Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders.

Cardiovascular disease (CVD) and type 2 diabetes (T2D) are increasing worldwide. This is mainly due to an unhealthy nutrition, implying that variation in CVD risk may be due to variation in the capacity to manage a nutritional load. We examined the genomic basis of postprandial metabolism. Our main purpose was to introduce the GEMM Family Study (Genetics of Metabolic Diseases in Mexico) as a multi-center study carrying out an ongoing recruitment of healthy urban adults. Each participant received a mixed meal challenge and provided a 5-hours’ time course series of blood, buffy coat specimens for DNA isolation, and adipose tissue (ADT)/skeletal muscle (SKM) biopsies at fasting and 3 h after the meal. A comprehensive profiling, including metabolomic signatures in blood and transcriptomic and proteomic profiling in SKM and ADT, was performed to describe tendencies for variation in postprandial response. Our data generation methods showed preliminary trends indicating that by characterizing the dynamic properties of biomarkers with metabolic activity and analyzing multi-OMICS data it could be possible, with this methodology and research design, to identify early trends for molecular biology systems and genes involved in the fasted and fed states.

In Mexico, 3 of 10 children are overweight. Fructose intake and relative abundance (RA) of Lactobacillus reuteri (L. reuteri) in the intestinal microbiota are associated with obesity and diabetes in adults, but studies in children are limited. This study evaluates the association between fructose intake and L. reuteri RA with adiposity and cardiometabolic risk markers in Mexican children dietary information, microbiota profiles, adiposity indicators (Body Mass Index, BMI and Waste Circumference, WC), and cardiometabolic markers were analyzed in 1087 children aged 6–12 years. Linear regression and path analysis models were used. High-tertile fructose intake and L. reuteri RA were positively associated with BMI (β_{Tertil 3 vs. Tertil 1} = 0.24 (95% CI, 0.04; 0.44) and β_{T3 vs. T1} = 0.52 (95% CI, 0.32; 0.72)) and WC (β_{T3 vs. T1} = 2.40 (95% CI, 0.93; 3.83) and β_{T3 vs. T1} = 3.40 (95% CI, 1.95; 4.90)), respectively. Also, these factors mediated by adiposity were positively correlated with high triglycerides and insulin concentrations and HOMA-IR (p ≤ 0.03) and negatively associated with HDL-C concentration (p < 0.01). High-tertile fructose intake and L. reuteri RA were directly associated with adiposity and indirectly associated though adiposity with metabolic disorders in children. In conclusion, fructose intake and L. reuteri RA were directly associated with adiposity and indirectly associated with metabolic disorders in children, mediated by adiposity.

We previously reported preliminary characterization of adipose tissue (AT) dysfunction through the adiponectin/leptin ratio (ALR) and fasting/postprandial (F/P) gene expression in subcutaneous (SQ) adipose tissue (AT) biopsies obtained from participants in the GEMM study, a precision medicine research project. Here we present integrative data replication of previous findings from an increased number of GEMM symptom-free (SF) adults (N = 124) to improve characterization of early biomarkers for cardiovascular (CV)/immunometabolic risk in SF adults with AT dysfunction. We achieved this goal by taking advantage of the rich set of GEMM F/P 5 h time course data and three tissue samples collected at the same time and frequency on each adult participant (F/P blood, biopsies of SQAT and skeletal muscle (SKM)). We classified them with the presence/absence of AT dysfunction: low (1) ALR. We also examined the presence of metabolically healthy (MH)/unhealthy (MUH) individuals through low-grade chronic subclinical inflammation (high sensitivity C-reactive protein (hsCRP)), whole body insulin sensitivity (Matsuda Index) and Metabolic Syndrome criteria in people with/without AT dysfunction. Molecular data directly measured from three tissues in a subset of participants allowed fine-scale multi-OMIC profiling of individual postprandial responses (RNA-seq in SKM and SQAT, miRNA from plasma exosomes and shotgun lipidomics in blood). Dynamic postprandial immunometabolic molecular endophenotypes were obtained to move towards a personalized, patient-defined medicine. This study offers an example of integrative translational research, which applies bench-to-bedside research to clinical medicine. Our F/P study design has the potential to characterize CV/immunometabolic early risk detection in support of precision medicine and discovery in SF individuals.

Cardiometabolic phenotypes such as obesity and impaired insulin action are key determinants of type 2 diabetes (T2D). Growing evidence highlights the postprandial state as a critical window in metabolic regulation, where epigenetic mechanisms, particularly DNA methylation in insulin-sensitive tissues, may play pivotal roles. However, their dynamics across prandial states in subcutaneous adipose tissue (SAT) remain unclear. We analyzed genome-wide DNA methylation in paired fasting and postprandial SAT biopsies from 29 asymptomatic, drug-naïve individuals classified as controls (n = 8), prediabetes n = 9), or T2D (n = 12). Postprandial samples followed a standardized mixed-meal test. DNA methylation was quantified using the Illumina MethylationEPIC array and analyzed through the Chip Analysis Methylation Pipeline (ChAMP) pipeline. Differential methylation was more pronounced postprandially, especially in the T2D group. After adjusting for age and sex, 4599 differentially methylated CpG sites (DMCs) were identified, with increased hypermethylation in T2D. A total of 130 DMCs across 99 genes, including LCLAT1, HLA-C, ZNF714, and HOOK2, were shared by prediabetes and T2D groups. Over-representation analysis revealed 202 enriched pathways related to insulin resistance, AMPK signaling, and immune responses. Additionally, 110 Differentially Methylated Regions (DMRs), including ZNF577 and AGPAT1, were detected. These findings reveal early, prandial-dependent epigenetic alterations in SAT that precede overt dysglycemia, offering insights into personalized prevention in T2D.