Determinants of Human Adipose Tissue Gene Expression: Impact of Diet, Sex, Metabolic Status, and Cis Genetic Regulation

Weight control diets favorably affect parameters of the metabolic syndrome and delay the onset of diabetic complications. The adaptations occurring in adipose tissue (AT) are likely to have a profound impact on the whole body response as AT is a key target of dietary intervention. Identification of environmental and individual factors controlling AT adaptation is therefore essential. Here, expression of 271 transcripts, selected for regulation according to obesity and weight changes, was determined in 515 individuals before, after 8-week low-calorie diet-induced weight loss, and after 26-week ad libitum weight maintenance diets. For 175 genes, opposite regulation was observed during calorie restriction and weight maintenance phases, independently of variations in body weight. Metabolism and immunity genes showed inverse profiles. During the dietary intervention, network-based analyses revealed strong interconnection between expression of genes involved in de novo lipogenesis and components of the metabolic syndrome. Sex had a marked influence on AT expression of 88 transcripts, which persisted during the entire dietary intervention and after control for fat mass. In women, the influence of body mass index on expression of a subset of genes persisted during the dietary intervention. Twenty-two genes revealed a metabolic syndrome signature common to men and women. Genetic control of AT gene expression by cis signals was observed for 46 genes. Dietary intervention, sex, and cis genetic variants independently controlled AT gene expression. These analyses help understanding the relative importance of environmental and individual factors that control the expression of human AT genes and therefore may foster strategies aimed at improving AT function in metabolic diseases.

[1]  Ramesh Ramakrishnan,et al.  High Throughput Gene Expression Measurement with Real Time PCR in a Microfluidic Dynamic Array , 2008, PloS one.

[2]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[3]  M. Blüher,et al.  A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism , 2012, Nature.

[4]  N. Viguerie,et al.  Peroxisome proliferator-activated receptor-alpha control of lipid and glucose metabolism in human white adipocytes. , 2010, Endocrinology.

[5]  Radu Dobrin,et al.  Dissecting Cis Regulation of Gene Expression in Human Metabolic Tissues , 2011, PloS one.

[6]  S. Melov,et al.  Human Embryonic Stem Cells Express Elevated Levels of Multiple Pro-Apoptotic BCL-2 Family Members , 2011, PloS one.

[7]  S. Grundy,et al.  Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International As , 2009, Circulation.

[8]  A. Chawla,et al.  Cidea is associated with lipid droplets and insulin sensitivity in humans , 2008, Proceedings of the National Academy of Sciences.

[9]  R. Tibshirani,et al.  Sparse inverse covariance estimation with the graphical lasso. , 2008, Biostatistics.

[10]  T. Larsen,et al.  The Diet, Obesity and Genes (Diogenes) Dietary Study in eight European countries – a comprehensive design for long‐term intervention , 2010, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[11]  M. Tisdale,et al.  Antidiabetic properties of zinc-alpha2-glycoprotein in ob/ob mice. , 2010, Endocrinology.

[12]  Pascal G. P. Martin,et al.  The key roles of elongases and desaturases in mammalian fatty acid metabolism: Insights from transgenic mice. , 2010, Progress in lipid research.

[13]  Herbert Tilg,et al.  Adipocytokines: mediators linking adipose tissue, inflammation and immunity , 2006, Nature Reviews Immunology.

[14]  L. Cupples,et al.  Gene-nutrient interactions with dietary fat modulate the association between genetic variation of the ACSL1 gene and metabolic syndrome , 2010, Journal of Lipid Research.

[15]  John Quackenbush,et al.  Data-driven normalization strategies for high-throughput quantitative RT-PCR , 2009, BMC Bioinformatics.

[16]  Ben van Ommen,et al.  Transcriptomic Coordination in the Human Metabolic Network Reveals Links between n-3 Fat Intake, Adipose Tissue Gene Expression and Metabolic Health , 2011, PLoS Comput. Biol..

[17]  R. Carroll,et al.  Covariate-adjusted linear mixed effects model with an application to longitudinal data , 2008, Journal of nonparametric statistics.

[18]  K. Kos,et al.  The adipokine zinc‐α2‐glycoprotein (ZAG) is downregulated with fat mass expansion in obesity , 2010, Clinical endocrinology.

[19]  A. Astrup,et al.  Diets with high or low protein content and glycemic index for weight-loss maintenance. , 2010, The New England journal of medicine.

[20]  Svati H Shah,et al.  A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. , 2009, Cell metabolism.

[21]  Z. Kováčová,et al.  Dietary intervention-induced weight loss decreases macrophage content in adipose tissue of obese women , 2011, International Journal of Obesity.

[22]  Eunjung Kim.  Insulin resistance at the crossroads of metabolic syndrome: Systemic analysis using microarrays , 2010, Biotechnology journal.

[23]  J. Scoazec,et al.  Subcutaneous adipose tissue remodeling during the initial phase of weight gain induced by overfeeding in humans. , 2012, The Journal of clinical endocrinology and metabolism.

[24]  Sung‐Min Ahn,et al.  Integrated Expression Profiling and Genome-Wide Analysis of ChREBP Targets Reveals the Dual Role for ChREBP in Glucose-Regulated Gene Expression , 2011, PloS one.

[25]  Korbinian Strimmer,et al.  An empirical Bayes approach to inferring large-scale gene association networks , 2005, Bioinform..

[26]  D. Langin,et al.  Adipokines and dietary interventions in human obesity , 2010, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[27]  H. Stefánsson,et al.  Genetics of gene expression and its effect on disease , 2008, Nature.

[28]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[29]  K. Clément,et al.  Adipose tissue transcriptome reflects variations between subjects with continued weight loss and subjects regaining weight 6 mo after caloric restriction independent of energy intake. , 2010, The American journal of clinical nutrition.

[30]  T. Pers,et al.  Macrophages and Adipocytes in Human Obesity , 2009, Diabetes.

[31]  Christophe Ambroise,et al.  SIMoNe: Statistical Inference for MOdular NEtworks , 2009, Bioinform..

[32]  Jin Jen,et al.  Quantitative miRNA Expression Analysis Using Fluidigm Microfluidics Dynamic Arrays , 2011, BMC Genomics.

[33]  F. Lönnqvist,et al.  Overexpression of the obese (ob) gene in adipose tissue of human obese subjects , 1995, Nature Medicine.

[34]  F. Karpe,et al.  Remodeling Phenotype of Human Subcutaneous Adipose Tissue Macrophages , 2008, Circulation.

[35]  M. Tenenhaus,et al.  Prediction of clinical outcome with microarray data: a partial least squares discriminant analysis (PLS-DA) approach , 2003, Human Genetics.

[36]  Z. Kováčová,et al.  Macrophage gene expression is related to obesity and the metabolic syndrome in human subcutaneous fat as well as in visceral fat , 2011, Diabetologia.

[37]  K. Clément,et al.  Regulation of inflammation‐related genes in human adipose tissue , 2007, Journal of internal medicine.

[38]  K. Clément,et al.  Contribution of energy restriction and macronutrient composition to changes in adipose tissue gene expression during dietary weight-loss programs in obese women. , 2008, The Journal of clinical endocrinology and metabolism.

[39]  M. Neville,et al.  Markers of de novo lipogenesis in adipose tissue: associations with small adipocytes and insulin sensitivity in humans , 2009, Diabetologia.

[40]  D. Gómez-Coronado,et al.  Gene expression profiling of subcutaneous adipose tissue in morbid obesity using a focused microarray: Distinct expression of cell-cycle- and differentiation-related genes , 2010, BMC Medical Genomics.

[41]  Bin Zhang,et al.  A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. , 2011, Genome research.

[42]  C. Brenan,et al.  Nanoliter high-throughput PCR for DNA and RNA profiling. , 2009, Methods in molecular biology.

[43]  Z. Kováčová,et al.  Worsening of obesity and metabolic status yields similar molecular adaptations in human subcutaneous and visceral adipose tissue: decreased metabolism and increased immune response. , 2010, Journal of Clinical Endocrinology and Metabolism.

[44]  K. Clément,et al.  Serum amyloid A: production by human white adipocyte and regulation by obesity and nutrition , 2005, Diabetologia.

[45]  Edward M. Reingold,et al.  Graph drawing by force‐directed placement , 1991, Softw. Pract. Exp..

[46]  Olga Ilkayeva,et al.  Adipose acyl-CoA synthetase-1 directs fatty acids toward beta-oxidation and is required for cold thermogenesis. , 2010, Cell metabolism.

[47]  E. Oda.  The Metabolic Syndrome as a Concept of Adipose Tissue Disease , 2008, Hypertension Research.

[48]  Eric E Schadt,et al.  Elucidating the role of gonadal hormones in sexually dimorphic gene coexpression networks. , 2009, Endocrinology.

[49]  A. Arnold,et al.  Tissue-specific expression and regulation of sexually dimorphic genes in mice. , 2006, Genome research.

[50]  A. Hamsten,et al.  Insulin regulation of MCP-1 in human adipose tissue of obese and lean women. , 2008, American journal of physiology. Endocrinology and metabolism.

[51]  Yoav Benjamini,et al.  Identifying differentially expressed genes using false discovery rate controlling procedures , 2003, Bioinform..

[52]  Mary Yannakoulia,et al.  Management of the metabolic syndrome and type 2 diabetes through lifestyle modification. , 2009, Annual review of nutrition.

[53]  T. Valle,et al.  Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. , 2001, The New England journal of medicine.

[54]  H. Towle,et al.  ChREBP•Mlx Is the Principal Mediator of Glucose-induced Gene Expression in the Liver* , 2006, Journal of Biological Chemistry.