Project description:Molecular mechanisms associated with pathophysiological variations in adipose tissue (AT) are not fully recognized. The main aim of this study was to identify novel candidate genes and miRNAs that may contribute to the pathophysiology of hyperplastic AT. Therefore, wide gene and microRNA (miRNA) expression patterns were assessed in subcutaneous AT of 16 morbidly obese women before and after surgery-induced weight loss. Validation of microarray data was performed by quantitative real-time PCR both longitudinally (n=25 paired samples) and cross-sectionally (25 obese vs. 26 age-matched lean women). Analyses in macrophages and differentiated human adipocytes were also performed to try to comprehend the associations found in AT. 5,018 different probe sets identified significant variations in gene expression after treatment (adjusted p-value<0.05). A set of 16 miRNAs also showed significant modifications. Functional analysis revealed changes in genes and miRNAs associated with cell cycle, development and proliferation, lipid metabolism, and the inflammatory response. Canonical affected pathways included TREM1, PI3K, and EIF2 signaling, hepatic stellate cell activation, and mitochondrial function. Increased expression of SLC27A2, ELOVL6, FASN, GYS2, LGALS12, PKP2, ACLY, and miR-575, as well as decreased FOS, EGFL6, PRG4, AQP9, DUSP1, RGS1, EGR1, SPP1, LYZ, miR-130b, miR-221, and miR-155, were further validated. The clustering of similar expression patterns for gene products with related functions revealed molecular footprints, some of them described for the first time, which elucidate changes in biological processes after the surgery-induced weight loss.
Project description:Molecular mechanisms associated with pathophysiological variations in adipose tissue (AT) are not fully recognized. The main aim of this study was to identify novel candidate genes and miRNAs that may contribute to the pathophysiology of hyperplastic AT. Therefore, wide gene and microRNA (miRNA) expression patterns were assessed in subcutaneous AT of 16 morbidly obese women before and after surgery-induced weight loss. Validation of microarray data was performed by quantitative real-time PCR both longitudinally (n=25 paired samples) and cross-sectionally (25 obese vs. 26 age-matched lean women). Analyses in macrophages and differentiated human adipocytes were also performed to try to comprehend the associations found in AT. 5,018 different probe sets identified significant variations in gene expression after treatment (adjusted p-value<0.05). A set of 16 miRNAs also showed significant modifications. Functional analysis revealed changes in genes and miRNAs associated with cell cycle, development and proliferation, lipid metabolism, and the inflammatory response. Canonical affected pathways included TREM1, PI3K, and EIF2 signaling, hepatic stellate cell activation, and mitochondrial function. Increased expression of SLC27A2, ELOVL6, FASN, GYS2, LGALS12, PKP2, ACLY, and miR-575, as well as decreased FOS, EGFL6, PRG4, AQP9, DUSP1, RGS1, EGR1, SPP1, LYZ, miR-130b, miR-221, and miR-155, were further validated. The clustering of similar expression patterns for gene products with related functions revealed molecular footprints, some of them described for the first time, which elucidate changes in biological processes after the surgery-induced weight loss.
Project description:ContextMitochondria are essential for cellular energy homeostasis, yet their role in subcutaneous adipose tissue (SAT) during different types of weight-loss interventions remains unknown.ObjectiveTo investigate how SAT mitochondria change following diet-induced and bariatric surgery-induced weight-loss interventions in 4 independent weight-loss studies.MethodsThe DiOGenes study is a European multicenter dietary intervention with an 8-week low caloric diet (LCD; 800 kcal/d; n = 261) and 6-month weight-maintenance (n = 121) period. The Kuopio Obesity Surgery study (KOBS) is a Roux-en-Y gastric bypass (RYGB) surgery study (n = 172) with a 1-year follow-up. We associated weight-loss percentage with global and 2210 mitochondria-related RNA transcripts in linear regression analysis adjusted for age and sex. We repeated these analyses in 2 studies. The Finnish CRYO study has a 6-week LCD (800-1000 kcal/d; n = 19) and a 10.5-month follow-up. The Swedish DEOSH study is a RYGB surgery study with a 2-year (n = 49) and 5-year (n = 37) follow-up.ResultsDiet-induced weight loss led to a significant transcriptional downregulation of oxidative phosphorylation (DiOGenes; ingenuity pathway analysis [IPA] z-scores: -8.7 following LCD, -4.4 following weight maintenance; CRYO: IPA z-score: -5.6, all P < 0.001), while upregulation followed surgery-induced weight loss (KOBS: IPA z-score: 1.8, P < 0.001; in DEOSH: IPA z-scores: 4.0 following 2 years, 0.0 following 5 years). We confirmed an upregulated oxidative phosphorylation at the proteomics level following surgery (IPA z-score: 3.2, P < 0.001).ConclusionsDifferentially regulated SAT mitochondria-related gene expressions suggest qualitative alterations between weight-loss interventions, providing insights into the potential molecular mechanistic targets for weight-loss success.
Project description:Bariatric surgery (BS) is the most effective treatment for obesity and has a positive impact on cardiometabolic risk and in the remission of type 2 diabetes. Following BS, the majority of fat mass is lost from the subcutaneous adipose tissue depot (SAT). However, the changes in this depot and functions and as well as its relative contribution to the beneficial effects of this surgery are still controversial. With the aim of studying altered proteins and molecular pathways in abdominal SAT (aSAT) after body weight normalization induced by BS, we carried out a proteomic approach sequential window acquisition of all theoretical mass spectra (SWATH-MS) analysis. These results were complemented by Western blot, electron microscopy and RT-qPCR. With all of the working tools mentioned, we confirmed that after BS, up-regulated proteins were associated with metabolism, the citric acid cycle and respiratory electron transport, triglyceride catabolism and metabolism, formation of ATP, pyruvate metabolism, glycolysis/gluconeogenesis and thermogenesis among others. In contrast, proteins with decreased values are part of the biological pathways related to the immune system. We also confirmed that obesity caused a significant decrease in mitochondrial density and coverage, which was corrected by BS. Together, these findings reveal specific molecular mechanisms, genes and proteins that improve adipose tissue function after BS characterized by lower inflammation, increased glucose uptake, higher insulin sensitivity, higher de novo lipogenesis, increased mitochondrial function and decreased adipocyte size.
Project description:Obesity has considerable effects on morbidity and mortality and the prevalence of obesity has been increasing rapidly worldwide during the past two decades. Even if obesity affects the entire individual, adipose tissue play a central role in the development of obesity. Expression profiling of adipose tissue may give insights into mechanisms contributing to obesity and obesity-related disorders. 24 obese subjects (6 women and 18 men, BMI 37.6 ± 4.9) received a very low calorie diet (450 kcal/d, Cambridge diet or Modifast) for 16 weeks. On average, patients lost 27.7 kg during the diet. Microarray expression analysis (Affymetrix U133A) in subcutaneous adipose tissue was performed before diet and after 16 weeks of diet.
Project description:To assess changes in total (TAT), subcutaneous (SAT), visceral (VAT), and intermuscular (IMAT) adipose tissue by whole-body MRI before surgery and at 12 months and 24 months post-surgery in a subset of participants of the Longitudinal Assessment of Bariatric Surgery-2.From 0 to 12 months, n?=?20 females and 3 males; from 12 to 24 months, n?=?42 females and 7 males. Paired t-tests and GLM repeated measures examined changes in TAT, SAT, VAT, and IMAT at 12 and 24 months, with sex and age as covariates.Changes from 0 to 12 months included weight (-41.9?±?12.1 kg; -36%), TAT (-33.5?±?9.6 kg; -56%), SAT (-29.2?±?8.2 kg; -55%), VAT (-3.3?±?1.6 kg; -73%), and IMAT (-0.99?±?0.68 kg; -50%), all P?<?0.001. In females, from 12 to 24 months, despite relative weight stability (-1.8?±?6.5 kg, -2%; P?=?0.085), VAT (-0.5?±?0.7 kg; -30%; P?<?0.001) and IMAT (-0.2?±?0.4 kg; -14%; P?=?0.012) decreased further. In males, from 12 to 24 months, weight increased (5.1?±?5.2 kg; 6%; P?=?0.04) with no significant changes in TAT or sub-depots.Bariatric surgery continues to induce favorable changes in body composition, i.e., persistent adipose tissue loss at 24 months in the absence of further significant weight loss.
Project description:Fibroblast growth factor 21 (FGF21) induces weight loss in mouse, monkey, and human studies. In mice, FGF21 is thought to cause weight loss by stimulating thermogenesis, but whether FGF21 increases energy expenditure (EE) in primates is unclear. Here, we explore the transcriptional response and gene networks active in adipose tissue of rhesus macaques following FGF21-induced weight loss. Genes related to thermogenesis responded inconsistently to FGF21 treatment and weight loss. However, expression of gene modules involved in triglyceride (TG) synthesis and adipogenesis decreased, and this was associated with greater weight loss. Conversely, expression of innate immune cell markers was increased post-treatment and was associated with greater weight loss. A lipogenesis gene module associated with weight loss was evaluated by testing the function of member genes in mice. Overexpression of NRG4 reduced weight gain in diet-induced obese mice, while overexpression of ANGPTL8 resulted in elevated TG levels in lean mice. These observations provide evidence for a shifting balance of lipid storage and metabolism due to FGF21-induced weight loss in the non-human primate model, and do not fully recapitulate increased EE seen in rodent and in vitro studies. These discrepancies may reflect inter-species differences or complex interplay of FGF21 activity and counter-regulatory mechanisms.