males as compared with the sneaker males that mature early and grow slower in this species. Show less

Variation in genes of the leptinergic-melanocortinergic system influence both body weight and height. Because short normal stature (SNS) is characterized by reduced body height, delayed maturation and leanness, allelic variation of genes in this pathway are hypothesized to affect this common condition. We analyzed the coding regions of LEP, MC4R, MRAP2 and BDNF in 185 children with SNS (height < 5th percentile) to search for non-synonymous and frameshift variants. For association studies (two-sided χ We detected eleven variants predicted to be protein-altering, four in MC4R, four in BDNF, and three in MRAP2. No variants were found in LEP. In vitro analysis implied reduced function for the MC4R variant p.Met215Ile. Loss-of-function is contrary to expectations based on obesity studies, and thus does not support that this variant is relevant for SNS. The minor SNP alleles at MC4R p.Val103Ile and BDNF p.Val66Met were nominally associated with SNS. Taken together, although genes of the leptinergic-melanocortinergic system are important for normal growth, our data do not support the involvement of rare mutations in LEP, MC4R, MRAP2 or BDNF in short normal stature. Show less

Genetic variants associated with dietary intake may be important as factors underlying the development of obesity. We investigated the associations between the obesity candidate genes (fat mass and obesity-associated (FTO), melanocortin-4 receptor (MC4R), leptin (LEP) and leptin receptor) and total energy intake and percentage of energy from macronutrients and ultra-processed foods before and during pregnancy. A sample of 149 pregnant women was followed up in a prospective cohort in Rio de Janeiro, Brazil. A FFQ was administered at 5-13 and 30-36 weeks of gestation. Genotyping was performed using real-time PCR. Associations between polymorphisms and the outcomes were investigated through multiple linear regression and ANCOVA having pre-pregnancy dietary intake as a covariate. The A-allele of FTO-rs9939609 was associated with a -6·5 % (95 % CI -12·3, -0·4) decrease in the percentage of energy from protein and positively associated with the percentage of energy from carbohydrates before pregnancy (β=2·6; 95 % CI 0·5, 4·8) and with a 13·3 % (95 % CI 0·7, 27·5) increase in the total energy intake during pregnancy. The C-allele of MC4R-rs17782313 was associated with a -7·6 % (95 % CI -13·8, -1·0) decrease in the percentage of energy from protein, and positively associated with the percentage of energy from ultra-processed foods (β=5·4; 95 % CI 1·1, 9·8) during pregnancy. ANCOVA results revealed changes in dietary intake from pre-pregnancy to pregnancy for FTO-rs9939609 (percentage of energy from ultra-processed foods, P=0·03), MC4R-rs17782313 (total energy intake, P=0·02) and LEP-rs7799039 (total energy intake, P=0·04; percentage of energy from protein, P=0·04). These findings suggest significant associations between FTO-rs9939609, MC4R-rs17782313 and LEP-rs7799039 genes and the components of dietary intake in pregnant women. Show less

Melanocortin 4 receptor (Mc4r) plays a crucial role in the central control of energy homeostasis, but its role in peripheral organs has not been fully explored. We have investigated the roles of hypothalamus-mediated energy metabolism during Xenopus limb regeneration. We report that hypothalamus injury inhibits Xenopus tadpole limb regeneration. By loss-of-function and gain-of-function studies, we show that Mc4r signaling is required for limb regeneration in regeneration-competent tadpoles and stimulates limb regeneration in later-stage regeneration-defective tadpoles. It regulates limb regeneration through modulating energy homeostasis and ROS production. Even more interestingly, our results demonstrate that Mc4r signaling is regulated by innervation and α-MSH substitutes for the effect of nerves in limb regeneration. Mc4r signaling is also required for mouse digit regeneration. Thus, our findings link vertebrate limb regeneration with Mc4r-mediated energy homeostasis and provide a new avenue for understanding Mc4r signaling in the peripheral organs. Show less

The melanocortin-4 receptor (MC4R) is a potential drug target for treatment of obesity, anxiety, depression, and sexual dysfunction. Crystal structures for MC4R are not yet available, which has hindered successful structure-based drug design. Using microsecond-scale molecular-dynamics simulations, we have investigated selective binding of the non-peptide antagonist MCL0129 to a homology model of human MC4R (hMC4R). This approach revealed that, at the end of a multi-step binding process, MCL0129 spontaneously adopts a binding mode in which it blocks the agonistic-binding site. This binding mode was confirmed in subsequent metadynamics simulations, which gave an affinity for human hMC4R that matches the experimentally determined value. Extending our simulations of MCL0129 binding to hMC1R and hMC3R, we find that receptor subtype selectivity for hMC4R depends on few amino acids located in various structural elements of the receptor. These insights may support rational drug design targeting the melanocortin systems. Show less

Obesity is increasingly becoming a major public health problem worldwide. Peripheral LKB1 inhibits white fat generation, but the effect of central LKB1 on diet-induced obesity (DIO) is unknown. Therefore, we examined whether LKB1 over-expression in the hypothalamus can inhibit the development of obesity. Adult male Sprague-Dawley rats were anesthetized and placed in a stereotaxic apparatus. LKB1-AAV-EGFP (2.0 × 108 or 2.0 × 1010 vector genomes) or Control-AAV-EGFP (2.0 × 108 vector genomes) was injected into the third ventricle. After administration, the rats were fed a high-fat diet (HFD) for 9 weeks to induce obesity. Rats fed a chow fat diet were used as normal controls. LKB1 delivery decreased body weight, energy intake, fat mass, and serum lipid levels. LKB1 also improved HFD-induced hepatic fatty degeneration. Interestingly, LKB1 over-expression in the hypothalamus activated the AMPK-POMC neurons-sympathetic nervous system (SNS) axis, which can release epinephrine to promote white fat browning. Conversely, the elevated expression of MC3R/MC4R inhibited food intake. These two factors worked together to inhibit the development of obesity. LKB1 in the hypothalamus may have therapeutic potential for DIO through the activation of the AMPK-POMC neurons-SNS axis. Show less

This review aims to present current information on genes underlying severe obesity, with the main emphasis on the three genes LEP, LEPR and MC4R. There is a substantial amount of evidence that variants in at least ten different genes are the cause of severe monogenic obesity. The majority of these are involved in the leptin-melanocortin signalling pathway. Due to the frequency of some of the identified variants, it is clear that monogenic variants also make a significant contribution to common obesity. The artificial distinction between rare monogenic obesity and common polygenic obesity is now obsolete with the identification of MC4R variants of strong effect in the general population. Show less

Melanocortin-4 receptor (MC4R) plays critical roles in the regulation of various physiological processes, such as energy homeostasis, reproduction and sexual function, cardiovascular function, and other functions in mammals. Although the functions of the MC4R in fish have not been extensively studied, the importance of MC4R in regulation of piscine energy expenditure and sexual functions is emerging. Swamp eel (Monopterus albus) is an economically and evolutionarily important fish widely distributed in tropics and subtropics. We cloned swamp eel mc4r (mamc4r), consisting of a 981 bp open reading frame encoding a protein of 326 amino acids. The sequence of maMC4R was homologous to those of several teleost MC4Rs. Phylogenetic and chromosomal synteny analyses showed that maMC4R was closely related to piscine MC4Rs. qRT-PCR revealed that mc4r transcripts were highly expressed in brain and gonads of swamp eel. The maMC4R was further demonstrated to be a functional receptor by pharmacological studies. Four agonists, α-melanocyte stimulating hormone (α-MSH), β-MSH, [Nle Show less

The hypothalamic G-protein-coupled-receptor melanocortin-4 receptor (MC4R) is a key player in the central circuit regulating energy expenditure and appetite. Heterozygous loss-of-function MC4R mutations are the most common known genetic cause of monogenic human obesity, with more than 200 mutations described to date, affecting 2-3% of the population in various cohorts tested. Homozygous or compound heterozygous MC4R mutations are much less frequent, and only few families have been described in which heterozygotes and homozygotes of the same mutation are found. We performed exome sequencing in a consanguineous Bedouin family with morbid obesity to identify the genetic cause of the disease. Clinical examination and biochemical assays were done to delineate the phenotype. We report the frequency of MC4R mutations in the large inbred Bedouin Israeli population. Furthermore, we describe consanguineous inbred Bedouin kindred with multiple individuals that are either homozygous or heterozygous carries of the same novel MC4R mutation (c.124G > T, p.E42*). All family members with the homozygous mutation exhibited morbid early-onset obesity, while heterozygote individuals had either a milder overweight phenotype or no discernable phenotype compared to wild type family members. While elder individuals homozygous or heterozygous for the MC4R mutation had abnormally high triglycerides, cholesterol, glucose and HbA1C levels, most did not. MC4R mutation homozygotes exhibited morbid early-onset obesity, while heterozygotes had a significantly milder overweight phenotype. Whereas obesity due to MC4R mutations is evident as of early age - most notably in homozygotes, the metabolic consequences emerge only later in life. Show less