METS-IR and all-cause mortality in Korean over 60 years old: Korean genome and epidemiology study-health examinees (KoGES-HEXA) cohorts.

Background: The metabolic score for insulin resistance index (METS-IR) is a novel non insulin-based marker that indicates the risk for metabolic syndrome and type 2 diabetes mellitus (T2DM). However, METS-IR has not been investigated in relation to all-cause mortality. We investigated the longitudinal effect of METS-IR on all-cause mortality in a significantly large cohort of Korean adults over 60 years old. Methods: Data were assessed from 30,164 Korean participants over 60 years of age from the Korean Genome and Epidemiology Study-Health Examinees (KoGES-HEXA) cohort data, linked with the death certificate database of the National Statistical Office. The participants were grouped into three according to METS-IR tertiles. We used multivariate Cox proportional-hazard regression models to prospectively assess hazard ratios (HRs) for all-cause mortality with 95% confidence intervals (CIs) over an 11-year postbaseline period. Results: During the mean 11.7 years of follow-up, 2,821 individuals expired. The HRs of mortality for METS-IR tertiles were 1.16 (95% CI, 1.01-1.34) in T3 after adjustment for metabolic parameters, but the T2 did not show statistical significance towards increases for incident mortality respectively. In subgroup analysis depending on the cause of mortality, higher METS-IR was associated with cancer mortality (HR, 1.23, 95% CI, 1.01-1.51) but not with cardiovascular mortality (HR, 1.14, 95% CI, 0.83-1.57) after adjustment for the same confounding variables. Conclusion: The METS-IR may be a useful predictive marker for all-cause mortality and cancer mortality, but not for cardiovascular mortality in subjects over 60 years of age. This implies that early detection and intervention strategies for metabolic syndrome could potentially benefit this identified group.

Exploring the bidirectional relationship between metabolic syndrome and thyroid autoimmunity: a Mendelian randomization study.

Background: Observational studies have reported a possible association between metabolic syndrome (MetS) and thyroid autoimmunity. Nevertheless, the relationship between thyroid autoimmunity and MetS remains unclear. The objective of this research was to assess the causal impact of MetS on thyroid autoimmunity through the utilization of Mendelian randomization (MR) methodology. Methods: We performed bidirectional MR to elucidate the causal relationship between MetS and their components and thyroid autoimmunity (positivity of TPOAb). Single nucleotide polymorphisms (SNPs) of MetS and its components were obtained from the publicly available genetic variation summary database. The Thyroidomics Consortium conducted a genome-wide association analysis, which provided summary-level data pertaining to thyroid autoimmunity. The study included several statistical methods, including the inverse variance weighting method (IVW), weighted median, simple mode, weight mode, and MR-Egger methods, to assess the causal link. In addition, to ensure the stability of the results, a sensitivity analysis was conducted. Results: IVW showed that MetS reduced the risk of developing thyroid autoimmunity (OR = 0.717, 95% CI = 0.584 - 0.88, P = 1.48E-03). The investigation into the causative association between components of MetS and thyroid autoimmune revealed a statistically significant link between triglycerides levels and the presence of thyroid autoimmunity (IVW analysis, OR = 0.603, 95%CI = 0.45 -0.807, P = 6.82E-04). The reverse analysis did not reveal any causal relationship between thyroid autoimmunity and MetS, including its five components. Conclusions: We have presented new genetic evidence demonstrating that MetS and its triglyceride components may serve as potential protective factors against thyroid autoimmunity.

Transgenic human C-reactive protein affects oxidative stress but not inflammation biomarkers in the aorta of spontaneously hypertensive rats.

BACKGROUND: C-reactive protein (CRP) is an acute inflammatory protein detected in obese patients with metabolic syndrome. Moreover, increased CRP levels have been linked with atherosclerotic disease, congestive heart failure, and ischemic heart disease, suggesting that it is not only a biomarker but also plays an active role in the pathophysiology of cardiovascular diseases. Since endothelial dysfunction plays an essential role in various cardiovascular pathologies and is characterized by increased expression of cell adhesion molecules and inflammatory markers, we aimed to detect specific markers of endothelial dysfunction, inflammation, and oxidative stress in spontaneously hypertensive rats (SHR) expressing human CRP. This model is genetically predisposed to the development of the metabolic syndrome. METHODS: Transgenic SHR male rats (SHR-CRP) and non-transgenic SHR (SHR) at the age of 8 months were used. Metabolic profile (including serum and tissue triglyceride (TAG), serum insulin concentrations, insulin-stimulated incorporation of glucose, and serum non-esterified fatty acids (NEFA) levels) was measured. In addition, human serum CRP, MCP-1 (monocyte chemoattractant protein-1), and adiponectin were evaluated by means of ELISA, histological analysis was used to study morphological changes in the aorta, and western blot analysis of aortic tissue was performed to detect expression of endothelial, inflammatory, and oxidative stress markers. RESULTS: The presence of human CRP was associated with significantly decreased insulin-stimulated glycogenesis in skeletal muscle, increased muscle and hepatic accumulation of TAG and decreased plasmatic cGMP concentrations, reduced adiponectin levels, and increased monocyte chemoattractant protein-1 (MCP-1) levels in the blood, suggesting pro-inflammatory and presence of multiple features of metabolic syndrome in SHR-CRP animals. Histological analysis of aortic sections did not reveal any visible morphological changes in animals from both SHR and SHR-CRP rats. Western blot analysis of the expression of proteins related to the proper function of endothelium demonstrated significant differences in the expression of p-eNOS/eNOS in the aorta, although endoglin (ENG) protein expression remained unaffected. In addition, the presence of human CRP in SHR in this study did not affect the expression of inflammatory markers, namely p-NFkB, P-selectin, and COX2 in the aorta. On the other hand, biomarkers related to oxidative stress, such as HO-1 and SOD3, were significantly changed, indicating the induction of oxidative stress. CONCLUSIONS: Our findings demonstrate that CRP alone cannot fully induce the expression of endothelial dysfunction biomarkers, suggesting other risk factors of cardiovascular disorders are necessary to be involved to induce endothelial dysfunction with CRP.

The advent of RNA-based therapeutics for metabolic syndrome and associated conditions: a comprehensive review of the literature.

Metabolic syndrome (MetS) is a prevalent and intricate health condition affecting a significant global population, characterized by a cluster of metabolic and hormonal disorders disrupting lipid and glucose metabolism pathways. Clinical manifestations encompass obesity, dyslipidemia, insulin resistance, and hypertension, contributing to heightened risks of diabetes and cardiovascular diseases. Existing medications often fall short in addressing the syndrome's multifaceted nature, leading to suboptimal treatment outcomes and potential long-term health risks. This scenario underscores the pressing need for innovative therapeutic approaches in MetS management. RNA-based treatments, employing small interfering RNAs (siRNAs), microRNAs (miRNAs), and antisense oligonucleotides (ASOs), emerge as promising strategies to target underlying biological abnormalities. However, a summary of research available on the role of RNA-based therapeutics in MetS and related co-morbidities is limited. Murine models and human studies have been separately interrogated to determine whether there have been recent advancements in RNA-based therapeutics to offer a comprehensive understanding of treatment available for MetS. In a narrative fashion, we searched for relevant articles pertaining to MetS co-morbidities such as cardiovascular disease, fatty liver disease, dementia, colorectal cancer, and endocrine abnormalities. We emphasize the urgency of exploring novel therapeutic avenues to address the intricate pathophysiology of MetS and underscore the potential of RNA-based treatments, coupled with advanced delivery systems, as a transformative approach for achieving more comprehensive and efficacious outcomes in MetS patients.

Identification of additional body weight QTLs in the Berlin Fat Mouse BFMI861 lines using time series data.

The Berlin Fat Mouse Inbred line (BFMI) is a model for obesity and metabolic syndrome. The sublines BFMI861-S1 and BFMI861-S2 differ in weight despite high genetic similarity and a shared obesity-related locus. This study focused on identifying additional body weight quantitative trait loci (QTLs) by analyzing weekly weight measurements in a male population of the advanced intercross line BFMI861-S1 x BFMI861-S2. QTL analysis, utilizing 200 selectively genotyped mice (GigaMUGA) and 197 males genotyped for top SNPs, revealed a genome-wide significant QTL on Chr 15 (68.46 to 81.40 Mb) for body weight between weeks 9 to 20. Notably, this QTL disappeared (weeks 21 to 23) and reappeared (weeks 24 and 25) coinciding with a diet change. Additionally, a significant body weight QTL on Chr 16 (3.89 to 22.79 Mb) was identified from weeks 6 to 25. Candidate genes, including Gpt, Cbx6, Apol6, Apol8, Sun2 (Chr 15) and Trap1, Rrn3, Mapk1 (Chr 16), were prioritized. This study unveiled two additional body weight QTLs, one of which is novel and responsive to diet changes. These findings illuminate genomic regions influencing weight in BFMI and emphasize the utility of time series data in uncovering novel genetic factors.

Correlation of Plasma and Salivary Osteocalcin Levels with Nascent Metabolic Syndrome Components with and Without Pre/Diabetes Biochemical Parameters / Correlación de los niveles de osteocalcina en plasma y saliva con los componentes del síndrome metabólico naciente con y sin parámetros bioquímicos de prediabetes

Objectives: This study aimed to compare and correlate plasma and salivary levels of cardiometabolic risk biomarkers’ of pharmacotherapy (appraised using colorimetric assays), adiposity, and atherogenicity indices. Methods: 61 Nascent MetS subjects vs. 30 lean normoglycemic and healthy controls were recruited in Family Medicine outpatient clinics/Jordan University Hospital (a referral medical center). Fasting blood and saliva specimens were collected. Clinical and anthropometric variables were determined along with atherogenecity and adiposity indices. Results: Among nascent MetS (metabolic syndrome) recruits, almost half were normoglycemic, 43% were prediabetic and 8% were diabetic. Pronouncedly Glycemic (FPG and Alc) and lipid parameters (TG, HDL-C and non-HDL-C), adiposity indices (BMI, WHR, WtHR, Conicity-index, BAI, LAP, VAI) and atherogenicity indices (AIP, TC/HDL-C, LDL-C/HDL-C, non-HDL-C/HDL-C and TG/HDL-C) were higher in the nascent MetS group (P<0.05 vs. controls). Markedly among the plasma cardiometabolic risk biomarkers (P<0.05 vs. controls) in the nascent MetS group, adipolin, cathepsin S, ghrelin, irisin, LBP, leptin, and osteocalcin were higher but plasma FGF1 levels were oddly lower. Significantly (P<0.05 vs. controls) nascent MetS –linked salivary levels of adipolin and LBP were higher as opposed to the lower cathepsin S. Only osteocalcin, amongst 9 metabolic risk biomarkers studied, had remarkably significant correlation between plasma and saliva levels, in both total sample and MetS patients (P<0.05). Markedly in the nascent MetS only group, both plasma and salivary osteocalcin correlated with FPG and A1c (P<0.05); salivary osteocalcin correlated with BMI and LAP (P<0.05). Likewise, in the total sample plasma osteocalcin correlated significantly with BMI, BAI, WHt R, SBP, DBP, TG, LAP, VAI, TG/HDL-C and AIP (P<0.05), while salivary osteocalcin had substantial correlations only with FPG and A1c (P<0.05). Conclusion: Association of nascent MetS-related plasma and salivary osteocalcin levels and clinical characteristics and indices propagate salivary osteocalcin as a non-invasive marker for clinical control of MetS-/preDM.(AU)

Peripheral artery disease mediating the effect of metabolic syndrome related diseases on lower limb ulcers: Mendelian randomization analysis.

Background: Previous observational studies have demonstrated a correlation between metabolic syndrome related diseases and an elevated susceptibility to ulcers of lower limb. It has been suggested that this causal relationship may be influenced by the presence of peripheral artery disease (PAD). Nevertheless, the precise contribution of these factors as determinants of ulcers of lower limb remains largely unexplored. Method: This research incorporated information on hypertension, BMI, hyperuricemia, type 2 diabetes, PAD, and ulcers of lower limb sourced from the GWAS database. Univariate Mendelian randomization (SVMR) and multivariate Mendelian randomization (MVMR) methods were employed to assess the association between metabolic syndrome related diseases, including hypertension, obesity, hyperuricemia, and type 2 diabetes, as well as to investigate whether this association was influenced by PAD. Results: Univariate Mendelian randomization analysis showed that genetically predicted hypertension, BMI, and type 2 diabetes were associated with an increased risk of PAD and ulcers of lower limb, and PAD was associated with an increased risk of ulcers of lower limb, but there is no causal relationship between hyperuricemia and ulcers of lower limb. The results of multivariate Mendelian randomization showed that PAD mediated the causal relationship between hypertension, obesity and ulcers of lower limb, but the relationship between type 2 diabetes and ulcers of lower limb was not mediated by PAD. Conclusion: Hypertension, BMI and type 2 diabetes can increase the risk of ulcers of lower limb, and PAD can be used as a mediator of hypertension and obesity leading to ulcers of lower limb, These findings may inform prevention and intervention strategies directed toward metabolic syndrome and ulcers of lower limb.

Metabolic syndrome risk in adult coffee drinkers with the rs301 variant of the LPL gene.

BACKGROUND: Metabolic syndrome (MetS), a cluster of metabolic and cardiovascular risk factors is influenced by environmental, lifestyle, and genetic factors. We explored whether coffee consumption and the rs301 variant of the lipoprotein lipase (LPL) gene are related to MetS. METHODS: We conducted multiple logistic regression analyses using data gathered from 9523 subjects in Taiwan Biobank (TWB). RESULTS: Our findings indicated that individuals who consumed coffee had a reduced odds ratio (OR) for MetS (0.750 (95% confidence interval [CI] 0.653-0.861) compared to non-coffee drinkers. Additionally, the risk of MetS was lower for individuals with the 'TC' and 'CC' genotypes of rs301 compared to those with the 'TT' genotype. Specifically, the OR for MetS was 0.827 (95% CI 0.721-0.949) for the 'TC' genotype and 0.848 (95% CI 0.610-1.177) for the 'CC' genotype. We observed an interaction between coffee consumption and the rs301 variant, with a p-value for the interaction of 0.0437. Compared to the reference group ('no coffee drinking/TT'), the ORs for MetS were 0.836 (95% CI 0.706-0.992) for 'coffee drinking/TT', 0.557 (95% CI 0.438-0.707) for 'coffee drinking/TC', and 0.544 (95% CI 0.319-0.927) for 'coffee drinking/CC'. Notably, MetS was not observed in non-coffee drinkers regardless of their rs301 genotype. CONCLUSION: Our findings suggest that rs301 genotypes may protect against MetS in Taiwanese adults who consume coffee compared to non-coffee drinkers.

Osteocalcin protects islet identity in low-density lipoprotein receptor knockout mice on high-fat diet.

Metabolic syndrome (MetS) is an increasing global health threat and strong risk factor for type 2 diabetes (T2D). MetS causes both hyperinsulinemia and islet size overexpansion, and pancreatic ß-cell failure impacts insulin and proinsulin secretion, mitochondrial density, and cellular identity loss. The low-density lipoprotein receptor knockout (LDLr-/-) model combined with high-fat diet (HFD) has been used to study alterations in multiple organs, but little is known about the changes to ß-cell identity resulting from MetS. Osteocalcin (OC), an insulin-sensitizing protein secreted by bone, shows promising impact on ß-cell identity and function. LDLr-/- mice at 12 months were fed chow or HFD for 3 months ± 4.5 ng/h OC. Islets were examined by immunofluorescence for alterations in nuclear Nkx6.1 and PDX1 presence, insulin-glucagon colocalization, islet size and %ß-cell and islet area by insulin and synaptophysin, and mitochondria fluorescence intensity by Tomm20. Bone mineral density (BMD) and %fat changes were examined by Piximus Dexa scanning. HFD-fed mice showed fasting hyperglycemia by 15 months, increased weight gain, %fat, and fasting serum insulin and proinsulin; concurrent OC treatment mitigated weight increase and showed lower proinsulin-to-insulin ratio, and higher BMD. HFD increased %ß and %islet area, while simultaneous OC-treatment with HFD was comparable to chow-fed mice. Significant reductions in nuclear PDX1 and Nkx6.1 expression, increased insulin-glucagon colocalization, and reduction in ß-cell mitochondria fluorescence intensity were noted with HFD, but largely prevented with OC administration. OC supplementation here suggests a benefit to ß-cell identity in LDLr-/- mice and offers intriguing clinical implications for countering metabolic syndrome.

Microglial Ffar4 deficiency promotes cognitive impairment in the context of metabolic syndrome.

Metabolic syndrome (MetS) is closely associated with an increased risk of dementia and cognitive impairment, and a complex interaction of genetic and environmental dietary factors may be implicated. Free fatty acid receptor 4 (Ffar4) may bridge the genetic and dietary aspects of MetS development. However, the role of Ffar4 in MetS-related cognitive dysfunction is unclear. In this study, we found that Ffar4 expression is down-regulated in MetS mice and MetS patients with cognitive impairment. Conventional and microglial conditional knockout of Ffar4 exacerbated high-fat diet (HFD)-induced cognitive dysfunction and anxiety, whereas microglial Ffar4 overexpression improved HFD-induced cognitive dysfunction and anxiety. Mechanistically, we found that microglial Ffar4 regulated microglial activation through type I interferon signaling. Microglial depletion and NF-κB inhibition partially reversed cognitive dysfunction and anxiety in microglia-specific Ffar4 knockout MetS mice. Together, these findings uncover a previously unappreciated role of Ffar4 in negatively regulating the NF-κB-IFN-ß signaling and provide an attractive therapeutic target for delaying MetS-associated cognitive decline.

Dietary Insulin Index (DII) and Dietary Insulin load (DIL) and Caveolin gene variant interaction on cardiometabolic risk factors among overweight and obese women: a cross-sectional study.

BACKGROUND AND OBJECTIVE: Studies have shown that Caveolin gene polymorphisms (CAV-1) are involved in chronic diseases, such as metabolic syndrome. Moreover, the dietary insulin index (DII) and dietary insulin load (DIL) have been shown to potentially elicit favorable effects on cardiovascular disease (CVD) risk. Therefore, this study sought to investigate the effect of DII DIL and CAV-1 interaction on CVD risk factors. METHODS: This cross-sectional study consisted of 333 overweight and obese women aged 18-48 years. Dietary intakes, DII, and DIL were evaluated using the 147-item food frequency questionnaire (FFQ). Serum profiles were measured by standard protocols. The CAV-1 rs 3,807,992 and anthropometric data were measured by the PCR-RFLP method and bioelectrical impedance analysis (BIA), respectively. Participants were also divided into three groups based on DII, DIL score, and rs3807992 genotype. RESULTS: This comparative cross-sectional study was conducted on 333 women classified as overweight or obese. Participants with A allele for the caveolin genotype and higher DII score showed significant interactions with high-density lipoprotein (HDL) (P for AA = 0.006 and P for AG = 0.019) and CRI-I (P for AA < 0.001 and P for AG = 0.024). In participants with AA genotype and greater DII score, interactions were observed in weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, CRI-II, fat-free mass (FFM), and skeletal muscle mass (SMM) (P < 0.079). Those with higher DIL scores and AA genotype had higher weight (P = 0.033), FFM (P = 0.022), and SMM (P = 0.024). In addition, DIL interactions for waist/hip ratio (WHR), waist circumference (WC), triglyceride (TG), CRI-I, and body fat mass (BFM) among individuals with AA genotype, while an HDL interaction was observed in individuals with AG and AA (P < 0.066). CONCLUSION: The findings of the present study indicate that people who carry the caveolin rs3807992 (A) allele and have greater DII and DIL scores are at higher risk for several cardiovascular disease and metabolic syndrome biomarkers. These results highlight that diet, gene variants, and their interaction, should be considered in the risk evaluation of developing CVD.

Metabolic syndrome, its components, and gastrointestinal cancer risk: a meta-analysis of 31 prospective cohorts and Mendelian randomization study.

BACKGROUND AND AIM: Cohort studies have linked metabolic syndrome (MetS) to gastrointestinal (GI) cancer risk. We aimed to evaluate the associations between MetS, its components, and combinations of MetS components with eight GI cancers risk. METHODS: We conducted a systematic search of prospective cohort studies and performed a meta-analysis. Subgroup analyses regarding diagnostic criteria, sex, cancer sites, histological subtypes, ethnic groups, and studies adjusted for alcohol consumption were carried out. Mendelian randomization (MR) was employed to evaluate the causality between 17 MetS-related traits and eight GI cancers among Europeans and Asians separately. RESULTS: Meta-analyses of 31 prospective studies indicated that MetS was significantly associated with an increased risk of colorectal cancer (CRC) (RR [95% CI] = 1.13 [1.12-1.15]), esophageal cancer (EC) (RR [95% CI] = 1.17 [1.03-1.32]), gallbladder cancer (GBC) (RR [95% CI] = 1.37[1.10-1.71]), liver cancer (LC) (RR [95% CI] = 1.46 [1.29-1.64]), and pancreatic cancer (PaC) (RR [95% CI] = 1.25 [1.20-1.30]), but not gastric cancer (GC) (RR [95% CI] = 1.11 [0.96-1.28]). Regarding the associations between MetS components and GI cancers risk, the following associations showed statistical significance: obesity-CRC/LC/EC/, hypertriglyceridemia-LC/PaC, reduced high-density lipoprotein (HDL)-CRC/LC/GC/PaC, hyperglycemia-CRC/LC/PaC, and hypertension-CRC/LC/EC/PaC. Sex-specific associations were observed between individual MetS components on GI cancers risk. Among the top three common combinations in both sexes, obesity + HTN + hyperglycemia had the strongest association with CRC risk (RR [95% CI] = 1.54 [1.49-1.61] for males and 1.27 [1.21-1.33] for females). MR analyses revealed causality in 16 exposure-outcome pairs: waist-to-hip ratio/BMI/HbA1c-CRC; BMI/childhood obesity/waist circumference/T2DM/glucose-EC; BMI/waist circumference/cholesterol-LC; cholesterol/childhood obesity/waist circumference/HbA1c-PaC; and HbA1c-GBC. These results were robust against sensitivity analyses. CONCLUSIONS: Since MetS is reversible, lifestyle changes or medical interventions targeting MetS patients might be potential prevention strategies for GI cancers.

Association Between Clonal Hematopoiesis Driver Mutations, Immune Cell Function, and the Vasculometabolic Complications of Obesity.

BACKGROUND: Obesity is accompanied by dysregulated inflammation, which can contribute to vasculometabolic complications including metabolic syndrome and atherosclerosis. Recently, clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for cardiovascular diseases. We aimed to determine how CHIP is related to immune cell function, systemic inflammation, and vasculometabolic complications in obese individuals. METHODS AND RESULTS: Two hundred ninety-seven individuals with overweight and obesity, between the ages of 54 and 81 years, were recruited in a cross-sectional study. Clonal hematopoiesis driver mutations (CHDMs) were identified with an ultrasensitive targeted assay. Assessment of carotid artery atherosclerosis was performed with ultrasound. Detailed immunological parameters, including cytokine production capacity of peripheral blood mononuclear cells, and targeted plasma proteomics analysis, were studied. Adipose tissue inflammation was determined in subcutaneous fat biopsies. Individuals with CHIP had higher concentrations of circulating IL (interleukin)-6. Total number of leukocytes and neutrophils were higher in individuals with CHIP. In contrast, ex vivo cytokine production capacity of peripheral blood mononuclear cells was significantly lower in individuals with CHIP. Sex-stratified analysis showed that men with CHDMs had significantly higher leukocyte and neutrophil counts, and ex vivo cytokine production capacity was lower in women with CHDMs. Surprisingly, the presence of atherosclerotic plaques was significantly lower in individuals with CHDMs. There was no relation between CHIP and metabolic syndrome. CONCLUSIONS: In individuals with overweight or obesity, CHDMs are not associated with vasculometabolic complications, but rather with a lower presence of carotid plaques. CHDMs associate with increased circulating inflammatory markers and leukocyte numbers, but a lower peripheral blood mononuclear cell cytokine production capacity.

Genetic evidence for the causal relations between metabolic syndrome and psychiatric disorders: a Mendelian randomization study.

Emerging evidence reveals associations between metabolic syndrome (MetS) and psychiatric disorders (PDs), although causality remains uncertain. Consequently, we conducted Mendelian randomization (MR) to systematically evaluate the causality between MetS and PDs. Linkage disequilibrium score regression estimated the heritability of PDs and their genetic correlations with MetS. In primary analyses, the main model employed inverse variance weighting method, with sensitivity analyses using various MR models to ensure robustness. Replication MR analyses, involving cohorts distinct from those in the primary analyses, were performed to validate the generalizability of the findings. Multivariable MR analyses were carried out to account for genetically predicted body mass index (BMI). As a result, genetic correlations of MetS with attention-deficit/hyperactivity disorder(ADHD), anorexia nervosa(ANO), major depressive disorder(MDD), and schizophrenia were identified. Causal effects of MetS on ADHD (OR: 1.59 [95% CI:1.45-1.74]), ANO (OR: 1.42 [95% CI:1.25-1.61]), MDD(OR: 1.23 [95% CI: 1.13-1.33]), and the effects of ADHD (OR: 1.03 [95% CI: 1.02-1.04]) and ANO (OR: 1.01 [95% CI: 1.01-1.02]) on MetS were observed in primary analyses. Results from sensitivity analyses and replication analyses were generally consistent with the primary analyses, confirming the robustness and generalizability of the findings. Associations between MetS and ADHD, as well as ANO persisted after adjusting for BMI, whereas the statistical significance of the association between MetS and MDD was no longer observable. These results contribute to a deeper understanding of the mechanisms underlying PDs, suggesting potential modifiable targets for public prevention and clinical intervention in specific PDs related to metabolic pathways.

Genetic variations in IKZF3, LET7-a2, and CDKN2B-AS1: Exploring associations with metabolic syndrome susceptibility and clinical manifestations.

BACKGROUND AND AIM: Metabolic syndrome (MetS) increases the risk of atherosclerosis and diabetes, but there are no approved predictive markers. This study assessed the role of specific genetic variations in MetS susceptibility and their impact on clinical manifestations. METHOD: In this study, a genotype-phenotype assessment was performed for IKZF3 (rs907091), microRNA-let-7a-2 (rs1143770), and lncRNA-CDKN2B-AS1 (rs1333045). RESULTS: Analyses indicate that while rs907091 and rs1143770 may have potential associations with MetS susceptibility and an increased risk of atherosclerosis and diabetes, there is an observed trend suggesting that the rs1333045 CC genotype may be associated with a decreased risk of MetS. The genotypes and allele frequencies of rs1333045 were significantly different between studied groups (OR = 0.56, 95% CI 0.38-0.81, p = 0.002, and OR = 0.71, 95% CI 0.55-0.92, p = 0.008), with the CC genotype displaying increased levels of HDL. Furthermore, the rs907091 TT genotype was associated with increased triglyceride, cholesterol, and HOMA index in MetS patients. Subjects with the CC genotype for rs1143770 had higher HbA1c and BMI. In silico analyses illustrated that rs907091 C remarkably influences the secondary structure and the target site of a broad spectrum of microRNAs, especially hsa-miR-4497. Moreover, rs1333045 creates a binding site for seven different microRNAs. CONCLUSION: Further studies on other populations may help confirm these SNPs as useful predictive markers in assessing the MetS risk.

Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis.

Metabolic syndrome combines major risk factors for cardiovascular disease, making deeper insight into its pathogenesis important. We here explore the mechanistic basis of metabolic syndrome by recruiting an essential patient cohort and performing extensive gene expression profiling. The mitochondrial fatty acid metabolism enzyme acyl-CoA synthetase medium-chain family member 3 (ACSM3) was identified to be significantly lower expressed in the peripheral blood of metabolic syndrome patients. In line, hepatic ACSM3 expression was decreased in mice with metabolic syndrome. Furthermore, Acsm3 knockout mice showed glucose and lipid metabolic abnormalities, and hepatic accumulation of the ACSM3 fatty acid substrate lauric acid. Acsm3 depletion markedly decreased mitochondrial function and stimulated signaling via the p38 MAPK pathway cascade. Consistently, Acsm3 knockout mouse exhibited abnormal mitochondrial morphology, decreased ATP contents, and enhanced ROS levels in their livers. Mechanistically, Acsm3 deficiency, and lauric acid accumulation activated nuclear receptor Hnf4α-p38 MAPK signaling. In line, the p38 inhibitor Adezmapimod effectively rescued the Acsm3 depletion phenotype. Together, these findings show that disease-associated loss of ACSM3 facilitates mitochondrial dysfunction via a lauric acid-HNF4a-p38 MAPK axis, suggesting a novel therapeutic vulnerability in systemic metabolic dysfunction.

PINK1 dominated mitochondria associated genes signature predicts abdominal aortic aneurysm with metabolic syndrome.

Abdominal aortic aneurysm (AAA) is typically asymptomatic but a devastating cardiovascular disorder, with overall mortality exceeding 80 % once it ruptures. Some patients with AAA may also have comorbid metabolic syndrome (MS), suggesting a potential common underlying pathogenesis. Mitochondrial dysfunction has been reported as a key factor contributing to the deterioration of both AAA and MS. However, the intricate interplay between metabolism and mitochondrial function, both contributing to the development of AAA, has not been thoroughly explored. In this study, we identified candidate genes related to mitochondrial function in AAA and MS. Subsequently, we developed a nomoscore model comprising hub genes (PINK1, ACSL1, CYP27A1, and SLC25A11), identified through the application of two machine learning algorithms, to predict AAA. We observed a marked disparity in immune infiltration profiles between high- and low-nomoscore groups. Furthermore, we confirmed a significant upregulation of the expression of the four hub genes in AAA tissues. Among these, ACSL1 showed relatively higher expression in LPS-treated RAW264.7 cell lines, while CYP27A1 exhibited a notable decrease. Moreover, SLC25A11 displayed a significant upregulation in AngII-treated VSMCs. Conversely, the expression level of PINK1 declined in LPS-stimulated RAW264.7 cell lines but significantly increased in AngII-treated VSMCs. In vivo experiments revealed that the activation of PINK1-mediated mitophagy inhibited the development of AAA in mice. In this current study, we have innovatively identified four mitochondrial function-related genes through integrated bioinformatic analysis. This discovery sheds light on the regulatory mechanisms and unveils promising therapeutic targets for the comorbidity of AAA and MS.

Risk of incident chronic kidney disease in metabolically healthy obesity and metabolically unhealthy normal weight: A systematic review and meta-analysis.

Studies have reported inconsistent results about the risk of incident chronic kidney disease (CKD) in people with metabolically healthy obesity (MHO). We designed this systematic review and meta-analysis to evaluate the risk of developing CKD in people with MHO and metabolically unhealthy normal weight (MUNW). We used a predefined search strategy to retrieve eligible studies from multiple databases up to June 20, 2022. Random-effects model meta-analyses were implied to estimate the overall hazard ratio (HR) of incident CKD in obesity phenotypes. Eight prospective cohort studies, including approximately 5 million participants with a median follow-up ranging between 3 and 14 years, were included in this meta-analysis. Compared to the metabolically healthy normal weight (MHNW), the mean differences in cardiometabolic and renal risk factors in MHO, MUNW, and metabolically unhealthy obesity (MUO) were evaluated with overall HR of 1.42, 1.49, and 1.84, respectively. Compared to MHNW, the mean estimated glomerular filtration rate (eGFR) and high-density lipoprotein (HDL) were significantly lower, and low-density lipoprotein (LDL), blood pressure, blood glucose, and triglycerides were higher in MHO and MUNW. In conclusion, MHO and MUNW are not benign conditions and pose a higher risk for incident CKD. Obesity, whether in the presence or absence of metabolic health, is a risk factor for CKD.

A cross-ancestry genome-wide meta-analysis, fine-mapping, and gene prioritization approach to characterize the genetic architecture of adiponectin.

Previous genome-wide association studies (GWASs) for adiponectin, a complex trait linked to type 2 diabetes and obesity, identified >20 associated loci. However, most loci were identified in populations of European ancestry, and many of the target genes underlying the associations remain unknown. We conducted a cross-ancestry adiponectin GWAS meta-analysis in ≤46,434 individuals from the Metabolic Syndrome in Men (METSIM) cohort and the ADIPOGen and AGEN consortiums. We combined study-specific association summary statistics using a fixed-effects, inverse variance-weighted approach. We identified 22 loci associated with adiponectin (p < 5×10-8), including 15 known and seven previously unreported loci. Among individuals of European ancestry, Genome-wide Complex Traits Analysis joint conditional analysis (GCTA-COJO) identified 14 additional distinct signals at the ADIPOQ, CDH13, HCAR1, and ZNF664 loci. Leveraging the cross-ancestry data, FINEMAP + SuSiE identified 45 causal variants (PP > 0.9), which also exhibited potential pleiotropy for cardiometabolic traits. To prioritize target genes at associated loci, we propose a combinatorial likelihood scoring formalism (Gene Priority Score [GPScore]) based on measures derived from 11 gene prioritization strategies and the physical distance to the transcription start site. With GPScore, we prioritize the 30 most probable target genes underlying the adiponectin-associated variants in the cross-ancestry analysis, including well-known causal genes (e.g., ADIPOQ, CDH13) and additional genes (e.g., CSF1, RGS17). Functional association networks revealed complex interactions of prioritized genes, their functionally connected genes, and their underlying pathways centered around insulin and adiponectin signaling, indicating an essential role in regulating energy balance in the body, inflammation, coagulation, fibrinolysis, insulin resistance, and diabetes. Overall, our analyses identify and characterize adiponectin association signals and inform experimental interrogation of target genes for adiponectin.