Obesity-related Genes Research Articles

Exploring the Interplay of Genetics and Nutrition in the Rising Epidemic of Obesity and Metabolic Diseases

Background: Obesity has become a significant global health issue. This multifaceted condition is influenced by genetic, environmental, and lifestyle factors, significantly influenced by nutrition. Aim: The study’s objective is to elucidate the relationship between obesity-related genes, nutrient intake, and the development of obesity and the importance of other metabolic diseases. Methods: A comprehensive literature review spanning the past two decades was conducted to analyze the contributions of genetic variants—including FTO, MC4R, and LEPR—and their associations with dietary habits, highlighting how specific nutrients affect gene expression and obesity risk and how the coexistence of metabolic diseases such as type 2 diabetes and osteoporosis may modulate these factors. Moreover, the role of epigenetic factors, such as dietary patterns that encourage the development of obesity, was explored. Discussion and Conclusions: By understanding the intricate relationships among genetics, nutrients, and obesity development, this study highlights the importance of personalized dietary strategies in managing obesity. Overall, an integrated approach that considers genetic predispositions alongside environmental influences is essential for developing effective prevention and treatment methodologies, ultimately contributing to better health outcomes in diverse populations.

Distribution of Variants and Identification of Novel Variants in Patients with Obesity Using Next-Generation Sequencing in Genes Associated with Obesity: A Single-Center Experience in Turkey

Background: Obesity has become a common public health problem all over the world today. In recent years, studies on the genetic etiology of obesity have gained importance. As a result of these studies, 127 obesity-related loci have been identified. Objectives: The aim of this work was to screen obesity-related genes and review the literature. Methods: In this retrospective study, 41 obesity-related genes were screened in 116 patients by next-generation sequencing. These genes are DYRK1B, LEP, LEPR, MC4R, NR0B2, POMC, UCP3, ADRB2, ADRB3, AGRP, MC3R, NTRK2, PCSK1, SIM1, CARTPT, ENPP1, PPARG, PPARGC1B, PYY, SDC3, UCP1, ADIPOQ, PBEF (NAMP), ADN (CFD), RETN, PGC1 (PPARGC1A), CCK, NPY, GLUT4 (SLC2A4), ADD1, SREBP1 (SREBF1), PTP1B (PTPN1), IRS-1, GHRL, BDNF, NEGR1, SH2B1, GIPR, TMEM18, FTO, and SLC22A1. Results: Seventy-six of our patients were female, and 40 were male. As a result, 43 variants were detected in 39 (34.4%) patients. Of these, GHRL c.152G>A, MC4R c.496G>A, SH2B1 c.2083G>A, GIPR c.548G>A, ADIPOQ c.268G>A, and BDNF c.5C>T variants have been previously reported in the literature. In addition to the aforementioned variants, there are 37 novel variants that have not been previously reported. Among these, we classified the UCP3 c.126 + 1G>T variant as “Pathogenic” according to the American College of Medical Genetics and Genomics (ACMG) criteria. Four of 37 novel variants, respectively, ADRB2 c.1160_1163delTTGT (p.Phe387Trp*55), MC4R c.895C>T (p.Pro299Ser), POMC c.304C>T (p.Gln102*), and NR0B2 c.265C>T (p.Gln89*), were classified as “Likely Pathogenic.” A total of 32 novel variants among 37 novel variants were categorized as variants of uncertain significance. Conclusions: Understanding the genetics of obesity is an essential step toward treating and preventing this disease, which has become a global health problem. With this study, we wanted to contribute to the literature by reporting previously reported and novel variants we detected in our patients with obesity.

Meta-analysis of FTO expression on the clinicopathologic characteristics and prognosis of gastric cancer.

Fat mass and obesity-related gene (FTO) is aberrantly expressed in various cancers including highly expressed in gastric cancer tissues. The aim of this meta-analysis was to explore the effect of FTO expression on clinicopathological and prognostic outcome of gastric cancer. China National Knowledge Infrastructure (CNK), Wanfang database, VIP database, Chinese biomedical literature database (CBM), PubMed, Web of Science, the Cochrane library and EMBASE database were searched to screen the literatures according to the inclusion criteria. The search time was the database establishment until May 2023. The two researchers independently searched and screened the literature, extracted pathological data, and conducted The Newcastle-Ottawa scale (NOS) quality evaluation. Analyze the correlation between FTO and pathological indicators of gastric cancer patients and the impact on prognosis, use and Stata 12.0, software for Meta-analysis. A total of 1619 patients were studied in this study. The results of the Meta-analysis showed that higher expression levels of FTO were associated with TMN stage (OR = 1.83, 95% CI: 1.11-3.03, P = .019), liver metastases (OR = 3.73, 95% CI: 1.49-9.31, P = .005), vascular invasion (OR = 2.22, 95% CI: 1.36-3.61, P = .001), poorer overall survival (OS) (HR = 0.46, 95% CI: 0.34-0.58, P < .001) and recurrence-free survival (HR = 0.56, 95% CI: 0.40-0.73, P < .001) in gastric cancer patients. There was no significant relationship with the degree of differentiation (OR = 1.08, 95% CI: 0.49-2.35, P = .852), age (OR = 0.89, 95% CI: 0.71-1.11, P = .306), and gender (OR = 0.92, 95% CI: 0.74-1.14, P = .432). High expression of FTO was associated with risk of distant metastases and poor prognosis for patients with gastric cancer. FTO may be a potential prognostic biomarker for gastric cancer, but due to the limited number of literature, the above results need further research.

DOR activation in mature oligodendrocytes regulates α-ketoglutarate metabolism leading to enhanced remyelination in aged mice.

The decreased ability of mature oligodendrocytes to produce myelin negatively affects remyelination in demyelinating diseases and aging, but the underlying mechanisms are incompletely understood. In the present study, we identify a mature oligodendrocyte-enriched transcriptional coregulator diabetes- and obesity-related gene (DOR)/tumor protein p53-inducible nuclear protein 2 (TP53INP2), downregulated in demyelinated lesions of donors with multiple sclerosis and in aged oligodendrocyte-lineage cells. Dor ablation in mice of both sexes results in defective myelinogenesis and remyelination. Genomic occupancy in oligodendrocytes and transcriptome profiling of the optic nerves of wild-type and Dor conditional knockout mice reveal that DOR and SOX10 co-occupy enhancers of critical myelinogenesis-associated genes including Prr18, encoding an oligodendrocyte-enriched, proline-rich factor. We show that DOR targets regulatory elements of genes responsible for α-ketoglutarate biosynthesis in mature oligodendrocytes and is essential for α-ketoglutarate production and lipid biosynthesis. Supplementation with α-ketoglutarate restores oligodendrocyte-maturation defects in Dor-deficient adult mice and improves remyelination after lysolecithin-induced demyelination and cognitive function in 17-month-old wild-type mice. Our data suggest that activation of α-ketoglutarate metabolism in mature oligodendrocytes can promote myelin production during demyelination and aging.

Genes Involved in Susceptibility to Obesity and Emotional Eating Behavior in a Romanian Population.

Obesity, a significant public health concern with high prevalence in both adults and children, is a complex disorder arising from the interaction of multiple genes and environmental factors. Advances in genome-wide association studies (GWAS) and sequencing technologies have identified numerous polygenic causes of obesity, particularly genes involved in hunger, satiety signals, adipocyte differentiation, and energy expenditure. This study investigates the relationship between six obesity-related genes (CLOCK, FTO, GHRL, LEP, LEPR, MC4R) and their impact on BMI, WC, HC, WHR, and emotional eating behavior in 220 Romanian adults. Emotional eating was assessed using the validated Emotional Eating Questionnaire (EEQ). Our analysis revealed significant variability in obesity-related phenotypes and emotional eating behaviors across different genotypes. Specifically, CLOCK/CC, FTO/AA, and LEP/AA genotypes were strongly associated with higher obesity metrics and emotional eating scores, while GHRL/TT and MC4R/CC were linked to increased BMI and WHR. The interplay between genetic predisposition and emotional eating behavior significantly influenced BMI and WHR, indicating a complex relationship between genetic and behavioral factors. This study, the first of its kind in Romania, provides a foundation for targeted interventions to prevent and reduce obesity and suggests potential strategies for gene expression modulation to mitigate the effects of emotional eating. Adopting a 'One Health' approach by creating an evidence base derived from both human and animal studies is crucial for understanding how to control obesity.

Genome-wide association study based on clustering by obesity-related variables uncovers a genetic architecture of obesity in the Japanese and the UK populations

Whether all obesity-related variants contribute to the onset of obesity or one or a few variants cause obesity in genetically heterogeneous populations remains obscure. Here, we investigated the genetic architecture of obesity by clustering the Japanese and British populations with obesity using obesity-related factors. In Step-1, we conducted a genome-wide association study (GWAS) with body mass index (BMI) as the outcome for eligible participants. In Step-2, we assigned participants with obesity (BMI ≥25 kg/m2) to five clusters based on obesity-related factors. Subsequently, participants from each cluster and those with a BMI <25 kg/m2 were combined. A GWAS was conducted for each cluster.Several previously identified obesity-related genes were verified in Step-1. Of the genes detected in Step-1, unique obesity-related genes were detected separately for each cluster in Step-2. Our novel findings suggest that a smaller sample size with increased homogeneity may provide insights into the genetic architecture of obesity.

The obesity-related mutation gene on nonalcoholic fatty liver disease.

The prevalence of overweight and obesity is increasing, leading to metabolic-associated fatty liver disease (MAFLD) characterized by excessive accumulation of liver fat and a risk of developing hepatocellular carcinoma (HCC). The driver gene mutations may play the roles of passengers that occur in single 'hotspots' and can promote tumorigenesis from benign to malignant lesions. We investigated the impact of high body weight and BMI on HCC survival using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. To explore the effects of obesity-related gene mutations on HCC, we collected driver mutation genes in 34 TCGA patients with BMI ≥ 27 and 23 TCGA patients with BMI < 27. The digital PCR performing the PBMC samples for the variant rate by clinical cohort of 96 NAFLD patients. Our analysis showed that obesity leads to significantly worse survival outcomes in HCC. Using cbioportal, we identified 414 driver mutation genes in patients with obesity and 127 driver mutation genes in non-obese patients. Functional analysis showed that obese-related genes significantly enriched the regulated lipid and insulin pathways in HCC. The insulin secretion pathway in patients with obesity HCC-specific survival identified ABCC8 and PRKCB as significant genes (p < 0.001). It revealed significant differences in gene mutation and gene expression profiles compared to non-obese patients. The digital PCR test ABCC8 variants were detected in PBMC samples and caused a 14.5% variant rate, significantly higher than that of non-obese NAFLD patients. The study findings showed that the gene ABCC8 was a patient with the obesity-related gene in NAFLD, which provides the probability that ABCC8 mutation contributes to the pre-cancer lesion biomarker for HCC.

Association of LEP rs2167270 and LEPR rs1137100 genetic variants with obesity in the Jordanian population cohort

Background Previous Genome Wide Association Studies (GWAS) of obesity susceptibility genes in different populations have confirmed the association of some variants with obesity, body mass index (BMI), and some related metabolic traits. To our knowledge, the current study is the first to investigate the genetic basis of obesity in the Jordanian population. The aim of our study is to investigate the occurrence and frequency of obesity-related genes in Jordanian individuals and any possible relationship between SNP genetic markers and phenotypic characteristics of studied individuals. Methods A total of 150 Jordanian unrelated adults, including 83 obese, 26 overweight, and 41 normal-weight subjects, were genotyped using the high resolution melt analysis (HRMA) and tested for the association of single nucleotide polymorphisms (SNPs), rs2167270 in LEP gene and rs1137100 in LEPR gene, with obesity risk, obesity/overweight risk, BMI, weight, height, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and blood level glucose. Results A significant association between obesity risk and the rs2167270 mutation in LEP gene was observed under a dominant model (odds ratio (OR) = 2.5147, 95% CI =1.0629 to 5.9494, p = 0.0358). A marginal (not significant) association between BMI and the rs2167270 mutation in LEP gene (p = 0.075), was also detected. Moreover, an association between rs2167270 mutation in LEP gene and glucose blood level was observed (p = 0.038). Total cholesterol and LDL-cholesterol also presented a weak association with the rs1137100 mutation in LEPR gene, with p = 0.071 and p = 0.078, respectively. Additionally, no significant association between LDL-cholesterol and the rs2167270 mutation in LEP gene was observed (p = 0.091). By contrast, there was no association between weight or height and the SNPs mutation evaluated in this study (p &gt; 0.05). Conclusions These results suggest that some SNPs in some obesity-related genes may contribute to obesity risk and its related anthropometric and metabolic traits in Jordanian population. To confirm these results, further studies on a larger Jordanian cohort should be carried out.

Efficacy of Probiotic Strains Lactobacillus sakei Probio65 and Lactobacillus plantarum Probio-093 in Management of Obesity: An In Vitro and In Vivo Analysis.

The prevalence of obesity, characterized by an excessive accumulation of adipose tissue and adipocyte hypertrophy, presents a major public health challenge. This study investigates the therapeutic potential of two probiotic strains, Lactobacillus sakei Probio65 and Lactobacillus plantarum Probio-093, in the context of obesity. Utilizing 3T3-L1 cell-derived human adipocytes, we assessed Probio65's and Probio-093's capacity to mitigate triglyceride accumulation and influence adipocytokine production in vitro. Subsequently, an in vivo trial with male C57BL/6J mice examined the effects of both probiotic strains on adipose tissue characteristics, body weight, fat mass, and obesity-related gene expression. This study employed both live and ethanol-extracted bacterial cells. The results demonstrated significant reductions in the triglyceride deposition, body weight, and adipose tissue mass in the treated groups (p < 0.05). Furthermore, both strains modulated adipokine profiles by downregulating proinflammatory markers such as PAI-1, leptin, TNF-α, STAMP2, F4/80, resistin, and MCP-1, and upregulating the insulin-sensitive transporter GLUT4 and the anti-inflammatory adiponectin (p < 0.05). Our findings suggest that Lactobacillus sakei Probio65 and Lactobacillus plantarum Probio-093 are promising agents for microbiome-targeted anti-obesity therapies, offering the effective mitigation of obesity and improvement in adipocyte function in a murine model.

Where do obesity and male infertility collide?

The parallel rise in obesity and male infertility in modern societies necessitates the identification of susceptibility genes underlying these interconnected health issues. In our study, we conducted a comprehensive search in the OMIM database to identify genes commonly associated with male infertility and obesity. Subsequently, we performed an insilico analysis using the REVEL algorithm to detect pathogenic single nucleotide polymorphisms (SNPs) in the coding region of these candidate genes. To validate our findings in vivo, we conducted a comprehensive analysis of SNPs and gene expression of candidate genes in 200 obese infertile subjects and 240 obese fertile individuals using ARMS-PCR. Additionally, we analyzed 20 fertile and 22 infertile obese individuals using Realtime-qPCR. By removing duplicated queries, we obtained 197 obesity-related genes and 102 male infertility-related genes from the OMIM database. Interestingly, the APOB gene was found in common between the two datasets. REVEL identified the rs13306194 variant as potentially pathogenic with a calculated score of 0.524. The study identified a significant association between the AA (P value = 0.001) genotype and A allele (P value = 0.003) of the APOB rs13306194 variant and infertility in obese men. APOB expression levels were significantly lower in obese infertile men compared to obese fertile controls (p < 0.01). Moreover, the AA genotype of rs13306194 APOB was associated with a significant decrease in APOB gene expression in obese infertile men (p = 0.05). There is a significant association between the Waist-to-Hip Ratio (WHR) and LH with infertility in the obese infertile group. These results are likely to contribute to a better understanding of the causes of male infertility and its association with obesity.

Identifying latent genetic interactions in genome-wide association studies using multiple traits

The "missing" heritability of complex traits may be partly explained by genetic variants interacting with other genes or environments that are difficult to specify, observe, and detect. We propose a new kernel-based method called Latent Interaction Testing (LIT) to screen for genetic interactions that leverages pleiotropy from multiple related traits without requiring the interacting variable to be specified or observed. Using simulated data, we demonstrate that LIT increases power to detect latent genetic interactions compared to univariate methods. We then apply LIT to obesity-related traits in the UK Biobank and detect variants with interactive effects near known obesity-related genes (URL: https://CRAN.R-project.org/package=lit).

Genetic risk score based on obesity-related genes and progression in weight loss after bariatric surgery: a 60-month follow-up study

BackgroundObesity is a polygenic multifactorial disease. Recent genome-wide association studies have identified several common loci associated with obesity-related phenotypes. Bariatric surgery (BS) is the most effective long-term treatment for patients with severe obesity. The huge variability in BS outcomes between patients suggests a moderating effect of several factors, including the genetic architecture of the patients. ObjectiveTo examine the role of a genetic risk score (GRS) based on 7 polymorphisms in 5 obesity-candidate genes (FTO, MC4R, SIRT1, LEP, and LEPR) on weight loss after BS. SettingUniversity hospital in Spain. MethodsWe evaluated a cohort of 104 patients with severe obesity submitted to BS (Roux-en-Y gastric bypass or sleeve gastrectomy) followed up for >60 months (lost to follow-up, 19.23%). A GRS was calculated for each patient, considering the number of carried risk alleles for the analyzed genes. During the postoperative period, the percentage of excess weight loss total weight loss and changes in body mass index were evaluated. Generalized estimating equation models were used for the prospective analysis of the variation of these variables in relation to the GRS. ResultsThe longitudinal model showed a significant effect of the GRS on the percentage of excess weight loss (P = 1.5 × 10–5), percentage of total weight loss (P = 3.1 × 10–8), and change in body mass index (P = 7.8 × 10–16) over time. Individuals with a low GRS seemed to experience better outcomes at 24 and 60 months after surgery than those with a higher GRS. ConclusionThe use of the GRS in considering the polygenic nature of obesity seems to be a useful tool to better understand the outcome of patients with obesity after BS.

Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.

Mechanism of Fat Mass and Obesity-Related Gene-Mediated Heme Oxygenase-1 m6A Modification in the Recovery of Neurological Function in Mice with Spinal Cord Injury.

This study examined the mechanism of fat mass and obesity-related gene (FTO)-mediated heme oxygenase-1 (HO-1) m6A modification facilitating neurological recovery in spinal cord injury (SCI) mice. FTO/HO-1 was identified as a key regulator of SCI as well as a potential target for treatment of SCI. An SCI mouse was treated with pcDNA3.1-FTO/pcDNA3.1-NC/Dac51. An oxygen/glucose deprivation (OGD) cell model simulated SCI, with cells treated with pcDNA3.1-FTO/si-HO-1/Dac51. Motor function and neurobehavioral evaluation were assessed using the Basso, Beattie, and Bresnahan (BBB) scale and modified neurological severity score (mNSS). Spinal cord pathology and neuronal apoptosis were assessed. Further, FTO/HO-1 mRNA and protein levels, HO-1 mRNA stability, the interaction of YTHDF2 with HO-1 mRNA, neuronal viability/apoptosis, and HO-1 m6A modification were evaluated. Spinal cord injury mice exhibited reduced BBB, elevated mNSS scores, disorganized spinal cord cells, scattered nuclei, and severe nucleus pyknosis. pcDNA3.1-FTO elevated FTO mRNA, protein expression, and BBB score; reduced the mNSS score of SCI mice; decreased neuronal apoptosis; improvedthe cell arrangement; and improved nucleus pyknosis in spinal cord tissues. OGD decreased FTO expression. FTO upregulation ameliorated OGD-induced neuronal apoptosis. pcDNA3.1-FTO reduced HO-1 mRNA and protein and HO-1 m6A modification, while increasing HO-1 mRNA stability and FTO in OGD-treated cells. FTO upregulated HO-1 by modulating m6A modification. HO-1 downregulation attenuated the effect of FTO. pcDNA3.1-FTO/Dac51 increased the HO-1 m6A level in mouse spinal cord tissue homogenate, reduced BBB, boosted mNSS scores of SCI mice, aggravated nucleus pyknosis, and increased neuronal apoptosis in spinal cord tissues, confirming that FTO mediated HO-1 m6A modification facilitated neurological recovery in SCI mice. The fat mass and obesity-related gene modulates HO-1 mRNA stability by regulating m6A modification levels, thereby influencing HO-1 expression and promoting neurological recovery in SCI mice.

Gamma-Aminobutyric Acid in Rice Bran Extract Exerts Antistress Effects in Mouse Models with Depressive-Like Behaviors.

Various neurotransmitters are involved in regulating stress systems. In this study, we investigated the effects of gamma-aminobutyric acid-rich rice bran extract (GRBe) in mice stressed by forced swimming and tail suspension tests. Four weeks of oral administration of GRBe (500-2000 mg/kg) reduced the levels of dopamine and corticosterone in the blood and brain while increasing serotonin levels. GRBe was involved not only in stress but also in regulating sleep and obesity-related genes. Modern society experiences diverse and tense lives because of urbanization and informatization, which cause excessive stress due to complicated interpersonal relationships, heavy work burden, and fatigue from the organized society. High levels of stress cause psychological instability and disrupt the balance in the autonomic nervous system, which maintains the body's equilibrium, resulting in cardiovascular and cerebrovascular diseases, hormonal imbalances, and sleep disorders. Therefore, our results suggest that GRBe is a useful substance that can relieve tension by ultimately influencing a depressive-like state by lowering the levels of neuronal substances, hormones, and cytokines involved in stress and sleep disorders.

Physiological Appetite Regulation and Bariatric Surgery.

Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can achieve limited weight loss. Bariatric surgery is an effective way of achieving substantial weight loss as well as glycemic control secondary to weight-related type 2 diabetes mellitus. It has been suggested that an anorexigenic gut hormone response following bariatric surgery contributes to weight loss. Understanding the changes in gut hormones and their contribution to weight loss physiology can lead to new therapeutic treatments for weight loss. Two distinct types of neurons in the arcuate hypothalamic nuclei control food intake: proopiomelanocortin neurons activated by the anorexigenic (satiety) hormones and neurons activated by the orexigenic peptides that release neuropeptide Y and agouti-related peptide (hunger centre). The arcuate nucleus of the hypothalamus integrates hormonal inputs from the gut and adipose tissue (the anorexigenic hormones cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin, and others) and orexigeneic peptides (ghrelin). Replicating the endocrine response to bariatric surgery through pharmacological mimicry holds promise for medical treatment. Obesity has genetic and environmental factors. New advances in genetic testing have identified both monogenic and polygenic obesity-related genes. Understanding the function of genes contributing to obesity will increase insights into the biology of obesity. This review includes the physiology of appetite control, the influence of genetics on obesity, and the changes that occur following bariatric surgery. This has the potential to lead to the development of more subtle, individualised, treatments for obesity.

Fat Mass and Obesity-Related (FTO) Gene Variant Is a Predictor of CVD in T2DM Patients.

Background: The role of the common FTO gene variant rs9939609 in obesity has been well established, and the FTO gene has a strong association with T2DM. Objective: To investigate the association of FTO gene variant rs9939609 with obesity-related parameters in T2DM and CVD patients. Materials and Methods: In this cross-sectional study, 280 subjects of either sex aged 45.10 ± 9.6 years were randomly divided into four groups, that is, T2DM, T2DM with CVD, nondiabetic with CVD disease, and normal control. These samples were genotyped by ARMS-PCR. The FTO gene association with obesity-related parameters in T2DM and CVD patients was analyzed by SPSS 22. Results: The TT genotype was the most common genotype (46.80%) in our study groups. The minor allele frequency (MAF) was significantly higher in T2DM patients (0.39 vs. 0.28), T2DM patients with CVD (0.43 vs. 0.28), and nondiabetic patients with CVD (0.35 vs. 0.28) as compared to control with p < 0.005. Carriers of the AA genotype of the FTO gene rs9939609 were significantly associated with increased BMI, WC, HbA1C, SBP, DBP, and TGs and lowered HDL cholesterol as compared to the TA and TT genotypes in T2DM and CVD patients with p < 0.005. The FTO gene variant rs9939609 showed a significant association with T2DM and CVD. The AA genotype odds ratio (OR) in T2DM was 1.48 (1.06-2.32), p = 0.006, and in CVD, it was 1.56 (1.04-2.4), p = 0.003. Conclusion: The FTO gene variant rs9939609 has a strong association with T2DM and CVD. The AA genotype of FTO gene variants rs9939609 showed a strong association with most of the risk factors of CVD and T2DM.

Targeted Nano-Based Systems for the Anti-Obesity Agent's Delivery.

Obesity is a global health concern and a chronic disease that is accompanied by excessive fat storage in adipose and nonadipose tissues. An increase in the body-mass index (BMI) is directly proportional to the 2- to 3.9-fold increase in all-cause mortality in obesity. If left untreated for a longer period, obesity-related metabolic, cardiovascular, inflammatory, and malignant diseases reduce life expectancy. Currently, most of the anti-obesity drugs have failed and fallen into disrepute, either due to their ineffectiveness or adverse effects. In this review, depending on their enhanced pharmacokinetic and biodistribution profiles, whether nanocarriers alter the basic properties and bioactivity of anti-obesity drugs used in clinical practice are debated. First, nanocarriers can improve the safety of still-used anti-obesity drugs by lowering their systemic toxicity through increasing targeting efficacy and preventing drug carrier toxicity. Second, when the micro-ribonucleic acids (miRNAs), which are aberrantly expressed in obesity and obesity-related diseases, are encapsulated into nanoparticles, they are effective in multiple obesity-related metabolic pathways and gene networks. Finally, a synergistic anti-obesity effect with low dose and low toxicity can be obtained with the combinatory therapy applied by encapsulating the anti-obesity drug and gene in the same nanocarrier delivery vehicle.

Central Channelopathies in Obesity.

As obesity has raised heightening awareness, researchers have attempted to identify potential targets that can be treated for therapeutic intervention. Focusing on the central nervous system (CNS), the key organ in maintaining energy balance, a plethora of ion channels that are expressed in the CNS have been inspected and determined through manipulation in different hypothalamic neural subpopulations for their roles in fine-tuning neuronal activity on energy state alterations, possibly acting as metabolic sensors. However, a remaining gap persists between human clinical investigations and mouse studies. Despite having delineated the pathways and mechanisms of how the mouse study-identified ion channels modulate energy homeostasis, only a few targets overlap with the obesity-related risk genes extracted from human genome-wide association studies. Here, we present the most recently discovered CNS-specific metabolism-correlated ion channels using reverse and forward genetics approaches in mice and humans, respectively, in the hope of illuminating the prospects for future therapeutic development.

From the reward network to whole-brain metrics: structural connectivity in adolescents and young adults according to body mass index and genetic risk of obesity.

Obesity is a multifactorial condition. Genetic variants, such as the fat mass and obesity related gene (FTO) polymorphism, may increase the vulnerability of developing obesity by disrupting dopamine signaling within the reward network. Yet, the association of obesity, genetic risk of obesity, and structural connectivity of the reward network in adolescents and young adults remains unexplored. We investigate, in adolescents and young adults, the structural connectivity differences in the reward network and at the whole-brain level according to body mass index (BMI) and the FTO rs9939609 polymorphism. One hundred thirty-two adolescents and young adults (age range: [10, 21] years, BMI z-score range: [-1.76, 2.69]) were included. Genetic risk of obesity was determined by the presence of the FTO A allele. Whole-brain and reward network structural connectivity were analyzed using graph metrics. Hierarchical linear regression was applied to test the association between BMI-z, genetic risk of obesity, and structural connectivity. Higher BMI-z was associated with higher (B = 0.76, 95% CI = [0.30, 1.21], P = 0.0015) and lower (B = -0.003, 95% CI = [-0.006, -0.00005], P = 0.048) connectivity strength for fractional anisotropy at the whole-brain level and of the reward network, respectively. The FTO polymorphism was not associated with structural connectivity nor with BMI-z. We provide evidence that, in healthy adolescents and young adults, higher BMI-z is associated with higher connectivity at the whole-brain level and lower connectivity of the reward network. We did not find the FTO polymorphism to correlate with structural connectivity. Future longitudinal studies with larger sample sizes are needed to assess how genetic determinants of obesity change brain structural connectivity and behavior.