Pathogenesis Of Obesity Research Articles

Elucidating macrophage scavenger receptor 1’s mechanistic contribution as a shared molecular mediator in obesity and thyroid cancer pathogenesis via bioinformatics analysis

IntroductionObesity is a disease characterized by the excessive accumulation of fat. Concurrently, thyroid carcinoma (THCA) stands as the foremost endocrine malignancy. Despite the observed escalation in concurrent prevalence of both conditions, the underlying interconnections remain elusive. This indicates the need to identify potential biomarkers to predict the pathways through which obesity and THCA coexist.MethodsThe study employed a variety of methods, including differential gene expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and gene enrichment analysis. It was also supplemented with immunohistochemical data from the Human Protein Atlas (HPA), advanced machine learning techniques, and related experiments such as qPCR, to identify important pathways and key genes shared between obesity and THCA.ResultsThrough differential gene expression analysis, WGCNA, and machine learning methods, we identified three biomarkers (IL6R, GZMB, and MSR1) associated with obesity. After validation analysis using THCA-related datasets and biological experiments, we selected Macrophage Scavenger Receptor 1 (MSR1) as a key gene for THCA analysis. The final analysis revealed that MSR1 is closely related to the degree of immune cell infiltration in patients with obesity and THCA, suggesting that this gene may be a potential intervention target for both obesity and THCA.DiscussionOur research indicates that MSR1 may influence the occurrence and development of obesity and THCA by regulating the infiltration level of immune cells. This lays the foundation for future research on targeted therapies based on their shared mechanisms.

Liver-expressed antimicrobial peptide 2 is a hepatokine regulated by ghrelin, nutrients, and body weight.

Liver-expressed antimicrobial peptide 2 (LEAP2) is a peptide that counteracts the hunger hormone ghrelin-induced functions. Recently, we showed that vertical sleeve gastrectomy (VSG) did not alter the serum LEAP2 concentration in individuals with obesity. Here, we investigated the effects of VSG in both chow diet (CD)-fed and high-fat diet (HFD)-fed mice. In CD-fed mice, VSG increased plasma LEAP2 levels and hepatic Leap2 mRNA levels while decreasing body weight, blood glucose levels, and ghrelin levels. Intraperitoneal (ip) administration of ghrelin reversed these changes. These effects were found in both male and female mice. In contrast, VSG or weight loss in HFD-induced obese mice decreased LEAP2 levels. After fasting, the plasma LEAP2 concentration was in the following order: hepatic vein > abdominal aorta > portal vein. A high glucose concentration robustly increased the plasma LEAP2 concentration in the hepatic vein and abdominal aorta but not in the portal vein. In addition, corn oil or palmitate increased LEAP2 expression and secretion. The increase in LEAP2 levels after the meal tolerance test was delayed in the human subjects with diabetes. Our data suggest that various factors (metabolic, hormonal, and nutritional) regulate LEAP2, and the liver is the predominant site for the production and secretion of LEAP2. Furthermore, the interaction between ghrelin and LEAP2 is involved in the pathogenesis of obesity and diabetes.

12611 The Thyroid Adapts Remarkably to Overnutrition to Mitigate Hypothyroidism

Abstract Disclosure: J. Rampy: None. A. Torres Manzo: None. K. Hoffsmith: None. M.A. Loberg: None. H. Wang: None. V.L. Weiss: None. N. Carrasco: None. Obesity affects >40% of the U.S. population and is one of today’s biggest public health concerns. Losing weight is challenging, and maintaining weight loss even more so, owing to the many biochemical and hormonal changes that occur in the pathogenesis of obesity, some of which do not reverse after weight loss. Thyroid hormones (THs) have far-reaching effects on whole-body energy balance. Their synthesis and release by the thyroid are finely regulated by central mechanisms to control serum TH levels. THs are also regulated by nutrient sensing, so that their levels modulate energy expenditure to match energy intake. Given the reciprocal and fine-tuned relationship between THs and energy balance, one would expect strong upregulation of TH levels to counteract diet-induced weight gain, but this is not consistently reported in obesity studies. Thus, we hypothesized that overnutrition impairs thyroid function, preventing a sustained increase in TH levels. We tested this hypothesis in male C57Bl/6J mice fed a high-fat diet and sucrose water. Strikingly, overnutrition decreased T4 levels after just 5 days—and within 3 weeks, we observed mild hypothyroidism, with increased thyroid stimulating hormone (TSH) levels and goiter. After 6 weeks, intrathyroidal T4 levels were significantly decreased, whereas the expression of the TH precursor thyroglobulin (TG) was unchanged, despite high TSH stimulation. Furthermore, we found increased expression of several ER stress-related proteins, including BiP, p-eIF2α, and PDI. These results suggest that TG was not upregulated because overnutrition-induced ER stress impaired protein translation. Remarkably, even though T4 levels were low, the thyroid maintained normal T3 levels, likely due to the pronounced histological and vascular changes we observed, which should promote TH availability. Some changes were consistent with the classical growth effects of TSH stimulation, while others were likely due to upregulation of adrenomedullin 2, a TSH-responsive angiogenic vasodilator. Preliminary studies in female mice showed similar results. Notably, we have observed similar histological changes in human thyroids, which strongly correlate with BMI. Collectively, our results, despite the unchanged T3 levels, are consistent with a struggling thyroid and a mildly hypothyroid state. Existing data suggest that low T4 can itself be problematic, particularly in metabolic tissues that generate T3, the more biologically active form, from T4 to levels beyond those of the T3 available from the bloodstream. Reversibility of this state is being investigated in ongoing experiments. The causal role that overnutrition plays in thyroid impairment and decreased TH availability in the pathogenesis of obesity has scarcely begun to be elucidated. Our work sheds new light on how overnutrition changes thyroid function and highlights the remarkable adaptability of the thyroid. Presentation: 6/1/2024

12380 Point Of Care Microscale Magnetic Resonance (µNMR) Effectively Monitors Mitigation Of Oxidative Stress By GLP-1 Treatment In A Preclinical Model Of Diabetic Nephropathy

Abstract Disclosure: A.T. Alves: ; co-founder. ; LarmorBio. S.S. Thamarath: ; co-founder. ; LarmorBio. S. Fjordside: Employee; Self; Novo Nordisk. S. Sassower, MS.EE: ; Co-founder. ; LarmorBio. R. Rohr: ; co-founder,CEO. ; LarmorBio. A.P. Chambers: Employee; Self; Novo Nordisk. Oxidative stress is a major driver in the pathogenesis of diabetes, obesity, and related (cardio-renal) disorders. Early detection and prevention of an oxidative stress overload can improve and potentially modify the long-term harmful outcomes associated with chronic hyperglycaemia. A novel assay was developed, that uses µNMR technology to directly monitor oxidative stress from 5 µL of plasma at the point of collection in less than 10 minutes. This assay is highly sensitive to redox changes in the blood microenvironment, including increased ferric iron (Fe3+), protein oxidation and lipid peroxidation. Here, we show the oxidative stress profiling of three groups of ZSF1 rats in a twelve week (11th -23rd week of age) observational study. Vehicle lean, vehicle obese, and glucagon-like-peptide-1 (GLP-1) treated obese ZSF1 rats (n = 8/group) were studied with the assay along with conventional diabetic/metabolic markers, blood glucose (BG), HbA1c, Albumin Creatinine Ratio (ACR). The kidney (immuno)histology studies, alpha-smooth muscle actin (aSMA) and leucocyte common antigen (CD45) were performed at the termination phase of the ZSF1 rats (23rd week of age). The results demonstrated that the assay distinguished obese rats from lean rats with statistical significance (P ≤ 0.01) independent of other in-life diabetic/metabolic markers. Significant correlations with urinary Albumin Creatinine Ratio (ACR, ρ = 0.64, P ≤ 0.0001) were established throughout the study. A positive quantitative association is highlighted with classic histological end points of organ damage, kidney fibrogenesis (aSMA, ρ = 0.23), and inflammation (CD45, ρ = 0.45). Moreover, the assay detected significantly reduced oxidative stress levels (e.g., P ≤ 0.01) in the GLP-1 drug treatment group at five weeks of follow-up. In summary, the µNMR assay effectively monitored oxidative stress and captured disease-modifying therapeutics. Presentation: 6/1/2024

Regulation of leptin signaling and diet-induced obesity by SEL1L-HRD1 ER-associated degradation in POMC expressing neurons

Endoplasmic reticulum (ER) homeostasis in the hypothalamus has been implicated in the pathogenesis of diet-induced obesity (DIO) and type 2 diabetes; however, the underlying molecular mechanism remain vague and debatable. Here we report that SEL1L-HRD1 protein complex of the highly conserved ER-associated protein degradation (ERAD) machinery in POMC-expressing neurons ameliorates diet-induced obesity and its associated complications, partly by regulating the turnover of the long isoform of Leptin receptors (LepRb). Loss of SEL1L in POMC-expressing neurons attenuates leptin signaling and predisposes mice to HFD-associated pathologies including fatty liver, glucose intolerance, insulin and leptin resistance. Mechanistically, nascent LepRb, both wildtype and disease-associated Cys604Ser variant, are misfolding prone and bona fide substrates of SEL1L-HRD1 ERAD. In the absence of SEL1L-HRD1 ERAD, LepRb are largely retained in the ER, in an ER stress-independent manner. This study uncovers an important role of SEL1L-HRD1 ERAD in the pathogenesis of central leptin resistance and leptin signaling.

Phytoactives for Obesity Management: Integrating Nanomedicine for Its Effective Delivery.

Obesity is a global health concern that requires urgent investigation and management. While synthetic anti-obesity medications are available, they come with a high risk of side-effects and variability in their efficacy. Therefore, natural compounds are increasingly being used to treat obesity worldwide. The proposition that naturally occurring compounds, mainly polyphenols, can be effective and safer for obesity management through food and nutrient fortification is strongly supported by extensive experimental research. This review focuses on the pathogenesis of obesity while reviewing the efficacy of an array of phytoactives used for obesity treatment. It details mechanisms such as enzyme inhibition, energy expenditure, appetite suppression, adipocyte differentiation, lipid metabolism, and modulation of gut microbiota. Comprehensive in vitro, in vivo, and preclinical studies underscore the promise of phytoactives in combating obesity, which have been thoroughly reviewed. However, challenges, such as poor bioavailability and metabolism, limit their potential. Advances in nanomedicines may overcome these constraints, offering a new avenue for enhancing the efficacy of phytoactives. Nonetheless, rigorous and targeted clinical trials are essential before applying phytoactives as a primary treatment for obesity.

The octagon of opportunities in obesity.

The Ominous Octet is a popular construct, which has been used to describe the aetiopathology of diabetes, as well as the endocrine causation of obesity. We utilize this model to create a smart and salutogenic rubric of obesity pathogenesis. Our optimistic Octagon of Opportunities lists eight causative or contributory factors, all of which are associated with the development of obesity. The model gives equal weightage to the biomedical and psychosocial arms of the biopsychosocial model of health. The framework encourages a proactive and comprehensive approach to the prevention and management of obesity.

Circadian gene signatures in the progression of obesity based on machine learning and Mendelian randomization analysis.

Obesity, a global health concern, is associated with a spectrum of chronic diseases and cancers. Our research sheds light on the regulatory role of circadian genes in obesity progression, providing insight into the immune landscape of obese patients, and introducing new avenues for therapeutic interventions. Expression files of multiple datasets were retrieved from the GEO database. By 80 machine-learning algorithm combinations and Mendelian randomization analysis, we discovered the key circadian genes contributing to and protecting against obesity. Subsequently, an immune infiltration analysis was conducted to examine the alterations in immune cell types and their abundance in the body and to investigate the relationships between circadian genes and immune cells. Furthermore, we delved into the molecular mechanisms of key genes implicated in obesity. Our study identified three key circadian genes (BHLHE40, PPP1CB, and CSNK1E) associated with obesity. BHLHE40 was found to promote obesity through various pathways, while PPP1CB and CSNK1E counteracted lipid metabolism disorders, and modulated cytokines, immune receptors, T cells, and monocytes. In conclusion, the key circadian genes (BHLHE40, CSNK1E, and PPP1CB) may serve as novel biomarkers for understanding obesity pathogenesis and have significant correlations with infiltrating immune cells, thus providing potential new targets for obese prevention and treatment.

Changes in serum ghrelin and resistin levels after sleeve gastrectomy versus one anastomosis gastric bypass: prospective cohort study.

Humoral factors and neural mechanisms play a central role in the pathogenesis of obesity and in weight loss following bariatric surgery. Although various hormones and adipokines, including ghrelin and resistin, are linked to obesity, studies analyzing the changes in fasting ghrelin and resistin levels in patients following one anastomosis gastric bypass (OAGB) are lacking. The authors aimed to investigate resistin and ghrelin levels before and after two commonly used bariatric procedures with different mechanisms of action: sleeve gastrectomy (SG) and OAGB. Fasting serum ghrelin and resistin levels were evaluated by using ELISA in a nonrandomized, prospective cohort study for the pattern of changes in the preoperative period and 1 week, 1 month, 3 months and, 12 months after surgery in age and sex-matched patients with BMI ≥40kg/m 2 undergoing either SG ( n =40) or OAGB ( n =40). Their relationships with demographic parameters such as body weight, BMI, presence of T2DM, HbA 1 C, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index were also evaluated. OAGB was superior in weight control compared to the SG group. There were significant differences in resistin and ghrelin levels between the OAGB and SG groups. Ghrelin decreased more in the SG group than the preoperative values. This change in ghrelin levels was more significant at 1 year after SG [preoperative mean (range) level of 334.2 (36.6-972.1) pg/ml decreased to 84 (9.1-227) pg/ml at 1 year] whereas in the OAGB group no significant change was observed [preoperative mean (range) level of 310 (146-548) pg/ml decreased to 264 (112-418) pg/ml at 1 year]. Resistin levels decreased in both groups, especially after 3 months and onward following both operations [the mean (range) resistin levels were 2.6 (0.87-5.4) ng/ml and decreased to 1.1 (0.5-2.4) ng/ml in the SG group vs 2.48 (0.89-6.43) ng/ml decreased to 0.72 (0.35-1.8) ng/ml in OAGB group at 1 year], which was in parallel with changes in HOMA-IR index, body weight, and BMI changes at 1st year. HOMA-IR index changes were similar, but more prominent after OAGB. OAGB was als3 three months and onward), and HOMA-IR changes. This is the first study to compare fasting ghrelin and resistin levels after OAGB and SG. Although similar changes were observed, ghrelin changes were more prominent after SG, whereas resistin were observed after OAGB. OAGB was superior in T2DM control, which was in parallel with weight loss, fasting resistin levels, and HOMA-IR changes suggesting a possible effect of resistin after OAGB in glucose metabolism and insulin resistance.

Overview of Natural Supplements for the Management of Diabetes and Obesity.

Bioactive compounds found in various natural sources, such as fruits, vegetables, and herbs, have been studied for their potential benefits in managing obesity and diabetes. These compounds include polyphenols, flavonoids, other antioxidants, fiber, and certain fatty acids. Studies have found that these compounds may improve insulin sensitivity, regulate blood sugar levels, and promote weight loss. However, the effects of these compounds can vary depending on the type and amount consumed, as well as individual factors, such as genetics and lifestyle. Nutraceutical substances have multifaceted therapeutic advantages, and they have been reported to have disease-prevention and health-promoting properties. Several clinically used nutraceuticals have been shown to target the pathogenesis of diabetes mellitus, obesity, and metabolic syndrome and their complications and modulate various clinical outcomes favorably. This review aims to highlight and comment on some of the most prominent natural components used as antidiabetics and in managing obesity.

Fine-Scale Haplotype Mapping Reveals an Association of the FTO Gene with Osteoporosis and Fracture Risk in Postmenopausal Women.

The Fat Mass and Obesity-Associated (FTO) gene encodes a demethylase, which modulates RNA N6-methyladenosine (m6A) and plays a regulatory role in adipocyte differentiation and the pathogenesis of human obesity. To understand the potential role of FTO in osteoporosis (OP), we investigated five single nucleotide variations (SNVs) in intron 1 (rs8057044, rs8050136, rs9939609, rs62033406, and rs9930506) of the FTO gene, and a missense SNV i.e., rs3736228 (A1330V), located in exon 18 of the LRP5 gene, in a cohort of postmenopausal women (n = 188) from Central Europe. Genotyping was performed with an allele discrimination assay, while haplotypes were reconstructed in the population by PHASE 2.1. The rs9930506 was strongly associated with OP (p < 0.0035), which was supported by Bonferroni correction (p < 0.0175), and all SNVs located in the FTO gene were more strongly associated with severe OP with fragility fractures. Among seventeen haplotypes detected for the FTO gene, two haplotypes (H1 and H9) were frequent (frequency > 10%) and distributed in three main haplotypes pairs (H1/H1, H1/H9 and H9/H9, respectively). The pathogenic pair H1/H9 was associated with a leaner phenotype, increased fracture risk, and a lower bone mineral density (BMD), and carried the heterozygous GA of rs9930506, while the protective pair H9/H9 was associated with an increased obesity risk and carried AA alleles of rs9939609. Concordant associations with OP, an increased fracture risk, and a lower BMD at all skeletal sites indicate that the FTO gene is a promising candidate for OP, explaining the complex relationship with obesity and offering new perspectives for the study of the epigenetic regulation of bone metabolism.

Exploration of the Human Microbiome’s Role in Health and Disease through the Lens of Genetics

The human microbiome is a complex ecosystem of bacteria residing in the body. It plays a crucial role in safeguarding the overall well-being of individuals while also making them more vulnerable to various diseases. The human microbiota, genetics, and health have a complex connection, which is significant for maintaining health and preventing infections. The microbiome has a role in several gastrointestinal, skin, dental, and systemic diseases, such as obesity, diabetes, and autoimmune disorders. Genetic variation and lifestyle and dietary choices modify the microbiome composition, thereby influencing the risk of developing severe infections. The microbiome impacts host gene expression and acts as a biomarker for several diseases. The gut microbiome and genes are linked in the pathogenesis of obesity and inflammatory bowel disease. Therefore, this review focuses on the relationship between the microbiome and genetics and elucidation of the complexity of this connection. Future research-based microbiome interventions to prevent diseases could lead to strategies for personalized medicine that enhance treatment efficacy and health outcomes.

The Role of Inflammatory Mediators in the Pathogenesis of Obesity.

Obesity is a pandemic of the 21st century, and the prevalence of this metabolic condition has enormously increased over the past few decades. Obesity is associated with a number of comorbidities and complications, such as diabetes and cardiovascular disorders, which can be associated with severe and fatal outcomes. Adipose tissue is an endocrine organ that secretes numerous molecules and proteins that are capable of modifying immune responses. The progression of obesity is associated with adipose tissue dysfunction, which is characterised by enhanced inflammation and apoptosis. Increased fat-tissue mass is associated with the dysregulated secretion of substances by adipocytes, which leads to metabolic alterations. Importantly, the adipose tissue contains immune cells, the profile of which changes with the progression of obesity. For instance, increasing fat mass enhances the presence of the pro-inflammatory variants of macrophages, major sources of tumour necrosis factor α and other inflammatory mediators that promote insulin resistance. The pathogenesis of obesity is complex, and understanding the pathophysiological mechanisms that are involved may provide novel treatment methods that could prevent the development of serious complications. The aim of this review is to discuss current evidence describing the involvement of various inflammatory mediators in the pathogenesis of obesity.

On the pathogenesis of obesity: causal models and missing pieces of the puzzle.

Application of the physical laws of energy and mass conservation at the whole-body level is not necessarily informative about causal mechanisms of weight gain and the development of obesity. The energy balance model (EBM) and the carbohydrate-insulin model (CIM) are two plausible theories, among several others, attempting to explain why obesity develops within an overall common physiological framework of regulation of human energy metabolism. These models have been used to explain the pathogenesis of obesity in individuals as well as the dramatic increases in the prevalence of obesity worldwide over the past half century. Here, we summarize outcomes of a recent workshop in Copenhagen that brought together obesity experts from around the world to discuss causal models of obesity pathogenesis. These discussions helped to operationally define commonly used terms; delineate the structure of each model, particularly focussing on areas of overlap and divergence; challenge ideas about the importance of purported causal factors for weight gain; and brainstorm on the key scientific questions that need to be answered. We hope that more experimental research in nutrition and other related fields, and more testing of the models and their predictions will pave the way and provide more answers about the pathogenesis of obesity than those currently available.

The Role of Fecal Microbiota Transplantation (FMT) in the Management of Metabolic Diseases in Humans: A Narrative Review.

The gut microbiota represents a complex ecosystem of trillions of microorganisms residing in the human gastrointestinal tract, which is known to interact with the host physiology and regulate multiple functions. Alterations in gut microbial composition, diversity, and function are referred to as dysbiosis. Dysbiosis has been associated with a variety of chronic diseases, including Clostridioides difficile infections, but also cardiometabolic diseases, including obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). The implication of gut microbiota dysbiosis in the pathogenesis of both obesity and T2DM has paved the way to implementing novel therapeutic approaches for metabolic diseases through gut microbial reconfiguration. These interventions include probiotics, prebiotics, and synbiotics, while a more innovative approach has been fecal microbiota transplantation (FMT). FMT is a procedure that delivers healthy human donor stool to another individual through the gastrointestinal tract, aiming to restore gut microbiota balance. Several studies have investigated this approach as a potential tool to mitigate the adverse metabolic effects of gut microbiota aberrations associated with obesity and T2DM. The aim of the present review was to critically summarize the existing evidence regarding the clinical applications of FMT in the management of obesity and T2DM and provide an update on the potential of this method to remodel the entire host microbiota, leading thus to weight loss and sustained metabolic benefits. Safety issues, long-term efficacy, limitations, and pitfalls associated with FMT studies are further discussed, emphasizing the need for further research and standardization in certain methodological aspects in order to optimize metabolic outcomes.

The role of gut microbiota in the obesity: a literature review

Introduction: Obesity is a multifactorial and polygenic condition that, according to the World Obesity Federation, will affect over 1 billion people by 2030. In this regard, research is being conducted regarding gut microbiota influence on the pathogenesis of this disease, such as inflammation and insulin resistance. Therefore, understanding the gut microbiota and the mechanism by which its modulation through diet and/or the use of probiotics can impact the host and contribute to the treatment of obesity is essential. Methods: A systematic review was conducted on the PubMed, Scielo, and ScienceDirect databases, following the PRISMA protocol, from January 2018 to September 2022. Results and Conclusion: 415 articles were found. 36 studies were evaluated, and 20 were included in this review. The use of calorierestricting diets, along with the consumption of grains and cereals, was found to be useful in reducing strains that promote inflammation and insulin resistance, factors that are associated with obesity pathogenesis, leading to weight reduction. Other studies examined probiotics use, which led to lipopolysaccharides and insulin resistance reduction, as well as a decrease in the quantity of pro-inflammatory cytokines associated with obesity and type 2 diabetes mellitus. Therefore, combining diets with probiotic therapies may be a strategy for microbiota modulation, aiming to reduce inflammatory markers and insulin resistance.

The independent association between 25 (OH) vitamin D deficiency, HOMA-IR, and lipid profile with APOE genotyping in obese cases with and without T2DM

IntroductionVitamin D deficiency, insulin resistance, dyslipidemia, and APOE genotyping are implicated in the pathogenesis of obesity and type 2 diabetes mellitus (T2DM). We wanted to find out if there was a link between a lack of 25(OH) vitamin D, HOMA-IR, and lipids and APOE genotyping in obese people with and without T2DM.MethodsWe divided 300 Egyptians of both sexes into three groups in a case-control study: 100 obese cases with a body mass index of more than 30, 100 obese cases diagnosed with T2DM, and 100 controls with a body mass index of less than 30. Levels of 25 (OH) vitamin D, fasting blood sugar (FBS), HbA1C, fasting insulin, HOMA-IR, and lipid profile parameters were measured, and APOE genotypes were assessed using Applied BiosystemsTM TaqMan® SNP Genotyping Assays.ResultsHigher levels of FBS, fasting insulin, HOMA-IR, and dyslipidemia were found in obese people with and without T2DM compared to the control group (p < 0.05). Lower levels of 25(OH) vitamin D were also found. Insulin resistance and lipid profile parameters, particularly in obese cases with T2DM, inversely correlate with vitamin D deficiency. The APOE genotyping analysis revealed strong links between vitamin D levels and certain APOE genotypes. Independent of metabolic parameters, higher vitamin D levels were associated with lower odds of E3/E4 and E4/E4 genotypes among obese cases with T2DM.ConclusionThis study highlights the independent role of vitamin D deficiency in modulating APOE genotypes in obese T2DM individuals. The findings suggest potential implications for personalized interventions targeting vitamin D status to mitigate genetic predispositions to metabolic disorders such as obesity and T2DM.

3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity.

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the BDNF, ADCY3, TMEM18 and FTO loci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene, ALKAL2 - an inflammation-responsive gene in nerve nociceptors - was observed at the key TMEM18 locus across multiple immune cell types. Interestingly, this observation was also supported through colocalization analysis using expression quantitative trait loci (eQTL) derived from the Genotype-Tissue Expression (GTEx) dataset, supporting an inflammatory and neurologic component to the pathogenesis of childhood obesity. Our comprehensive appraisal of 3D genomic datasets generated in a myriad of different cell types provides genomic insights into pediatric obesity pathogenesis.

Metaboepigenetic regulation of gene expression in obesity and insulin resistance.

Variation in DNA methylation (DNAm) in adipose tissue is associated with the pathogenesis of obesity and insulin resistance. The activity of enzymes involved in altering DNAm levels is dependent on several metabolite cofactors. To understand the role of metabolites as mechanistic regulators of epigenetic marks, we tested the association between selected plasma metabolites and DNAm levels in the adipose tissue of African Americans. In the AAGMEx cohort (N = 256), plasma levels of metabolites were measured by untargeted liquid chromatography-mass spectrometry; adipose tissue DNAm and transcript levels were measured by reduced representation bisulfite sequencing, and expression microarray, respectively. Among the 21 one-carbon metabolism pathway metabolites evaluated, six were associated with gluco-metabolic traits (PFDR < 0.05, for BMI, SI, or Matsuda index) in AAGMEx. Methylation levels of 196, 116, and 180 CpG-sites were associated (P < 0.0001) with S-adenosylhomocysteine (SAH), cystine, and hypotaurine, respectively. Cis-expression quantitative trait methylation (cis eQTM) analyses suggested the role of metabolite-level-associated CpG sites in regulating the expression of adipose tissue transcripts, including genes in G-protein coupled receptor signaling pathway. Plasma SAH level-associated CpG sites chr19:3403712 and chr19:3403735 were also associated with the expression of G-protein subunit alpha 15 (GNA15) in adipose. The expression of GNA15 was significantly correlated with BMI (β = 1.87, P = 1.9 × 10-16) and SI (β = -1.61, P = 2.49 × 10-5). Our study suggests that a subset of metabolites modulates the methylation levels of CpG sites in specific loci and, in turn, regulates the expression of transcripts involved in obesity and insulin resistance.

Investigation of Trace Element Levels and Toxic Metals in Obese Children: A Single-Center Experienc.

The complete role of factors contributing to the pathogenesis of childhood obesity remains to be fully elucidated. Limited research has addressed trace elements in the context of child obesity. Our objective was to assess trace element and lead (Pb), copper (Cu) (are toxic metal) levels in both healthy and obese children, and to investigate the potential correlations between these elements and obesity-related anthropometric measurements, lipid profiles, as well as insulin and glucose levels. Furnace atomic absorption spectrophotometry was employed to measure the concentrations of trace elements in the serum. Additionally, fasting glucose, insulin, and lipid levels were determined in obese children (body mass index ≥ 95th percentile for age and sex), along with 50 healthy children. Only the obesity group underwent an oral glucose tolerance test (OGTT). Significantly reduced levels of Fe, Mg, Zn, and Co were observed in obese children, whereas Cu, Pb, and Mn levels were elevated (P < .001, P <.001, P = .002, P = .008, P <.001, P = .001, P = .007, respectively). Significant positive correlations were found between the 2-hour glucose level in OGTT and Mn (P = .013), as well as between peak insulin and insulin levels at the 30th and 60th minutes, and Fe (P = .001, P = .025, P = .001). This study indicates that an imbalance in trace element levels and the accumulation of Pb may be associated with obesity, while levels of Mn and Fe may be linked to glucose intolerance.