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 lowgrade 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.
Overweight children and childhood obesity are a public health problem in Mexico. Obesity is traditionally assessed using body mass index (BMI), but an excess of adiposity does not necessarily reflect a high BMI. Thus, body composition indexes are a better alternative. Our objective was to generate body composition percentile curves in children from Mexico City. A total of 2026 boys and 1488 girls aged 6 to 12 years old were studied in Mexico City. Body weight, height, and BMI calculation were measured. Total body fat percentage (TBFP) was derived from the skinfold thicknesses, and fat mass (FMI) and free fat mass indexes (FFMI) were calculated. Finally, age- and gender-specifıc smoothed percentile curves were generated with Cole’s Lambda, Mu, and Sigma (LMS) method. In general, height, weight, waist circumference (WC), and TBFP were higher in boys, but FFM was higher in girls. TBFP appeared to increase significantly between ages 8 and 9 in boys (+2.9%) and between ages 10 and 11 in girls (+1.2%). In contrast, FFM% decreased noticeably between ages 8 and 9 until 12 years old in boys and girls. FMI values peaked in boys at age 12 (P97 = 14.1 kg/m2) and in girls at age 11 (P97 = 8.8 kg/m2). FFMI percentiles increase at a steady state reaching a peak at age 12 in boys and girls. Smoothed body composition percentiles showed a different pattern in boys and girls. The use of TBFP, FMI, and FFMI along with BMI provides valuable information in epidemiological, nutritional, and clinical research.
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.
Obesity remains as a global epidemic characterized by progressive metabolic dysregulation in glucose homeostasis. Along with a genetic association in the development of T2D, epigenetic regulation has been suggested as a significant contributor in altered gene expression. Recent studies have described DNA methylation changes in insulin-sensitive tissues involved in T2D pathogenesis, however epigenetic dynamics on early stages to metabolic alterations is still unclear. We investigated potential DNA methylation signatures in 34 asymptomatic individuals from the GEMM family study. We compared differentially methylated CpG sites (DMC: B value>0 and delta Beta >|10%|; Infinium EPIC array) from subcutaneous adipose tissue (SCAT) in different groups of individuals according to BMI (kg/m2) and HbA1c (%) levels as follow: Group A Control (C): n=9, 22.0±1.9 kg/m2, 4.8±0.3%; Group B Overweight (OW) with normal HbA1c: n=6, 27.8±1.6 kg/m2, 5±0.2%; Group C Obese (OB) with normal HbA1c: n=6, 34.6±4.2 kg/m2, 5.2±0.2%; Group D Prediabetes (PD): n=7, 31.1±5.7 kg/m2, 5.9±0.2% and Group E T2D: n=6, 30.6±7.3 kg/m2, 7.2±0.9%. We found 43 overlapping genes with shared pathways in all groups, mainly those related to metabolism and adipogenesis. We also documented particular altered methylated genes, in each group (OW: 386, OB:1005, PD:76 and T2D:189). Pathway enrichment analysis in OB and T2D was mainly related to glucose metabolism, while in OW and PD was NOTCH signaling. All groups displayed a consistent hypermethylation in RARA, ESR1 and NCOR2, well known genes involved in lipid metabolism. Additionally, we describe for the first time, a progression toward hypomethylation in ARHGAP15 and MTAP, related with an impaired metabolic status. Otherwise, analysis of overlapping CpG sites revealed a consistently hypermethylated state in OW (86.42%), OB (86.48%) and PD (51.72%), in contrast with the hypomethylation state (56.3%) observed in the T2D group, previously observed elsewhere (1). In conclusion, comparison of methylation in SCAT obtained from OW, OB, PD and T2D individuals, display potential pathways and DMC signatures specific in each group. Common novel overlapping genes in global DNA methylation profiles of SCAT, were also observed. Reference: (1) Barajas-Olmos et al., BMC Med Genet. 2018 Feb 21;19(1):1-8. Nothing to Disclose: FE, FB, AM, EH, GEMM, ER, RB, LO.
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