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Epigenetic-sensitive mechanisms, mainly DNA methylation, mirror the relationship between environmental and genetic risk factors able to affect the sensitiveness to development of obesity and its comorbidities. Bariatric and metabolic surgery may reduce obesity-related cardiovascular risk through tissue-specific DNA methylation changes. Among the most robust results, differential promoter methylation of ACACA, CETP, CTGF, S100A8, and S100A9 genes correlated significantly with the levels of mRNA before and after gastric bypass surgery (RYGB) in obese women. Additionally, promoter hypermethylation of NFKB1 gene was significantly associated with reduced blood pressure in obese patients after RYGB suggesting useful non-invasive biomarkers. Of note, sperm-related DNA methylation signatures of genes regulating the central control of appetite, such as MC4R, BDNF, NPY, and CR1, and other genes including FTO, CHST8, and SH2B1 were different in obese patients as compared to non-obese subjects and patients who lost weight after RYGB surgery. Importantly, transgenerational studies provided relevant evidence of the potential effect of bariatric and metabolic surgery on DNA methylation. For example, peripheral blood biospecimens isolated from siblings born from obese mothers before bariatric surgery showed different methylation signatures in the insulin receptor and leptin signaling axis as compared to siblings born from post-obese mothers who underwent surgery. This evidence suggests that bariatric and metabolic surgery of mothers may affect the epigenetic profiles of the offspring with potential implication for primary prevention of severe obesity. We update on tissue-specific epigenetic signatures as potential mechanisms underlying the restoration of metabolic health after surgery suggesting useful predictive biomarkers. Show less

Amylin is a 37-amino acid polypeptide that has been found to be involved in feeding regulation in some mammals, birds, and goldfish. We cloned amylin of Siberian sturgeon and detected its distribution pattern in 15 tissues. The expression levels in the periprandial period (pre-and post-feeding), the changes in the food intake, and the expression levels of related appetite factors after the intraperitoneal injection of amylin were detected. The expression of amylin was found to be the highest in the hypothalamus. Compared with 1 h pre-feeding, the expression levels of amylin in the hypothalamus and duodenum were increased significantly 1 h post-feeding. Compared with the control group (saline), intraperitoneal injection of 50 ng/g, 100 ng/g, and 200 ng/g of amylin significantly inhibited food intake at 1 h post injection, but not at 3 h and 6 h. The injection of 50 ng/g, 100 ng/g, and 200 ng/g amylin significantly inhibited the cumulative feed. After 1 h of 50 ng/g amylin injection, the levels of MC4R and somatostatin in the hypothalamus increased significantly, while the levels of amylin and NPY decreased significantly. The levels of CCK in the valvular intestine were increased significantly. Insulin in the duodenum was also increased significantly, but there was no significant change in ghrelin in the duodenum. These results show that amylin inhibits feeding in Siberian sturgeon by down-regulating the appetite-stimulating factor NPY and up-regulating the appetite-suppressing factors somatostatin, MC4R, CCK, and insulin. This study provides a theoretical basis for studying the feeding function and action mechanisms of amylin in Siberian sturgeon. Show less

This population-based longitudinal study is the first investigation that assesses the association of common MC4R SNPs with the obesity-related parameters over time and determines the effect of risk alleles during the three adulthood life periods (early, middle, and late) in a large Iranian cohort, a population with a unique genetic make-up that has been understudied and relatively unexplored. We obtained the genotype of 5370 unrelated adults who participated in the ongoing Tehran Cardiometabolic Genetic Study (TCGS) cohort project for the common MC4R SNPs. Linear regression and linear mixed model analyses were performed to examine the effect of MC4R polymorphisms on maximum BMI and other obesity-related factors over time. We recognized that several SNPs associated with the maximum BMI and the increased BMI, waist circumference, and waist-hip ratio across Iranian adults over a lifetime. Interestingly, we found that rs9954571-A has a yet unreported protective role against obesity-related factors, including BMI, waist circumference, waist-hip ratio, and triglyceride level. Additionally, a survey of the impact of the MC4R risk score throughout the adulthood life periods indicated that the MC4R risk score is influenced both the elevated BMI and waist circumference only during the early adulthood period. Our findings can expand our knowledge about the MC4R genetic variant's contributions to adulthood obesity and highlight the importance of evaluating the genetic components affecting obesity over a lifetime, which could be considered for obesity clinical screening and treatment. Show less

Nutritional and lifestyle interventions can contribute to prevent and treat obesity and its complications; however, genetic background may influence the success of a therapy. The aim of this pilot study is to evaluate the effects of the interaction between nutrigenetic variants and nutritional intervention, as well as the changes in clinical parameters and the adherence to Mediterranean diet (MedDiet) and to physical activity, of 18 overweight or obese subjects affected by T2D or dysglycemia included in a nutritional program. The subjects' clinical parameters as well as their PREDIMED score and physical activity levels were recorded and compared at baseline, at 6 months and at the end of the intervention. Rs9939609 in FTO, rs17782313 near MC4R, rs326 in LPL, rs16147 in NPY, rs2943641 near IRS-1 were genotyped. The subjects carrying the A allele in FTO lost less weight (p = 0.022) and had a lower BMI decrease from baseline to 12 months (p-interaction = 0.047) than TT carriers. In addition, there was a significant PREDIMED score modification over time, according to genotypes for FTO rs9939609 (p = 0.025) and NPY rs16147 (p = 0.039), respectively. These preliminary findings show a significant interaction between genetic variants and the PREDIMED score, suggesting that individuals carrying the FTO variant may lose less weight than non-carriers through diet/lifestyle intervention. Show less

The increasing number of obese children and adolescence is a major problem in health-care systems. Currently, the gold standard for the treatment of these patients with obesity is a multicomponent lifestyle intervention. Unfortunately, this strategy is not leading to a substantial and long-lasting weight loss in the majority of patients. This is the reason why there is an urgent need to establish new treatment strategies for children and adolescents with obesity to reduce the risk for the development of any comorbidities like cardiovascular diseases or diabetes mellitus type 2. In this review, we outline available pharmacological therapeutic options for children and compare the available study data with the outcome of conservative treatment approaches. We discussed, in detail, how knowledge about underlying molecular mechanisms might support the identification of effective antiobesity drugs in the future and in which way this might modulate current treatment strategies to support children and adolescence with obesity to lose body weight. Show less

Mitochondria are essential organelles required for several cellular processes ranging from ATP production to cell maintenance. To provide energy, mitochondria are transported to specific cellular areas in need. Mitochondria also need to be recycled. These mechanisms rely heavily on trafficking events. While mechanisms are still unclear, hypothalamic mitochondria are linked to obesity. We used C2 domain protein 5 (C2CD5, also called C2 domain-containing phosphoprotein [CDP138]) whole-body KO mice primary neuronal cultures and cell lines to perform electron microscopy, live cellular imaging, and oxygen consumption assay to better characterize mitochondrial alteration linked to C2CD5. This study identified that C2CD5 is necessary for proper mitochondrial trafficking, structure, and function in the hypothalamic neurons. We previously reported that mice lacking C2CD5 were obese and displayed reduced functional G-coupled receptor, melanocortin receptor 4 (MC4R) at the surface of hypothalamic neurons. Our data suggest that in neurons, normal MC4R endocytosis/trafficking necessities functional mitochondria. Our data show that C2CD5 is a new protein necessary for normal mitochondrial function in the hypothalamus. Its loss alters mitochondrial ultrastructure, localization, and activity within the hypothalamic neurons. C2CD5 may represent a new protein linking hypothalamic dysfunction, mitochondria, and obesity. Show less

Dysregulation of metabolic regulatory hormones often occurs during the progress of obesity. Key regulatory hormone insulin-growth hormone (GH) balance has recently been proposed to maintain metabolism profiles. Time-restricted feeding (TRF) is an effective strategy against obesity without detailed research on pulsatile GH releasing patterns. TRF was performed in an over-eating melanocortin 4 receptor-knockout (MC4RKO) obese mouse model using normal food. Body weight and food intake were measured. Series of blood samples were collected for 6-h pulsatile GH profile, glucose tolerance test, and insulin tolerance test at 5, 8, and 9 weeks of TRF, respectively. Indirect calorimetric recordings were performed by the Phenomaster system at 6 weeks for 1 week, and body composition was measured by nuclear magnetic resonance spectroscopy (NMR). Substrate- and energy metabolism-related gene expressions were measured in terminal liver and subcutaneous white adipose tissues. TRF increased pulsatile GH secretion in dark phase and suppressed hyperinsulinemia in MC4RKO obese mice to reach a reduced insulin/GH ratio. This was accompanied by the improvement in insulin sensitivity, metabolic flexibility, glucose tolerance, and decreased glucose fluctuation, together with appropriate modification of gene expression involved in substrate metabolism and adipose tissue browning. NMR measurement showed that TRF decreased fat mass but increased lean mass. Indirect calorimeter recording indicated that TRF decreased the respiratory exchange ratio (RER) reflecting consumption of more fatty acid in energy production in light phase and increased the oxygen consumption during activities in dark phase. TRF effectively decreases hyperinsulinemia and restores pulsatile GH secretion in the overeating obese mice with significant improvement in substrate and energy metabolism and body composition without reducing total caloric intake. Show less

Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction and is estimated to affect approximately 10% of women in the United States. It has been suggested that HSDD is associated with an imbalance of hormone and neurotransmitter levels in the brain, resulting in decreased excitation, increased inhibition, or a combination of both. Evidence suggests neurotransmitters, including dopamine (DA), norepinephrine, and serotonin, as well as hormones such as estradiol and testosterone, contribute to female sexual desire and response. Current treatments for HSDD include psychotherapy, and two US Food and Drug Administration-approved medications for premenopausal women: flibanserin, a serotonin mixed agonist and antagonist, and bremelanotide, a melanocortin receptor (MCR) agonist. Melanocortins are endogenous neuropeptides associated with the excitatory pathway of the female sexual response system. MCRs are found throughout the body, including the brain. Bremelanotide is an MCR agonist that nonselectively activates several of the receptor subtypes, of which subtype 4 (MC4R) is the most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area (mPOA) of the hypothalamus in the brain, and is important for female sexual function. Animal studies suggest that bremelanotide may affect female sexual desire by activating presynaptic MC4Rs on neurons in the mPOA of the hypothalamus, leading to increased release of DA, an excitatory neurotransmitter that increases sexual desire. This review presents what is known about the mechanism of action of bremelanotide in the context of treating HSDD. Show less

The strong hormonal dysregulation associated with obesity is responsible for the disruption of several reproductive events. Sertoli cells (SCs) function is dependent on energetic homeostasis and thus, directly associated with energy homeostasis regulating hormones. To further understand the influence of those hormones with SCs function and obesity, we hypothesize that human SCs express obesity-related genes (ORG; MC4R, GNPDA2, TMEM18, and FTO) and that they respond to energy homeostasis regulating hormones (leptin, ghrelin, and glucagon-like protein 1 [GLP-1]) stimuli. To test our hypothesis, SCs were cultured with increasing doses of leptin (0, 5, 25, or 50 ng/ml, for 24 h), ghrelin (0, 20, 100, and 500 pM, for 24 h), and GLP-1 (10, 1000, or 1 × 105 pM, for 6 h). The presence and abundance of ORG transcripts and proteins in SCs were accessed by polymerase chain reaction techniques, Western blot analysis, and immunofluorescence staining. Our results show that human SCs express MC4R, GNPDA2, TMEM18, and FTO in specific cellular locations. MC4R and FTO expression in human SCs was not responsive to the treatments. However, GNPDA2 and TMEM18 expression increased after exposure to the highest concentration of leptin and ghrelin, respectively. We highlight for the first time that human SCs express ORG and that these are responsive to energy homeostasis hormonal stimuli. GNPDA2 and TMEM18 expression respond in opposite directions according to overall energy status, mediated by energy homeostasis regulating hormones. Leptin and ghrelin control of ORG expression by human SCs can be associated with overweight-related infertility and subfertility in males. Show less

The role and significance of liver-derived cytokines in cancer-associated cachexia syndrome remain elusive. Here we report that combinatorial counterbalances of the leptin and Igf1 signaling pathways in hepatocellular carcinoma (HCC) models significantly relieves cachexia. Double transgenic zebrafish models of HCC that stably displayed focal lesions, anorexia, and wasting of adipose and muscle tissues were first generated. Knockout of lepr or mc4r from these zebrafish partially restored appetite and exerted moderate or no effect on tissue wasting. However, genetic replenishment of Igf1 in a lepr-mutant background effectively relieved the cachexia-like phenotype without affecting tumor growth. Similarly, administration of napabucasin, a Stat3/Socs3 inhibitor, on the zebrafish HCC model, mammalian cell lines with exogenous IGF1, and two mouse xenograft models restored insulin sensitivity and rescued the wasting of nontumor tissues. Together, these results describe the synergistic impact of leptin and Igf1 normalization in treating certain HCC-associated cachexia as a practical strategy. SIGNIFICANCE: Disruption of leptin signaling with normalized Igf1 expression significantly rescues anorexia, muscle wasting, and adipose wasting in Ras- and Myc-driven zebrafish models of HCC. Show less

Decades of research have produced extensive evidence of the contribution of genetic factors to the efficacy and toxicity of antipsychotics. Numerous genetic variants in genes controlling drug availability or involved in antipsychotic processes have been linked to treatment variability. The complex mechanism of action and multitarget profile of most antipsychotic drugs hinder the identification of pharmacogenetic markers of clinical value. Nevertheless, the validity of associations between variants in CYP1A2, CYP2D6, CYP2C19, ABCB1, DRD2, DRD3, HTR2A, HTR2C, BDNF, COMT, MC4R genes and antipsychotic response has been confirmed in independent candidate gene studies. Genome wide pharmacogenomic studies have proven the role of the glutamatergic pathway in mediating antipsychotic activity and have reported novel associations with antipsychotic response. However, only a limited number of the findings, mainly functional variants of CYP metabolic enzymes, have been shown to be of clinical utility and translated into useful pharmacogenetic markers. Based on the currently available information, actionable pharmacogenetics should be reduced to antipsychotics' dose adjustment according to the genetically predicted metabolic status (CYPs' profile) of the patient. Growing evidence suggests that such interventions will reduce antipsychotics' side-effects and increase treatment safety. Despite this evidence, the use of pharmacogenetics in psychiatric wards is minimal. Hopefully, further evidence on the clinical and economic benefits, the development of clinical protocols based on pharmacogenetic information, and improved and cheaper genetic testing will increase the implementation of pharmacogenetic guided prescription in clinical settings. Show less

The quality of pork products from local breeds in extensive systems depends, among other things, on pig production. In particular, the variability in climatic conditions and feeding resources may influence the properties of tissues at slaughter and the quality of pork and processed products. The present study (part 2) was part of a larger project that assessed the influence of the finishing season and feeding resources on carcass and tissue traits and the quality of meat and dry-cured ham from Gascon pigs in an extensive system. Following the specifications of the Protected Designation of Origin "Noir de Bigorre", castrated Gascon males were reared on rangelands (grassland and forest areas) and received a supplementary diet from 5 to 6 months of age until slaughter at a minimum of 12 months and ca. 170 kg BW. Three finishing seasons were considered: Winter (n = 18), Spring (n = 22) and Autumn (n = 23). To estimate the specific effects of season on quality traits and avoid bias due to effects of genes known to influence these traits, polymorphisms in the RYR1, PRKAG3, MC4R and LEPR genes were included in the analysis models. Compared to Winter pigs, Spring and Autumn pigs had higher ultimate pH in the semimembranosus and gluteus medius (GM) muscles, lower meat lightness (P < 0.05) and tended to have higher GM intramuscular fat (IMF) content (P < 0.10). They also had higher GM contents of saturated, monounsaturated and polyunsaturated fatty acids (FAs) than Winter pigs (P < 0.05). Spring pigs had the lowest n-6:n-3 polyunsaturated FA ratio and the highest GM α-tocopherol content (P < 0.001), indicating pig grazing. The finishing season did not influence the processing yield of dry-cured hams (24-month process). Within each seasonal group, ten hams selected for genetic variability and IMF content were analyzed by a trained sensory panel. The season did not modify the appearance or odor, but influenced texture and taste. Hams from Winter and Spring pigs had higher tenderness and melting fat scores than hams from Autumn pigs (P < 0.01). Hams from Spring pigs had higher taste intensity and salty taste (P < 0.01) but lower positive tastes (e.g. fruits, forest) than hams from the other groups. Overall, finishing season had moderate effects on ham sensory traits. Furthermore, our results reveal high redness, tenderness, taste and odor intensity, and low rancid flavor of hams from Gascon pigs produced in an extensive system. Show less

Melanocortin-4 receptor ( Pertinent 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. Seventy 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/m Our 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. Show less

Psoriatic patients have considerably higher odds of being obese compared with the general population; however, the exact pathophysiological link between psoriasis and obesity needs to be elucidated. To investigate the association of psoriasis with established obesity-related gene variants, we conducted a population-based case-control study including 3541 subjects (574 psoriasis cases and 2967 controls from the general Hungarian population). Genotyping of 20 SNPs at ADIPOQ, BDNF, FTO, GNPDA2, LEPR, MC4R, NEGR1, NPY, PPARG, TMEM18, and UCP2 were determined, and differences in genotype and allele distributions were investigated. Multiple logistic regression analyses were implemented. Analysis revealed an association between the G allele of the rs1137101 polymorphism (LEPR gene) and obesity risk (OR: 3.30 (1.45; 7.50), Our results suggest that in psoriatic patients, there are prominent differences in the causes of obesity that should be accounted for, including not only environmental factors but also patient characteristics, such as the time of disease onset as well as genetic factors. Show less

Brain G-protein coupled receptors have been hypothesized to be potential targets for maintaining or restoring cognitive function in normal aged individuals or in patients with neurodegenerative disease. A number of recent reports suggest that activation of melanocortin receptors (MCRs) in the brain can significantly improve cognitive functions of normal rodents and of different rodent models of the Alzheimer's disease. However, the potential impact of normative aging on the expression of MCRs and their potential roles for modulating cognitive function remains to be elucidated. In the present study, we first investigated the expression of these receptors in six different brain regions of young (6 months) and aged (23 months) rats following assessment of their cognitive status. Correlation analysis was further performed to reveal potential contributions of MCR subtypes to spatial learning and memory. Our results revealed statistically significant correlations between the expression of several MCR subtypes in the frontal cortex/hypothalamus and the hippocampus regions and the rats' performance in spatial learning and memory only in the aged rats. These findings support the hypothesis that aging has a direct impact on the expression and function of MCRs, establishing MCRs as potential drug targets to alleviate aging-induced decline of cognitive function. Show less

Around 30% of the patients that undergo bariatric surgery (BS) do not reach an appropriate weight loss. The OBEGEN study aimed to assess the added value of genetic testing to clinical variables in predicting weight loss after BS. A multicenter, retrospective, longitudinal, and observational study including 416 patients who underwent BS was conducted (Clinical.Trials.gov- NCT02405949). 50 single nucleotide polymorphisms (SNPs) from 39 genes were examined. Receiver Operating Characteristic (ROC) curve analysis were used to calculate sensitivity and specificity. Satisfactory response to BS was defined as at nadir excess weight loss >50%. A good predictive model of response [area under ROC of 0.845 (95% CI 0.805-0.880), Show less

To compare the binding and agonistic activity of Acthar Acthar Gel and synthetic MCR agonists exhibited the highest binding at MC1R, lowest binding at MC5R, and moderate binding at MC3R and MC4R. Acthar Gel stimulated the production of cAMP in all 5 MCR-expressing cell lines, with MC2R displaying the lowest level of full agonist activity, 3-, 6.6-, and 10-fold lower than MC1R, MC3R, and MC4R, respectively. Acthar Gel was a partial agonist at MC5R. The synthetic MCR agonists induced full activity at all 5 MCRs, with the exception of α-MSH having no activity at MC2R. Acthar Gel treatment had less of an impact on Acthar Gel bound to and activated each MCR tested in this study, with partial agonist activity at MC5R and the lowest level of full agonist activity at MC2R, which distinguished it from synthetic MCR agonists. The minimal activity of Acthar Gel at MC2R corresponded to lower endogenous corticosteroid production. Show less

Melanocortin-3 receptor (MC3R) is a regulator of energy homeostasis, and interaction of MC3R and melanocortin-2 receptor accessory protein 2 (MRAP2) plays a critical role in MC3R signaling of mammals. However, the physiological roles of MC3R in teleosts are not well understood. In this study, qRT-PCR was used to measure gene expression. Radioligand binding assay was used to study the binding properties of topmouth culter MC3R (caMC3R). Intracellular cAMP generation was determined by RIA, and caMC3R expression was quantified with flow cytometry. We showed that culter mc3r had higher expression in the CNS. All agonists could bind and stimulate caMC3R to increase dose dependently intracellular cAMP accumulation. Compared to human MC3R, culter MC3R showed higher constitutive activity, higher efficacies, and Rmax to alpha-melanocyte-stimulating hormone (α-MSH), des-α-MSH, and adrenocorticotrophic hormone. Both caMRAP2a and caMRAP2b markedly decreased caMC3R basal cAMP production. However, only caMRAP2a significantly decreased cell surface expression, Bmax, and Rmax of caMC3R. Expression analysis suggested that MRAP2a and MRAP2b might be more important in regulating MC3R/MC4R signaling during larval period, and reduced mc3r, mc4r, and pomc expression might be primarily involved in modulation of MC3R/MC4R in adults. These data indicated that the cloned caMC3R was a functional receptor. MRAP2a and MRAP2b had different effects on expression and signaling of caMC3R. In addition, expression analysis suggested that MRAP2s, receptors, and hormones might play different roles in regulating culter development and growth. Show less

Melanocortin receptor-4 (MC4R) gene mutations are associated with early-onset severe obesity, and the identification of potential pathological variants is crucial for the clinical management of patients with obesity. To explore whether and how a novel heterozygous MC4R variant (MC4R-F313Sfs*29), identified in a young boy (body mass index [BMI] 38.8 kg/m2) during a mutation analysis conducted in a cohort of patients with obesity, plays a determinant pathophysiological role in the obesity development. The genetic screening was carried out in a total of 209 unrelated patients with obesity (BMI ≥ 35 kg/m2). Structural and functional characterization of the F313Sfs*29-mutated MC4R was performed using computational approaches and in vitro, using HEK293 cells transfected with genetically encoded biosensors for cAMP and Ca2+. The F313Sfs*29 was the only variant identified. In vitro experiments showed that HEK293 cells transfected with the mutated form of MC4R did not increase intracellular cAMP or Ca2+ levels after stimulation with a specific agonist in comparison with HEK293 cells transfected with the wild type form of MC4R (∆R/R0 = -90% ± 8%; P < 0.001). In silico modeling showed that the F313Sfs*29 mutation causes a major reorganization in the cytosolic domain of MC4R, thus reducing the affinity of the putative GalphaS binding site. The newly discovered F313Sfs*29 variant of MC4R may be involved in the impairment of α-MSH-induced cAMP and Ca2+ signaling, blunting intracellular G protein-mediated signal transduction. This alteration might have led to the dysregulation of satiety signaling, resulting in hyperphagia and early onset of obesity. Show less

Contrasting with the predicted anorexigenic effect of increasing brain serotonin signaling, long-term use of selective serotonin reuptake inhibitor (SSRI) antidepressants correlates with body weight (BW) gain. This adverse outcome increases the risk of transitioning to obesity and interferes with treatment compliance. Here, we show that orally administered fluoxetine (Flx), a widely prescribed SSRI, increased BW by enhancing food intake in healthy mice at 2 different time points and through 2 distinct mechanisms. Within hours, Flx decreased the activity of a subset of brainstem serotonergic neurons by triggering autoinhibitory signaling through 5-hydroxytryptamine receptor 1a (Htr1a). Following a longer treatment period, Flx blunted 5-hydroxytryptamine receptor 2c (Htr2c) expression and signaling, decreased the phosphorylation of cAMP response element-binding protein (CREB) and STAT3, and dampened the production of pro-opiomelanocortin (POMC, the precursor of α-melanocyte stimulating hormone [α-MSH]) in hypothalamic neurons, thereby increasing food intake. Accordingly, exogenous stimulation of the melanocortin 4 receptor (Mc4r) by cotreating mice with Flx and lipocalin 2, an anorexigenic hormone signaling through this receptor, normalized feeding and BW. Flx and other SSRIs also inhibited CREB and STAT3 phosphorylation in a human neuronal cell line, suggesting that these noncanonical effects could also occur in individuals treated long term with SSRIs. By defining the molecular basis of long-term SSRI-associated weight gain, we propose a therapeutic strategy to counter this effect. Show less

To study the abundance of obesity-related gene (ORG) mRNA in human spermatozoa and its association with sperm quality parameters, embryonic development, and pregnancy rates after assisted reproduction treatment (ART). Cross-sectional study of spermatozoa ORG mRNA expression, and sperm and embryonic development parameters of infertile couples attending a single ART center. University, in collaboration with a medically assisted reproduction center. One hundred six couples seeking fertility treatment and receiving ART. Expression of spermatozoa ORG mRNA was assessed by quantitative reverse transcription-polymerase chain reaction. Sperm and embryonic development parameters were measured by board-certified embryologists. Serum β-human chorionic gonadotropin levels and fetal heartbeat detection on ultrasound were used to document biochemical and clinical pregnancy, respectively. Correlations between the abundance of ORG transcripts in spermatozoa and sperm quality, embryonic development, and achievement of pregnancy. The abundance of spermatozoa FTO mRNA was positively correlated with total sperm count (r = 0.5030), fertilization rate (r = 0.4854), embryo cleavage rate (r = 0.5705), and high-quality embryo rate (r = 0.6982). The abundance of spermatozoa MC4R transcript was negatively correlated with sperm viability (r = -0.3111) and positively correlated with biochemical pregnancy (r = 0.4420). The abundance of MC4R and GNPDA2 transcripts was higher in spermatozoa of men with asthenozoospermia and teratozoospermia than in those with normozoospermia. To our knowledge, this is the first report showing that the abundance of MC4R and FTO transcripts in spermatozoa is associated with sperm and embryo quality parameters, as well as pregnancy rates. Overall, these results further support the view that male factors beyond classic sperm quality parameters, namely the abundance of ORG transcripts, also affect the outcome of ART. Show less

The melanocortin receptors (MC1R-MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further improve the potency and selectivity of MC4R (ant)agonist peptide ligands, we designed and synthesized a series of cyclic peptides based on the recent crystal structure of MC4R in complex with the well-characterized antagonist Show less

Hypothalamic regulation of feeding and energy expenditure is a fundamental and evolutionarily conserved neurophysiological process critical for survival. Dysregulation of these processes, due to environmental or genetic causes, can lead to a variety of pathological conditions ranging from obesity to anorexia. Melanocortins and endogenous cannabinoids (eCBs) have been implicated in the regulation of feeding and energy homeostasis; however, the interaction between these signaling systems is poorly understood. Here, we show that the eCB 2-arachidonoylglycerol (2-AG) regulates the activity of melanocortin 4 receptor (MC4R) cells in the paraventricular nucleus of the hypothalamus (PVN Show less

The aim of this review was to assess whether the presence of rs9939609 and rs17782313 polymorphisms increase the risk for obesity among children and adolescents. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and it was registered in PROSPERO. The search was performed in the PubMed/Medline, The Cochrane Library, and Web of Science databases. The risk of bias of the studies was accessed using the Newcastle-Ottawa scale and JBI Critical Appraisal Checklist for Analytical. The search of the databases retrieved 859 references. Twelve studies were eligible to be included in this systematic review. Five studies founded a positive association between overweight and obesity in children and adolescents with the presence of the rs17783213 and four studies with rs9939609. Three studies did not find an association between overweight and obesity in children and adolescents with the presence of rs17782313 or rs9939609. One found a protective effect for obesity in individuals with risk A allele referring to rs9939609, one found a synergistic effect in relation to the presence of polymorphisms rs17782313 and rs9939609 for obese phenotype, and one observed that the presence together of the rs9939609, rs17782313, and rs12970134 MC4R were significant for the presence of obesity in children and adolescents. The results suggest that depending on the population evaluated and ethnicity, the polymorphisms rs17782313 and rs9939609 could be associated with overweight and obesity in children and adolescents. Show less

We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 Almost all Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for Show less

Intramuscular fat (IMF) is an important meat-quality trait of pigs, which influences pork's shearing force, hydraulics, tenderness and juicy flavor. However, to achieve a higher percentage of lean meat, pigs with lower backfat thickness (BF) are intensively selected for, which may lead to a reduction in pork quality. Therefore, the objective of this study was to locate loci that affect IMF without changing BF. A single-step GWAS was performed on 950 Duroc pigs genotyped by a 50K SNP chip in order to detect genomic variants relevant to IMF and BF. The significant SNPs detected were afterwards divided into a BF subset (seven SNPs), an IMF subset (11 SNPs) and a subset of both traits (12 SNPs), according to their P-value and LD. After SNP and QTL annotation, our results indicated that SSC1: 167938652, 166363826, 164829874 and 167171587 might be associated with IMF without changing BF. In the subset of both traits, we found that the combined effect of ALGA0006602 (SSC1: 159538854) and 12784636 (SSC1: 160773437) might improve the IMF without changing BF. Our gene annotation result showed that TLE3, ITGA11, SMAD6, PAQR5 and [RNF152 Show less

In mammals, knockout of LEPR results in a hyperphagic, morbid obese, and diabetic phenotype, which supports that leptin plays an important role in the control of appetite and energy metabolism, and that its receptor, LEPR, mediates these effects. To date, little is known about the role(s) of lepr in teleost physiology. We investigated a zebrafish (Danio rerio) homozygous lepr knockout (lepr Show less