title: Central obesity and altered peripheral adipose tissue gene expression characterize the NAFLD patient with insulin resistance: Role of nutrition and insulin challenge.
abstract: OBJECTIVE
  Insulin resistance (IR) and white adipose tissue (WAT) dysfunction frequently are associated with nonalcoholic fatty liver disease (NAFLD); however, the pathogenic mechanisms contributing to their clustering are not well defined. The aim of this study was to define some nutritional, anthropometric, metabolic, and genetic mechanisms contributing to their clustering.
  
  
  METHODS
  Forty-five (20 men, 25 women) patients (age 45.7 ± 11.1 y) with recent diagnosis of NAFLD were grouped according to IR state. Energy balance was assessed using a food questionnaire and indirect calorimetry, and body composition with anthropometry and dual-energy x-ray absorptiometry. Biochemical and hormonal parameters combined with adipose tissue gene expression were determined. Microarray analysis of gene expression was performed in a subset of WAT samples from IR patients (n = 9), in the fasted state, after specific test meals (monounsaturated fatty acid [MUFA], saturated fat [SAT], and carbohydrate-rich) and after being challenged with insulin.
  
  
  RESULTS
  IR patients exhibited higher trunk fat to leg fat ratio (P < 0.05) and had a higher ratio of SAT/MUFA fat intake (P < 0.05) than insulin-sensitive (IS) individuals. Deposition of fat in the trunk but not in the leg was directly related to liver enzyme levels (P < 0.05). IR patients also had lower adiponectin serum levels and leptin (LEP) mRNA expression in WAT compared with IS patients (P < 0.01 and P < 0.05, respectively). Microarray analysis after insulin challenge confirmed that insulin treatment induces the expression of PPARG gene and LEP and decreases GCGR gene (P < 0.05 for all) in WAT. No changes in these genes were observed in the postprandial state induced after the acute effect of specific diets.
  
  
  CONCLUSIONS
  Patients exhibiting NAFLD and IR had preferential central fat deposition directly related to their serum alanine aminotransferase levels. These patients showed peripheral adipose tissue dysfunction and exhibited inappropriately low LEP biosynthesis that could be partially restored after anabolic conditions induced by insulin signaling.
authors.affiliation: Insulin Resistance, Metabolism and Adipose Tissue Unit, Maimonides Institute of Biomedical Research, University Hospital Reina Sofia, Córdoba, Spain; Endocrinology and Nutrition Services, University Hospital Reina Sofia, Cordoba, Spain. Electronic address: japaniaguag@yahoo.es.
authors.forename: J A
authors.initials: JA
authors.lastname: Paniagua
authors.affiliation: Insulin Resistance, Metabolism and Adipose Tissue Unit, Maimonides Institute of Biomedical Research, University Hospital Reina Sofia, Córdoba, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Escandell-Morales
authors.affiliation: Insulin Resistance, Metabolism and Adipose Tissue Unit, Maimonides Institute of Biomedical Research, University Hospital Reina Sofia, Córdoba, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Gil-Contreras
authors.affiliation: Department of Sport and informatics, Pablo of Olavide University, Seville, Spain.
authors.forename: F J
authors.initials: FJ
authors.lastname: Berral de la Rosa
authors.affiliation: Insulin Resistance, Metabolism and Adipose Tissue Unit, Maimonides Institute of Biomedical Research, University Hospital Reina Sofia, Córdoba, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Romero-Jimenez
authors.affiliation: Insulin Resistance, Metabolism and Adipose Tissue Unit, Maimonides Institute of Biomedical Research, University Hospital Reina Sofia, Córdoba, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gómez-Urbano
authors.affiliation: Insulin Resistance, Metabolism and Adipose Tissue Unit, Maimonides Institute of Biomedical Research, University Hospital Reina Sofia, Córdoba, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Sanchez-Lopez
authors.affiliation: Insulin Resistance, Metabolism and Adipose Tissue Unit, Maimonides Institute of Biomedical Research, University Hospital Reina Sofia, Córdoba, Spain; Laboratory Services, University Hospital Reina Sofia, Cordoba, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Bellido
authors.affiliation: Liver Research Unit, University Hospital Reina Sofia, Maimonides Institute of Biomedical Research, Cordoba, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Poyato
authors.affiliation: Insulin Resistance, Metabolism and Adipose Tissue Unit, Maimonides Institute of Biomedical Research, University Hospital Reina Sofia, Córdoba, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Calatayud
authors.affiliation: Metabolic Research Laboratories Institute of Metabolic Science, Addenbrooke's Hospital Cambridge, Cambridge, England.
authors.forename: A J
authors.initials: AJ
authors.lastname: Vidal-Puig
mesh_terms: D015502:Absorptiometry, Photon; D052242:Adiponectin / Q000097:blood; D052436:Adipose Tissue, White / Q000378:metabolism*; D000328:Adult; D001823:Body Composition; D015992:Body Mass Index; D018592:Cross-Over Studies; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004734:Energy Metabolism; D005227:Fatty Acids / Q000008:administration & dosage; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage; D005234:Fatty Liver / Q000178:diet therapy / Q000235:genetics*; D005247:Feeding Behavior; D005260:Female; D015870:Gene Expression; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D015850:Interleukin-6 / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D009752:Nutritional Status; D056128:Obesity, Abdominal / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D011795:Surveys and Questionnaires; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D052242:Adiponectin; D004040:Dietary Carbohydrates; D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D007328:Insulin; D015850:Interleukin-6; D020738:Leptin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha
keywords: Adipokines and leptin; Adipose tissue dysfunction; Insulin resistance; Nonalcoholic fatty liver disease