Obese Gene Research Articles

THU143 A Novel Maternally Inherited GNAS Variant In A Family With Hyperphagia And Obesity

Abstract Disclosure: P. Purushothaman: None. A. Ramakrishnan: None. E.F. Gevers: None. Introduction: Heterozygous inactivating mutations in the maternal allele of the GNAS gene typically result in pseudohypoparathyroidism (PHP) characterized by developmental delay, short stature, obesity, hormone resistance and bone abnormalities. Recently, GNAS variants were also described in 1% of patients in the UK Genetics of Obesity cohort, resulting in reduced MC4R signalling. Here, we report another novel GNAS variant in family with hyperphagia and obesity and only mild features of PHP. Case: The proband presented at 6 years with hyperphagia and obesity from age 3 years. BMI was 30.4 (4.1 SDS) with height +1.9 SDS, and head circumference (HC) + 3.0 SDS. She had subtle brachydactyly, short toes and a café au lait patch. Developmental milestones and cognitive achievements were mildly delayed. Her 12-year-old brother [ height +2.1 SDS, weight +3.1 SDS, BMI 29.55 (2.9 SDS), HC +3.6 SDS] had been followed in an obesity clinic for a few years with hyperphagia, obesity, delayed developmental milestones and a recent diagnosis of autism. He also had subtle brachydactyly, as did the mother who was also obese (BMI 38.9) with a normal height but had normal cognition. Results: In the proband, initial investigations did not suggest hormone resistance. However, at 8.7 years, PTH was high [9.5 pmol/L (0.7-5.6)] with normal calcium and Vitamin D; TSH 6.6 mU/L (<6), FT4 11.8 pmol/L (10.8 - 19.0). She had hyperlipidaemia and fatty liver. X-ray hand showed generalised mild brachydactyly with a short right fifth metacarpal. In the brother, PTH tested for the first time at 12.9 years was 18.4 pmol/L (1.6-6.9), calcium and vitamin D were normal; TSH 4.04 mU/L (<4.2) and FT4 13.4 pmol/L. Next Generation Sequencing using the Cambridge Obesity gene panel detected a novel heterozygous (c.791A>C, p.(Asn264Thr) variant in exon 10 of GNAS in the proband and subsequently in the mother and brother confirming maternal inheritance. This variant has not been reported in control databases (1000 Genomes, ESP, ExAC and gnomAD, Human Gene Mutation Database and ClinVar). The variant is in a highly conserved region susceptible to missense mutations and has been classified as pathogenic using ACMG and ACGS guidelines. Discussion: In conclusion, we describe a novel heterozygous inactivating GNAS variant c.791A>C, p.Asn264Thr resulting in hyperphagia, obesity, developmental delay, macrocephaly, mild brachydactyly, tall stature and variable biochemical mild hormone resistance in 2 siblings and resulting in obesity, mild brachydactyly without cognitive impairment in the mother. These cases demonstrate the clinical heterogeneity of the monogenic disease. Clinical and biochemical screening for PHP and genetic screening for GNAS variants should be performed in patients presenting with obesity, even in the absence of classical signs of PHP, to reduce diagnostic delay. Presentation: Thursday, June 15, 2023

SAT027 Novel Obesity-Associated Melanocortin 4 Receptor Variants Modulate Signaling Differently

Abstract Disclosure: A.V. Rodriguez Rondon: None. M.S. Welling: None. E.L. van den Akker: None. E.F. van Rossum: None. P.J. Delhanty: None. J.A. Visser: None. Melanocortin-4 receptor (MC4R) is a G-protein-coupled receptor expressed in the hypothalamus regulating appetite and energy expenditure. Extensive evidence from genetic and biological studies show that MC4R is a key player in the homeostatic regulation of body weight. MC4R loss of function (LoF) variants are the most common cause of monogenic obesity. We have identified 1 homozygous and 16 heterozygous MC4R variants in patients with obesity at our academic Obesity Center CGG, Erasmus MC. The impact of these variants on MC4R signaling and the association with obesity are unknown. Here, we functionally characterized these variants by analyzing four different aspects of MC4R signaling. HEK293 cells were transiently transfected with expression plasmids encoding wild type (WT) or variant MC4R and stimulated with melanocyte stimulating hormone. Cyclic AMP response (cAMP) was measured using GloSensor cAMP bioluminescence assay, and β-arrestin-2 recruitment (βarr2) was measured using NanoBiT complementation luminescence assay. Furthermore, HiBiT Detection System was used to measure cell surface expression, and serum response element (SRE) reporter assay was used to measure extracellular signal-regulated kinase (ERK) activation. Variants were classified according to the percent of maximum response (Emax) relative to WT: complete LoF (cLoF): 0-20%; partial LoF (pLoF): 20-80%; WT: 80-120%; gain of function (GoF): >120%. The MC4R variants were identified by sequencing the MC4R gene of adult and pediatric patients with obesity using an obesity gene panel. Eleven of these variants have not been functionally studied previously. The median age of onset obesity for all patients is 3 years (range 0 – 6). Furthermore, the median BMI of the adult patients was 48.8 kg/m2 (range 36 - 58.8) and the median BMI-SDS of the pediatric patients was +4.2 SDS (range +3 – 7). Twelve out of 17 patients presented with hyperphagia. MC4R variants had differential effects on signaling. In 7 out of 17 variants, cLoF for cAMP was observed. This could be explained in 6 out of 7 of these variants due to lack of cell surface expression. Intriguingly, five out of 17 variants had a normal or GoF cAMP response and normal ERK activation. However, three out of these 5 variants showed cLoF or pLoF for βarr2, indicating a disrupted desensitization mechanism. In addition, the remaining five variants displayed pLoF for most studied pathways. We show that these MC4R variants identified in our patients with obesity affect signaling differently, through modulation of cAMP, βarr2, cell surface expression, and ERK pathways. This demonstrates the value of examining different aspects of MC4R signaling to understand possible biased effects of variants on these pathways. Overall, our results show the clinical importance of assessing the effect of MC4R variants on a range of molecular signaling mechanisms to determine their association with obesity. Presentation: Saturday, June 17, 2023

The Role of the Nuclear Receptor FXR in Arsenic-Induced Glucose Intolerance in Mice.

Inorganic arsenic in drinking water is prioritized as a top environmental contaminant by the World Health Organization, with over 230 million people potentially being exposed. Arsenic toxicity has been well documented and is associated with a plethora of human diseases, including diabetes, as established in numerous animal and epidemiological studies. Our previous study revealed that arsenic exposure leads to the inhibition of nuclear receptors, including LXR/RXR. To this end, FXR is a nuclear receptor central to glucose and lipid metabolism. However, limited studies are available for understanding arsenic exposure-FXR interactions. Herein, we report that FXR knockout mice developed more profound glucose intolerance than wild-type mice upon arsenic exposure, supporting the regulatory role of FXR in arsenic-induced glucose intolerance. We further exposed mice to arsenic and tested if GW4064, a FXR agonist, could improve glucose intolerance and dysregulation of hepatic proteins and serum metabolites. Our data showed arsenic-induced glucose intolerance was remarkably diminished by GW4064, accompanied by a significant ratio of alleviation of dysregulation in hepatic proteins (83%) and annotated serum metabolites (58%). In particular, hepatic proteins "rescued" from arsenic toxicity by GW4064 featured members of glucose and lipid utilization. For instance, the expression of PCK1, a candidate gene for diabetes and obesity that facilitates gluconeogenesis, was repressed under arsenic exposure in the liver, but revived with the GW4064 supplement. Together, our comprehensive dataset indicates FXR plays a key role and may serve as a potential therapeutic for arsenic-induced metabolic disorders.

Effects of Weight Loss and Aerobic Exercise Training on Adi-Pose Tissue Zinc α2-Glycoprotein and Associated Genes in Obesity.

Zinc α2-glycoprotein (ZAG) has been implicated in fatty acid metabolism and utilization and is lower in obese and higher in cachexic adults compared to those of normal weight. Previous studies suggest that ZAG binds to the beta3-adrenergic receptor (β3AR) to influence fatty acid metabolism in adipose tissue by regulating hormone sensitive lipase (HSL). The purpose of this study is to investigate the effects of a six-month weight loss (WL) or aerobic exercise (AEX) intervention on adipose tissue and skeletal muscle ZAG mRNA levels and protein expression, as well as the expression of β3AR, and HSL. Abdominal adipose tissue (AB) and gluteal adipose tissue (Glut) and vastus lateralis muscle biopsies were performed before and after WL (n = 13) or AEX (n = 13). ZAG, HSL, and β3AR expressions were determined by RT-PCR, and ZAG and HSL plasma levels by ELISA. Body weight decreased by 9.69% (p < 0.001) in WL and did not change with AEX. Maximal oxygen consumption (VO2max) increased by 7.1% (p < 0.005) after WL and by 16.69% (p < 0.001) after AEX. WL significantly decreased body weight with a reduction of percentage of fat, fat mass, fat-free mass (FFM). AEX decreased percent fat and increased VO2max, but did not change fat mass and FFM. Abdominal ZAG and HSL mRNA levels did not change significantly after WL or AEX. There were no changes in plasma ZAG, HSL and adipose tissue β3AR mRNA levels after WL and AEX. ZAG, HSL and β3AR mRNA expressions in adipose tissue are positively associated each other. Adipose tissue abdominal and gluteal HSL are negatively associated with HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), and both ZAG and HSL adipose tissue are negatively associated with fasting glucose and the glucose area under the curve. Further work is needed to elucidate the role of ZAG and HSL in the propensity for weight gain and the ability of exercise to mitigate these responses.

The Effect of Estrogen Hormone on Leptin Receptor in Small Intestine of Ovariectomized Rats

Objective: Leptin, a 16 kDa hormone encoded by the obese (Ob) gene, is known for its role in regulating food intake, body composition, and energy expenditure. Leptin receptor expression has been demonstrated in several tissues, including the small intestine. Weight gain may occur in humans after menopause or in animals following ovariectomy. Estrogen affects leptin and leptin receptor expressions. In this study, we aimed to contribute to the etiology of obesity by investigating the effects of E2 on leptin receptors in the small intestines of ovariectomized rats as a model of postmenopausal conditions. Materials and Methods: Bilateral ovariectomy was performed on 6-month-old Sprague-Dawley female rats. Ovariectomized rats (Ovx) were injected with 0.2 ml of sesame oil/rat/day or E2 (25 µg/rat/day) and euthanized at the 18th, 90th, or 162nd hours. Duodenum, jejunum, and ileum samples were fixed and embedded in paraffin using standard methods. The expression of leptin receptors were detected in the small intestine through immunohistochemistry. Results: Leptin receptor expression was found in the villi and crypt epithelium of the small intestine and in Brunner’s gland of the duodenum. E2 administration increased the leptin receptor expressions on the epithelium of villi and crypt in the duodenum and jejunum at the 90th hour (p&lt;0.05); ileum at the 18th hour (p&lt;0.05); and also on the epithelium of villi in the duodenum at the 162nd hour (p&lt;0.05). Conclusion: Our results indicate that E2 may upregulate the expression of leptin receptors in the small intestine, where glucose and other nutrients are absorbed after food intake and digestion, depending on the timing.

Analyzing Active Compounds in Elateriospermum tapos Yogurt for Maternal Obesity: A Network Pharmacology and Molecular Docking Study.

Maternal obesity, characterized by an elevated body mass index (BMI) during pregnancy, is known to have adverse effects on the offspring. However, a recent study suggests that Elateriospermum tapos (E. tapos) yogurt may hold potential in mitigating excessive weight retention post-pregnancy. Thus, this study aims to employ network pharmacology to explore the pharmacological effects of the bioactive compounds present in E. tapos yogurt against maternal obesity. Initially, a screening process is conducted to identify the bioactive compounds in E. tapos yogurt, followed by the prediction of potential gene targets for these compounds using Swiss Target Prediction and the SuperPred databases. Maternal obesity-associated genes are sourced from the OMIM, DisGeNet, and GeneCards databases. The interaction between the identified compounds and maternal obesity genes is established via protein-protein interaction analysis, gene ontology examination, and KEGG pathway analysis. To validate the results, molecular docking studies are conducted using AutoDock Tools software. The findings reveal that out of the 64 compounds analyzed, three meet the screening criteria, resulting in a total of 380 potential gene targets. Among these targets, 240 are shared with maternal obesity-related genes. Further analysis demonstrates the favorable affinity of these active compounds with key targets, linking them to biological processes involving protein phosphorylation, inflammation, as well as the pathways related to lipid metabolism, atherosclerosis, and the other signaling pathways. In conclusion, this study provides valuable insights into the potential pharmacological effects of the bioactive compounds found in E. tapos yogurt against maternal obesity. These findings open avenues for further exploration and potential therapeutic interventions targeting maternal obesity.

Transcript profile of CLSTN3B gene in human white adipose tissue is associated with obesity and mitochondrial gene program

Transcript profile of <i>CLSTN3B</i> gene in human white adipose tissue is associated with obesity and mitochondrial gene program

Eosinophils protect from metabolic alterations triggered by obesity.

Eosinophils are generally related to helminth infections or allergies. Their association with metabolic alterations and adipose tissue (AT) remodeling has been demonstrated mainly in animal models of obesity. However, their physiological role in driving metabolic features has not yet been well described. Herein, we aimed to evaluate the participation of eosinophils in metabolic and adipose tissue homeostasis in mice and humans, focusing on a translational perspective. Male BALB/c wild-type (WT) mice and GATA-1 knockout (Δdb/GATA-1-/-) mice were followed until 16-week-age in a regular diet or were fed with a high-refined-carbohydrate (HC) diet or high-fat (HF) diet for eight weeks. In subjects with obesity, clinical parameters and omental AT gene expression were evaluated. Eosinophils lack in mice fed a regular diet induced insulin resistance and increased adiposity. Their adipose tissue showed augmented cytokine levels, which could be attributed to increased leukocytes in the tissue, such as neutrophils and pro-inflammatory macrophages. Bone marrow transplant from WT mice to Δdb/GATA-1-/- mice showed some improvement in glucose metabolism with lower adipose tissue mass accretion. Upon an unhealthy diet challenge, Δdb/GATA-1-/- mice fed HC diet showed a mild degree of adiposity and glucose metabolic dysfunction severe in those mice fed HF diet. The expression of eosinophil markers in omental AT from humans with severe obesity was positively correlated to eosinophil cytokines and insulin sensitivity surrogate markers and negatively correlated to systemic insulin, HOMA-IR, and android fat mass. Eosinophils seem to have a physiological role by controlling systemic and adipose tissue metabolic homeostasis by modulating glucose metabolism, inflammation, and visceral fat expansion, even in lean mice. Indeed, eosinophils also seem to modulate glucose homeostasis in human obesity.

Energy Expenditure Homeostasis Requires ErbB4, an Obesity Risk Gene, in the Paraventricular Nucleus.

Obesity affects more than a third adult population in the United States; the prevalence is even higher in patients with major depression disorders. GWAS studies identify the receptor tyrosine kinase ErbB4 as a risk gene for obesity and for major depression disorders. We found that ErbB4 was enriched in the paraventricular nucleus of the hypothalamus (PVH). To investigate its role in metabolism, we deleted ErbB4 by injecting a Cre-expressing virus into the PVH of ErbB4-floxed male mice and found that PVH ErbB4 deletion increased weight gain without altering food intake. ErbB4 PVH deletion also reduced nighttime activity and decreased intrascapular brown adipose tissue (iBAT) thermogenesis. Analysis of covariance (ANCOVA) revealed that ErbB4 PVH deletion reduced O2 consumption, CO2 production and heat generation in a manner independent of body weight. Immunostaining experiments show that ErbB4+ neurons in the PVH were positive for oxytocin (OXT); ErbB4 PVH deletion reduces serum levels of OXT. We characterized mice where ErbB4 was specifically mutated in OXT+ neurons and found reduction in energy expenditure, phenotypes similar to PVH ErbB4 deletion. Taken together, our data indicate that ErbB4 in the PVH regulates metabolism likely through regulation of OXT expressing neurons, reveal a novel function of ErbB4 and provide insight into pathophysiological mechanisms of depression-associated obesity.

Identification and analysis of key genes in adipose tissue for human obesity based on bioinformatics

BackgroundObesity is a complex condition that is affected by a variety of factors, including the environment, behavior, and genetics. However, the genetic mechanisms underlying obesity remains poorly elucidated. Therefore, our study aimed at identifying key genes for human obesity using bioinformatics analysis. MethodsThe microarray datasets of adipose tissue in humans were downloaded from the Gene Expression Omnibus (GEO) database. After the selection of differentially expressed genes (DEGs), we used Lasso regression and Support Vector Machine (SVM) algorithm to further identify the feature genes. Moreover, immune cell infiltration analysis, gene set variation analysis (GSVA), GeneCards database and transcriptional regulation analysis were conducted to study the potential mechanisms by which the feature genes may impact obesity. We utilized receiver operating characteristic (ROC) curve to analysis the diagnostic efficacy of feature genes. Finally, we verified the feature genes in cell experiments and animal experiments. The statistical analyses in validation experiments were conducted using SPSS version 28.0, and the graph were generated using GraphPad Prism 9.0 software. The bioinformatics analyses were conducted using R language (version 4.2.2), with a significance threshold of p < 0.05 used. Results199 DEGs were selected using Limma package, and subsequently, 5 feature genes (EGR2, NPY1R, GREM1, BMP3 and COL8A1) were selected through Lasso regression and SVM algorithm. Through various bioinformatics analyses, we found some signaling pathways by which feature genes influence obesity and also revealed the crucial role of these genes in the immune microenvironment, as well as their strong correlations with obesity-related genes. Additionally, ROC curve showed that all the feature genes had good predictive and diagnostic efficiency in obesity. Finally, after validation through in vitro experiments, EGR2, NPY1R and GREM1 were identified as the key genes. ConclusionsThis study identified EGR2, GREM1 and NPY1R as the potential key genes and potential diagnostic biomarkers for obesity in humans. Moreover, EGR2 was discovered as a key gene for obesity in human adipose tissue for the first time, which may provide novel targets for diagnosing and treating obesity.

Alzheimer's Disease: Causal Effect between Obesity and APOE Gene Polymorphisms.

Currently studies on the correlation between obesity and Alzheimer's disease (AD) are still unclear. In addition, few indicators have been used to evaluate obesity, which has failed to comprehen-sively study the correlations between body fat mass, body fat distribution, and AD. Thus, this study innovatively utilized bioinformatics and Mendelian randomization (MR) to explore the key targets of obesity-induced AD, and investigate the causal associations between different types of obesity and key targets. The common targets of obesity and AD were screened using the GeneCards database, and functional and pathway annotations were carried out, thereby revealing the key target. MR analysis was conducted between body anthropometric indexes of obesity and the key target using an IVW model. Bioinformatics analysis revealed Apolipoprotein E (APOE) as the key target of obesity-induced AD. MR results showed that body mass index (BMI) had a negative causal association with APOE2, while body fat percentage (BFP) and trunk fat percentage (TFP) had no significant causal association with APOE2; BMI, BFP, and TFP had a negative causal association with APOE3, and none had any significant causal association with APOE4. In conclusion, there is a correlation between obesity and AD, which is mainly due to the polymorphism of the APOE gene rather than adipose tissue distribution. APOE3 carriers may be more susceptible to obesity, while the risk of AD caused by APOE2 and APOE4 may not be induced by obesity. This study sheds new light on current disputes. At the same time, it is suggested to regulate the body fat mass of APOE3 carriers in the early stage, and to reduce the risk of AD.

Deciphering the genetic landscape of obesity: a data-driven approach to identifying plausible causal genes and therapeutic targets

ObjectivesGenome-wide association studies (GWAS) have successfully revealed numerous susceptibility loci for obesity. However, identifying the causal genes, pathways, and tissues/cell types responsible for these associations remains a challenge, and standardized analysis workflows are lacking. Additionally, due to limited treatment options for obesity, there is a need for the development of new pharmacological therapies. This study aimed to address these issues by performing step-wise utilization of knowledgebase for gene prioritization and assessing the potential relevance of key obesity genes as therapeutic targets.Methods and resultsFirst, we generated a list of 28,787 obesity-associated SNPs from the publicly available GWAS dataset (approximately 800,000 individuals in the GIANT meta-analysis). Then, we prioritized 1372 genes with significant in silico evidence against genomic and transcriptomic data, including transcriptionally regulated genes in the brain from transcriptome-wide association studies. In further narrowing down the gene list, we selected key genes, which we found to be useful for the discovery of potential drug seeds as demonstrated in lipid GWAS separately. We thus identified 74 key genes for obesity, which are highly interconnected and enriched in several biological processes that contribute to obesity, including energy expenditure and homeostasis. Of 74 key genes, 37 had not been reported for the pathophysiology of obesity. Finally, by drug-gene interaction analysis, we detected 23 (of 74) key genes that are potential targets for 78 approved and marketed drugs.ConclusionsOur results provide valuable insights into new treatment options for obesity through a data-driven approach that integrates multiple up-to-date knowledgebases.

Dynamic interaction of obesity, age, MCP-1 Level, and ACE-1 gene with the severity of knee osteoarthritis: a cross-sectional study.

A total of 80 knee OA patients were included in this cross-sectional study. The severity of knee OA was determined based on the Kellgren-Lawrence system. All patients underwent physical and radiological examination; monocyte chemoattractant protein 1 (MCP-1) markers were measured. The parameters of the ACE-1 gene were examined with sequencing DNA. There was a significant relationship between age and severity of knee OA (P=0.007), with subjects aged greater than or equal to 65 having a 3.56-fold higher risk of developing moderate to severe OA than subjects aged less than 65. There was a significant difference between body weight and knee OA severity (P=0.026), in which subjects weighing greater than or equal to 60kg had 3.14 times the risk of experiencing severe knee OA. Multivariate regression analysis indicated that age was the strongest independent variable for knee OA severity compared with body weight. MCP-1 levels were significantly higher in mild knee OA than in moderate to severe knee OA. The DD genotype of the ACE-1 gene increases the risk of severe knee OA by four times in subjects aged greater than or equal to 65 compared to subjects aged less than 65. However, the DD genotype of the ACE-1 gene does not increase the risk of severe knee OA in subjects weighing greater than or equal to 60kg. While obesity and age were found to be associated with the severity of knee OA, age emerged as the independent risk factor for knee OA severity. Furthermore, MCP-1 levels were significantly higher in cases of mild knee OA compared to severe knee OA. It was observed that the DD genotype of the ACE-1 gene increases the risk of severe knee OA in individuals aged 65 years or older.

Using the collaborative cross to identify the role of host genetics in defining the murine gut microbiome

BackgroundThe human gut microbiota is a complex community comprised of trillions of bacteria and is critical for the digestion and absorption of nutrients. Bacterial communities of the intestinal microbiota influence the development of several conditions and diseases. We studied the effect of host genetics on gut microbial composition using Collaborative Cross (CC) mice. CC mice are a panel of mice that are genetically diverse across strains, but genetically identical within a given strain allowing repetition and deeper analysis than is possible with other collections of genetically diverse mice.Results16S rRNA from the feces of 167 mice from 28 different CC strains was sequenced and analyzed using the Qiime2 pipeline. We observed a large variance in the bacterial composition across CC strains starting at the phylum level. Using bacterial composition data, we identified 17 significant Quantitative Trait Loci (QTL) linked to 14 genera on 9 different mouse chromosomes. Genes within these intervals were analyzed for significant association with pathways and the previously known human GWAS database using Enrichr analysis and Genecards database. Multiple host genes involved in obesity, glucose homeostasis, immunity, neurological diseases, and many other protein-coding genes located in these regions may play roles in determining the composition of the gut microbiota. A subset of these CC mice was infected with Salmonella Typhimurium. Using infection outcome data, an increase in abundance of genus Lachnospiraceae and decrease in genus Parasutterella correlated with positive health outcomes after infection. Machine learning classifiers accurately predicted the CC strain and the infection outcome using pre-infection bacterial composition data from the feces.ConclusionOur study supports the hypothesis that multiple host genes influence the gut microbiome composition and homeostasis, and that certain organisms may influence health outcomes after S. Typhimurium infection.1cB2MLUGvinhfMFtS15p86Video

Association of Fat, Mass and Obesity (FTO) Gene Polymorphism with Diabetes and Prediabetes in Pakistani Population

Obesity and Type 2 Diabetes Mellitus (T2DM) have become the most prevalent public health issue around the world. The etiology of obesity and T2DM is multifactorial; with genes like Fat, Mass and Obesity-associated or FTO gene add to the complexity of the disease and diagnosis. Pakistan has recently been reported the highest prevalence of T2DM in the world. Since Pakistanis have a unique genetic disposition to T2DM due to the influence of genetic variations like rs9939609 in the FTO gene, as it is likely to be quantifiably different against the global genetic backdrop. A total of 300 participants were enrolled in this study, belonging to Dera Ismail Khan and Peshawar districts. Blood samples were collected from the enrolled patients following ethical approval and informed consent. HbA1c was used as a criterion for classifying non-diabetic controls, prediabetic, and diabetic patients. Patients’ anthropometric and demographic variables were recorded. Blood samples were subjected to both clinical chemistry and genetic analysis. Biochemically, samples were tested for HbA1c and lipid profile, whereas rs9939609 single nucleotide polymorphism (SNP) was assayed through direct sequencing. Demographic data showed that age and body mass index (BMI) were significantly higher in pre-diabetic and diabetic groups compared to the non-diabetic one. There was also statistically significant difference among the three groups in terms of their lipid profile parameters. Frequency of FTO-rs9939609 genotype distribution, however, was not significantly different in the three groups but patients with AA genotypes are 1.34 and 1.59 times more likely to develeop prediabetes and diabetes as compared to patients with TT genotypes. Lack of statistical association with FTO-rs9939609 SNP notwithstanding, our data reinforced the link between dyslipidemia, obesity and glycemic index.

Editor's Summaries of the Articles Published in This Issue of Molecular Medicine Communications

In this issue Yusuf and colleagues investigated the association of association of fat, mass and obesity (FTO) gene polymorphism with diabetes and prediabetes in Pakistani population, Mannan and colleagues did a variant analysis of FOXE1 gene in non-syndromic cleft lip and palate in Peshawar, Pakistan, Zaib et al determined the frequency of p53 mutations and Epstein-Barr virus in Pakistani gastric cancer patients and investigated their association with the tumor grade, Rehman and her colleagues made an analysis of comparative effectiveness &amp; renoprotective effects of hypoglycemic drugs for type 2 diabetes mellitus, and Ain et al reviewed the sources and mechanisms of chemoresistance in hepatocellular carcinoma.

A Novel Leptin Receptor LEPR Variant in a Toddler With Early-Onset Fatal Obesity.

Monogenic obesity generally results in severe early-onset obesity associated with abnormal feeding behavior and endocrine disorders. We report here an extremely severe case of early-onset obesity associated with hyperphagia in an 11-month-old boy without other signs of a syndromic obesity. He developed severe obstructive sleep apnea, dyslipidemia, hepatic steatosis with cytolysis, and acanthosis nigricans with insulin resistance in the first months of life. Laboratory investigations showed an elevated serum leptin level (80.03 ng/mL, normal range 2.45-6.55 ng/mL). Next-generation sequencing of obesity genes panel identified a novel homozygous intronic variant in leptin receptor gene (LEPR), c.703 + 5G>A, predicting affected splicing that resulted in a frameshift, premature stop, and truncation of the protein beyond the cytokine receptor homology domain 1. The child died at 27 months of age in the absence of available specific drug therapy.

Melanocortin-4 receptor and proopiomelanocortin: Candidate genes for obesity in domestic shorthair cats.

Obesity is an escalating global health problem affecting both humans and companion animals. In cats it is associated with increased mortality and multiple diseases, including diabetes mellitus. Two genes coding for proteins known to play a critical role in energy homeostasis across species are the proopiomelanocortin (POMC) gene and the melanocortin-4 receptor (MC4R) gene. A missense variant in the coding sequence of the feline MC4R (MC4R:c.92C>T) has been reported to be associated with diabetes and overweight in domestic shorthair cats, and while variants in the POMC gene are known to cause obesity in humans and dogs, variants in POMC and their association with feline obesity and diabetes mellitus have not been investigated to date. The current study aimed to assess the association between the previously described MC4R variant and body condition score (BCS), as well as body fat content (%BF) in 89 non-diabetic domestic shorthair cats. Furthermore, we investigated the feline POMC gene as a potential candidate gene for obesity. Our results indicate that the MC4R:c.92C>T polymorphism is not associated with BCS or %BF in non-diabetic domestic shorthair cats. The mutation analysis of all POMC exons identified two missense variants, with a variant in exon 1 (c.28G>C; p.G10R) predicted to be damaging. The variant was subsequently assessed in all 89 cats, and cats heterozygous for the variant had a significantly increased body condition score (p = 0.03) compared with cats homozygous for the wild-type allele. Results from our study provide additional evidence that the previously described variant in MC4R is not associated with obesity in domestic shorthair cats. More importantly, we have identified a novel variant in the POMC gene, which might play a role in increased body condition score and body fat content in domestic shorthair cats.

CagriSema and the link between obesity and type 2 diabetes

In The Lancet, Juan P Frias and colleagues report positive results in a phase 2 trial evaluating the safety and efficacy of co-administered cagrilintide and semaglutide (CagriSema) for type 2 diabetes, 1 Frias JP Deenadayalan S Erichsen L et al. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet. 2023; (published online June 23.)https://doi.org/10.1016/S0140-6736(23)01163-7 Google Scholar approximately 2 years after a phase 1b study showed early efficacy in the treatment of obesity. 2 Enebo LB Berthelsen KK Kankam M et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet. 2021; 397: 1736-1748 Summary Full Text Full Text PDF PubMed Google Scholar The role of a gut–brain axis in energy balance has been intensely studied since the 1994 discovery of leptin as a hormone produced by adipose tissue in response to feeding. 3 Zhang Y Proenca R Maffei M Barone M Leopold L Friedman JM Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372: 425-432 Crossref PubMed Scopus (11820) Google Scholar In the years that followed, many investigations led to the current understanding of energy regulation to include signalling in the liver and endocrine pancreas through both classic incretins (eg, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 [GLP-1]) and the unique hormone co-secreted with insulin (amylin). Research also showed that abnormal energy balance can be improved by perturbing the axis via altering or bypassing segments of the gastrointestinal tract with bariatric surgery. 4 Ashrafian H le Roux CW Metabolic surgery and gut hormones—a review of bariatric entero-humoral modulation. Physiol Behav. 2009; 97: 620-631 Crossref PubMed Scopus (88) Google Scholar And nearly 30 years later, gut hormone analogues, notably liraglutide, semaglutide, and tirzepatide, have been investigated as effective treatments for both type 2 diabetes and obesity. CagriSema is currently also being evaluated as a drug to treat both type 2 diabetes and obesity. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trialIn people with type 2 diabetes, treatment with CagriSema resulted in clinically relevant improvements in glycaemic control (including CGM parameters). The mean change in HbA1c with CagriSema was greater versus cagrilintide, but not versus semaglutide. Treatment with CagriSema resulted in significantly greater weight loss versus semaglutide and cagrilintide and was well tolerated. These data support further investigation of CagriSema in this population in longer and larger phase 3 studies. Full-Text PDF

A Review of Genes Associated with Obesity Susceptibility: Findings from Association Studies

Obesity is described as the accumulation of excess body fat. Several health issues are caused by excess fat, including cancer, type 2 diabetes, and cardiovascular disease. Additionally, obesity rates among schoolchildren and young adults are rising globally, putting young people at risk of chronic diseases. Genetics, epigenetic modification, epigenomics, and environmental factors influence inheritance patterns significantly. This systematic study aimed to classify and investigate the polymorphisms of novel candidate obesity genes. Several genes have been suggested, includingat mass and obesity-associated gene (FTO), leptin gene (LEP), leptin receptor gene (LEPR), peroxisome proliferatoractivated receptor gamma gene (PPARG), melanocortin 4 receptor (MC4R), insulin-induced gene 2 (INSIG2), proprotein convertase subtilisin/kexin type 1 (PCSK1), adrenoceptor beta 2 (ADRB2), and uncoupling protein 2 (UCP2). The study’s literature review identified genes in scientific papers published in databases such as Web of Science, PubMed, Google Scholar, Embase, and others over the past three decades. There is evidence that genetic variations contribute to childhood obesity, adolescent obesity, and young adult obesity. Identifying functional differences and further defining the implicated molecularly and physiologically involved genes andpathways in efficient therapeutic approaches in fighting. Technological advances have recently demonstrated that genetic changes and mutations can be used as biological markers, risk indicators, and therapeutic targets.