Search Results (159)

Nero Siciliano (NS) is an autochthonous pig breed reared in northeastern Sicily; despite its high-quality meat products, NS is currently endangered. This study aimed to evaluate the genetic variability at nine loci within candidate genes for meat traits—Melanocortin 4 Receptor (MC4R), Ryanodine Receptor 1 (RYR1), Class 3 Phosphoinositide 3-Kinase (PIK3C3) and Leptin (LEP)—to provide useful information for preservation and exploitation of the NS pig breed. Distribution of the genetic variants was assessed in a representative sample of 87 pigs (18 boars and 69 sows) collected in nine farms located in the original breeding area. Genotypes have been determined using PCR-RFLP and Sanger sequencing. Alleles linked to different growth rates and back fat deposition showed high frequencies (MC4R c.175C—0.93; LEP g.3469T—0.91) in the whole sample. Deviations from Hardy–Weinberg equilibrium and different allele distribution in boars and sows were observed. The RYR1 g.1843T allele, associated with Malignant Hyperthermia and Pale Soft Exudative meat defect, was reported in seven heterozygote pigs (q = 0.04) with one farm exhibiting a frequency of 0.29. Our results suggest the need for continuous monitoring of the genetic variants in NS both to maintain high meat quality and eradicate the RYR1 g.1843T allele. Full article

Mammals display a wide range of coat colors, with the melanocortin 1 receptor gene (MC1R) playing a pivotal role in the genetic regulation of pigmentation. In this study, we investigated MC1R genetic variants in goat populations from four Asian countries to identify genetic factors associated with coat color variation. The complete coding sequence of MC1R was analyzed to detect variants and determine genotypes in goats from Nepal (n = 122), the Philippines (n = 110), Cambodia (n = 30), and Kazakhstan (n = 30). Seven variants were identified, three of which were novel, while four had been previously reported in other goat populations. Among the novel variants, a frameshift mutation (c.147delG) unique to Nepalese goats was predicted to cause substantial disruption of the MC1R protein structure, suggesting its potential role in coat color determination. Additionally, two known missense variants (c.676A > G and c.801C > G) were inferred to affect MC1R function and may contribute to pigmentation variation. Further investigations with larger sample sizes are warranted to clarify the phenotypic effects of these genotypic variants and to better understand the genetic basis of coat color in goats. Full article

Obesity is a major global health challenge associated with significant metabolic and gastrointestinal comorbidities. While metabolic and bariatric surgery remains the gold standard for durable weight loss, the desire for additional options has fueled the development of endoscopic bariatric therapies (EBTs) as another tool for weight loss. This review examines established EBTs, including endoscopic sleeve gastroplasty (ESG), intragastric balloons (IGBs), and transoral outlet reduction (TORe), alongside emerging therapies such as duodenal mucosal resurfacing (DMR), incisionless anastomosis creation, and fully automated endoscopic gastric remodeling systems. ESG has demonstrated durable weight loss, favorable safety, and superior cost-effectiveness compared to pharmacotherapy alone, while combination strategies using EBTs and anti-obesity medications (AOMs), particularly GLP-1 receptor agonists, have resulted in greater total-body weight loss than either modality alone. Genetic variation, particularly within the leptin–melanocortin pathway, may predict response to endoscopic interventions and guide personalized treatment selection. Novel investigational procedures such as DMR, automated or robotic gastric remodeling, and magnetic or ultrasound-assisted gastric bypass show promising early results. Endoscopic therapies are poised to become increasingly central to the personalized, scalable management of obesity and related metabolic diseases. Full article

The large yellow croaker, or Larimichthys crocea, is highly prized for its golden color and nutritional content. The purpose of this study was to investigate the differences in body composition, mucus biochemical indices and body color in five strains of large yellow croakers (body weight: 347.01 ± 5.86 g). To conduct genetic diversity analyses of the populations, a total of 50 tailfin samples were randomly chosen from the following populations of large yellow croakers: wild (LYC1), Dai-qu population (LYC2), Yongdai 1 (LYC3), Min-yuedong population (LYC4), and Fufa 1 (LYC5). The findings demonstrated that the LYC3 group’s pigment contents, crude protein, crude lipid, and chromatic values were comparable to those of the LYC1 group (p > 0.05). There was no significant difference between the LYC1 and LYC5 groups’ mucus superoxide dismutase (SOD) and catalase (CAT) activities (p > 0.05). The alkaline phosphatases (ALP), acid phosphatases (ACP), and lysozyme (LYS) activities of the mucus in the LYC1 group were not significantly different from the LYC3 group (p > 0.05). The back skin mRNA expressions of tyrosinase (tyr), tyrosinase-related protein 1 (tyrp1), dopachrome tautomerase (dct), microphtalmia-associated transcription factor (mitf), and melanocortin 1 receptor (mc1r) were significantly up-regulated in the LYC2 and LYC4 groups compared to the LYC1, LYC3, and LYC5 groups (p < 0.05). Forkhead box d3 (foxd3), paired box 3 (pax3), purine nucleoside phosphorylase 4a (pnp4a), aristaless-like homeobox 4a (alx4a), cAMP dependent protein kinase (pka), anaplastic lymphoma kinase (alk), leukocyte receptor tyrosine kinase (ltk), and colony stimulating factor (fms) were among the mRNA expressions of the abdominal skin in the LYC1, LYC3, and LYC5 groups significantly higher than those in the LYC2 and LYC4 groups (p < 0.05). In conclusion, the LYC3 group’s crude protein, crude lipid, carotenoid, and lutein contents were most similar to those of the large yellow croaker found in the wild. Furthermore, the molecular mechanism underlying the variations in body color among the various strains of large yellow croakers was supplied for additional research. Full article

Background: Single-minded homolog 1 (SIM1) gene mutations with autosomal dominant inheritance have been related to hyperphagia and early-onset severe obesity. SIM1 is implicated in the development of hypothalamic nuclei, which play a crucial role in energy homeostasis. The development of melanocortin neural circuits in the hypothalamus is promoted by other factors such as Semaphorine 3 (SEMA3) and its receptors, such as PLXNA1-4 and NRP1-2. Loss-of-function across multiple SEMA3/NRP/PLXNA genes can collectively contribute to obesity onset. Case Description: A 3-year-old male was referred for the first time to Outpatient pediatric endocrinology due to early-onset and progressive severe obesity and hyperphagia. He presented neurobehavior disorders and partial diabetes insipidus. At age 6, the child was diagnosed with obesity-related complications, including hyperinsulinemia, impaired glucose tolerance, hypercholesterolemia, hepatic steatosis, and hypovitaminosis. The NGS analysis revealed four variants related to obesity: SIM1, SEMA3C, PLXNA4, and CREBBP gene mutations. Conclusions: The case presents the association of SIM-1 gene mutation with other obesity-related variants. The interactive and cumulative effects of the identified variants could coexist in the determination of severe obesity through abnormalities in the development and function of hypothalamic melanocortin circuits related to energy homeostasis. Although the pathogenic mutation of the SIM1 gene plays the main role, the complex clinical picture may be related to the possible cumulative effect of the other genetic mutations. Full article

Effective molecular imaging and targeted cancer therapy rely on receptor-specific targeted delivery systems that are both metabolically stable and kinetically inert for optimal in vivo performance. Until now, no single metal complexing agent has demonstrated the versatility to coordinate metals across the periodic table while maintaining the kinetic inertness required for clinical theranostic applications. Therefore, enhancing the in vivo kinetic stability of radiolabeled, cell-targeting, biologically active compounds remains a critical goal to minimize unintended accumulation of radioactivity in collateral tissues. This review describes the usage of NOTA [NOTA = 1,4,7-triazacyclononane-1,4,7-triacetic acid] and derivatives of NOTA, a metal complexing agent that has been found to have the ability to effectively coordinate with a wide range of radiometals, including metal-radiohalogens, to form stable complexes. This enables the development of new cell-targeting small molecule and peptide conjugates with the potential to resist demetallation in vivo, thereby reducing radionuclide uptake in non-target tissues. Herein, we discuss the design and development of NOTA-based, cell-targeting, small molecules having very high affinity and selectivity for the GRPR (Gastrin-Releasing Peptide Receptor), the SSTR2 (Somatostatin Receptor Subtype 2), and the MC1R (Melanocortin-1) receptors that are present on the surfaces of numerous solid primary human tumors and their metastatic counterparts. Full article

Background/Objectives: Severe early-onset obesity is a complex condition shaped by genetic and metabolic influences. The melanocortin 4 receptor (MC4R) gene plays a crucial role in energy balance, and pathogenic variants are associated with monogenic forms of obesity. This study aims to examine the clinical, metabolic, and genetic characteristics of a patient with severe early-onset obesity and his family, to assess the contribution of an MC4R variant to the observed phenotype. Methods: A 22-year-old male with severe obesity, first recognized at age 3, underwent detailed clinical, metabolic, and genetic evaluations. Laboratory assessments included insulin, lipid profile, uric acid, and IGF-1 levels. Whole-exome sequencing (WES) was performed on the patient and selected family members to identify potential pathogenic variants associated with obesity. Results: Clinical assessment revealed a body mass index (BMI) of 44.68 kg/m², hyperinsulinemia (98.2 µIU/mL), prediabetes (HbA1c: 5.85%), dyslipidemia, hyperuricemia (421.0 µmol/L), and elevated IGF-1 levels (646.7 ng/mL). WES identified a heterozygous MC4R:c.216C>G (p.Asn72Lys) variant present in the patient, his mother, and maternal relatives. This variant, with a population frequency of 0.0004%, is predicted as likely pathogenic by SIFT, MutationTaster, and PrimateAI. However, its segregation pattern suggests a complex inheritance mechanism rather than classical autosomal dominant or recessive inheritance. Conclusions: Early genetic testing in individuals with severe obesity is essential for guiding personalized treatment strategies. Although the MC4R:c.216C>G variant may contribute to the patient’s metabolic profile, further functional studies are required to confirm its pathogenicity and elucidate its role in obesity pathogenesis. Full article

Background: Glucagon-like peptide-2 (GLP-2) is a gut hormone secreted in response to nutrient intake and regulates lipid metabolism in the gut. The present study aims to elucidate the underlying mechanism of GLP-2 in stimulating gut lipid secretion in the fasted state by testing whether GLP-2 signals through the brain’s GLP-2 receptor and melanocortin 4 receptor (MC4R). Methods: Sprague-Dawley rats were implanted with a mesenteric lymph duct cannula for measuring gut lipid secretion and an intracerebroventricular cannula for infusion of a GLP-2R antagonist (GLP-2(11-33)), an MC4R antagonist (SHU9119), or saline as a control. The rat received a lipid infusion into the small intestine and a peritoneal injection of GLP-2 five hours later. Results: Brain administration of a GLP-2R antagonist or an MC4R antagonist attenuated the stimulatory effects of peripheral GLP-2 on lymph triglyceride output. These effects were associated with differential changes in the expression of key genes in jejunal endothelial cells, smooth muscle cells, and neuronal cells. Conclusions: These results support the involvement of central GLP-2R and MC4R in a neural pathway for GLP-2 to mobilize lipids stored in the gut during the post-absorptive state. Full article

Gonadotropin-inhibitory hormone (GnIH) is well-established as a negative regulator of reproductive physiology and behavior across vertebrates, acting on the hypothalamic–pituitary–gonadal (HPG) axis; however, recent data have also demonstrated its involvement in the control of metabolic processes. GnIH neurons and fibers have been identified in hypothalamic regions associated with feeding behavior and energy homeostasis, with GnIH receptors being expressed throughout the hypothalamus. GnIH does not act alone in the hypothalamus, but rather interacts with the melanocortin system, as well as with other neuropeptides. GnIH and its receptors are also expressed in peripheral tissues involved in important metabolic functions. Therefore, the local action of GnIH in peripheral organs, including the pancreas, gastrointestinal tract, gonad, and adipose tissue, is also suggested. This review aims to provide a comprehensive summary of the emerging role of GnIH in metabolic regulation at both the central and peripheral levels. Full article

Background/Objectives MC4R expression and its role in colorectal and anaplastic thyroid cancers, where resistance to therapy and lack of standard treatments remain significant challenges, are poorly understood. This study aimed to investigate MC4R as a potential therapeutic target in these cancers using the selective antagonist ML00253764 (ML), alone and in combination with vinorelbine (VNR) and irinotecan (or its active metabolite SN-38). Methods: Human colorectal adenocarcinoma HT-29, Caco-2, and anaplastic thyroid carcinoma 8305C cell lines were used. MC4R expression was assessed by Real-Time PCR with validated primers (Assay ID Hs00271877_s1), immunofluorescence, and Western blotting. Proliferation and apoptosis assays were conducted with ML, and synergy with VNR and SN-38 was evaluated by Combination Index and Loewe methods. ERK1/2 phosphorylation was measured using an ELISA assay. In vivo studies were conducted by injecting tumor cells into Athymic Nude-Foxn1nu mice, treated with ML, VNR, irinotecan, or their combinations. Results: MC4R expression was confirmed in all cell lines. ML treatment inhibited MC4R, producing antiproliferative and pro-apoptotic effects, with IC₅₀ values of 7667 ± 2144.6 nM (8305C), 806.4 ± 321.8 nM (HT-29), and 2993 ± 1135.2 nM (Caco-2). In combination with VNR and SN-38, ML exhibited significant synergy in vitro and reduced tumor volume in vivo without causing weight loss or adverse effects in mice. Conclusions This study identifies ML as a promising therapeutic agent that, when combined with chemotherapy, may offer a novel strategy for treating colorectal and anaplastic thyroid cancers. Full article

Genetic obesity results from loss-of-function mutations, including those affecting the leptin–melanocortin system, which regulates body weight. Pro-opiomelanocortin (POMC)-derived neurohormones act as ligands for melanocortin receptors (MCRs), regulating the leptin–melanocortin pathway through protein–protein interactions. Loss-of-function mutations in the genes encoding POMC, MC3R, and MC4R can lead to the dysregulation of energy expenditure and feeding balance, early-onset obesity, and developmental dysregulation. Recent studies have identified new genetic regulatory mechanisms and potential biomarker regions for the POMC gene and MC4R secondary messenger pathway associated with obesity. Recent advances in crystal structure studies have enhanced our understanding of the protein interactions in this pathway. This narrative review focuses on recent developments in two key areas related to POMC regulation and the leptin–melanocortin pathway: (1) genetic variations in and functions of POMC, and (2) MC3R and MC4R variants that lead to genetic obesity in humans. Understanding these novel mutations in POMC and MC4R/MC3R, as well as their structural and intracellular mechanisms, may help identify strategies for the treatment and diagnosis of obesity, particularly childhood obesity. Full article

Onychostoma macrolepis is not only a protected Cyprinid species in the wild but also an emerging commercial aquaculture fish in China. The objective of this research was to genetically modify the genes associated with commercial traits by CRISPR/Cas9 for the protection and utilization of the germplasm resources of O. macrolepis. To that end, one-cell stage embryos were obtained via hormone-induced ovulation and artificial insemination in O. macrolepis. Eight genes related to body color, growth, intermuscular bone, and sex differentiation were mutated in O. macrolepis using the CRISPR/Cas9 system by microinjection of gRNA/Cas9 mRNA. The optimal dose of gRNA/Cas9 mRNA was determined by injection of different concentrations of tyr (tyrosinase)-gRNA/Cas9 and examination of the mutation rate and hatching rate of embryos. Indels were detected by T7 endonuclease I digestion and Sanger sequencing. F0 mutants with high mutation rates were selected for phenotype analyses. Disruption of body color gene tyr, mpv17 (mitochondrial inner membrane protein MPV17), and csf1ra (colony-stimulating factor 1 receptor, a) resulted in obvious phenotype with decreased or even absence of melanophores, iridophores, and xanthophores, respectively. Mutation of mstnb (myostatin b) led to improved growth performance. Mutation of mc4r (melanocortin 4 receptor) led to no obvious phenotype. Mutation of runx2b (RUNX family transcription factor 2b) and bmp6 (bone morphogenetic protein 6) resulted in decreased or absence of intermuscular bones, as revealed by alizarin red S staining. Mutation of cyp19a1a (cytochrome P450, family 19, subfamily A, polypeptide 1a) resulted in ovarian degeneration as revealed by gonadal histological examination. Therefore, this study successfully obtained mutants with obvious phenotypes of genes associated with body color, growth, intermuscular bone, and sex differentiation by CRISPR/Cas9 in O. macrolepis. Full article

Recent findings have revealed that melanocortin 1 receptor (MC1R) deficiency leads to Parkinson’s disease-like dopaminergic neurodegeneration in the substantia nigra (SN). However, its precise distribution and expressing-cell type in the SN remain unclear. Therefore, in this study, we analyzed the localization and characteristics of MC1R in the SN using histological methods, including in situ hybridization and immunohistochemistry. Our findings reveal that MC1R was slightly present in dopaminergic neurons in the ventral tier of SN pars compacta dorsal (vSNCD), a region particularly vulnerable to PD-related neurodegeneration. Notably, we discovered that MC1R is highly present in parvalbumin (PV)-positive neurons, which were also vesicular GABA transporter messenger RNA-expressing inhibitory neurons of the lateral SN pars reticulata (lSNR). Intracellular analysis demonstrated that MC1R was present not only in the plasma membrane but also in mitochondrial and endoplasmic reticulum membranes. Furthermore, MC1R co-localized with attractin (Atrn), a known MC1R modulator, in nearly all MC1R-positive neurons. Therefore, it has been suggested that MC1R and Atrn work together to regulate dopaminergic neurons in the SN through both direct expression and indirect modulation via PV-positive inhibitory neurons. These findings provide new insights into MC1R’s role in the SN and its potential contribution to PD pathophysiology Full article

The skin is the largest body organ that can be physiologically affected by exposure to radiofrequency electromagnetic fields (RF-EMFs). We investigated the effect of RF-EMFs on melanogenesis; Mel-Ab melanocytes were exposed to 1760 MHz radiation with a specific absorption rate of 4.0 W/kg for 4 h/day over 4 days. Exposure to the RF-EMF led to skin pigmentation, with a significant increase in melanin production in Mel-Ab melanocytes. The phosphorylation level of cAMP response element binding protein (CREB) and the expression of microphthalmia-associated transcription factor (MITF), which regulate the expression of tyrosinase, were significantly increased in Mel-Ab after RF-EMF exposure. Interestingly, the expression of tyrosinase was significantly increased, but tyrosinase activity was unchanged in the RF-EMF-exposed Mel-Ab cells. Additionally, the expression of p53 and melanocortin 1 receptor (MC1R), which regulate MITF expression, was significantly increased. These results suggest that the RF-EMF induces melanogenesis by increasing phospho-CREB and MITF activity. Importantly, when Mel-Ab cells were incubated at 38 °C, the melanin production and the levels of tyrosinase significantly decreased, indicating that the increase in melanin synthesis by RF-EMF exposure is not due to a thermal effect. In conclusion, RF-EMF exposure induces melanogenesis in Mel-Ab cells through the increased expression of tyrosinase via the activation of MITF or the phosphorylation of CREB, which are initiated by the activation of p53 and MC1R. Full article

In mammals, the maintenance of energy homeostasis relies on complex mechanisms requiring tight synchronization between peripheral organs and the brain. Thyroid hormones (THs), through their pleiotropic actions, play a central role in these regulations. Hypothyroidism, which is characterized by low circulating TH levels, slows down the metabolism, which leads to a reduction in energy expenditure as well as in lipid and glucose metabolism. The objective of this study was to evaluate whether the metabolic deregulations induced by hypothyroidism could be avoided through regulatory mechanisms involved in metabolic flexibility. To this end, the response to induced hypothyroidism was compared in males from two mouse strains, the wild-derived WSB/EiJ mouse strain characterized by a diet-induced obesity (DIO) resistance due to its high metabolic flexibility phenotype and C57BL/6J mice, which are prone to DIO. The results show that propylthiouracil (PTU)-induced hypothyroidism led to metabolic deregulations, particularly a reduction in hepatic lipid synthesis in both strains. Furthermore, in contrast to the C57BL/6J mice, the WSB/EiJ mice were resistant to the metabolic dysregulations induced by hypothyroidism, mainly through enhanced lipid metabolism in their adipose tissue. Indeed, WSB/EiJ mice compensated for the decrease in hepatic lipid synthesis by mobilizing lipid reserves from white adipose tissue. Gene expression analysis revealed that hypothyroidism stimulated the hypothalamic orexigenic circuit in both strains, but there was unchanged melanocortin 4 receptor (Mc4r) and leptin receptor (LepR) expression in the hypothyroid WSB/EiJ mice strain, which reflects their adaptability to maintain their body weight, in contrast to C57BL/6J mice. Thus, this study showed that WSB/EiJ male mice displayed a resistance to the metabolic dysregulations induced by hypothyroidism through compensatory mechanisms. This highlights the importance of metabolic flexibility in the ability to adapt to disturbed circulating TH levels. Full article