title: GIP increases adipose tissue expression and blood levels of MCP-1 in humans and links high energy diets to inflammation: a randomised trial.
abstract: OBJECTIVE
  Obesity is associated with elevated monocyte chemoattractant protein-1 (MCP-1), a proinflammatory chemokine related to diabetes and cardiovascular disease. Since obesity is triggered by energy dense diets, we hypothesised that nutrient induced intestinal hormones such as glucose-dependent insulinotropic peptide (GIP) may directly stimulate the release of chemokines from adipose tissue and induce low-grade inflammation.
  
  
  METHODS
  GIP effects on gene expression and secretion of inflammatory markers were studied by microarray analysis and PCR from human subcutaneous fat biopsies of slightly obese but healthy volunteers in the metabolic ward of German Institute of Human Nutrition, Department of Clinical Nutrition, Potsdam-Rehbrücke. To allocate the participants to the study arms they were numbered in order of their recruitment and then assigned to the groups by a random number generator. In a randomised, single-blind (participants) crossover design, the participants received GIP infusions in postprandial concentrations (2 pmol kg(-1) min(-1)) or saline (154 mmol/l NaCl) infusions for 240 min either alone, in combination with hyperinsulinaemic-euglycaemic (EU) or hyperinsulinaemic-hyperglycaemic (HC) clamps. Possible mechanisms of GIP effects were investigated in single and co-cultures of macrophage and adipocyte cell lines and in primary human monocytes, macrophages and adipocytes.
  
  
  RESULTS
  A total of 17 participants were randomised to the following groups: EU with GIP infusion (n = 9); EU with NaCl infusion (n = 9); HC with GIP infusion (n = 8); HC with NaCl infusion (n = 8); sole GIP infusion (n = 11) and sole placebo infusion (n = 11). All 17 individuals were analysed. The study is completed. In human subcutaneous adipose tissue (hSCAT), infusions of GIP significantly increased inflammatory chemokine and cytokine gene networks in transcriptomic microarray analyses. Particularly MCP-1 (180 ± 26%), MCP-2 (246 ± 58%) and IL-6 (234 ± 40%) mRNA levels in adipose tissue as well as circulating plasma concentrations of MCP-1 (165 ± 12 vs 135 ± 13 pg/ml; GIP vs saline after 240 min; p < 0.05 for all variables) in humans increased independently of circulating insulin or glucose plasma concentrations. GIP stimulation increased Mcp-1 mRNA-expression in co-cultures of differentiated 3T3L1-adipocytes and RAW 264.7 macrophages but not in the isolated cell lines. Similarly, GIP increased MCP-1 transcripts in co-cultures of primary human macrophages with human adipocytes. GIP receptor (GIPR) transcripts were present in primary monocytes and the different cell lines and induced activation of extracellular related kinase (ERK) as well as increases in cAMP, indicating functional receptors.
  
  
  CONCLUSIONS
  Our findings suggest that the nutrient induced gut hormone GIP may initiate adipose tissue inflammation by triggering a crosstalk of adipocytes and macrophages involving MCP-1.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00774488.
  
  
  BACKGROUND
  This work was supported by the German Research Foundation (DFG): grant No. Pf164/021002.
authors.affiliation: Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbruecke, Arthur-Scheunert-Allee 155, 14558, Nuthetal, Germany.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Gögebakan
authors.forename: Martin A
authors.initials: MA
authors.lastname: Osterhoff
authors.forename: Rita
authors.initials: R
authors.lastname: Schüler
authors.forename: Olga
authors.initials: O
authors.lastname: Pivovarova
authors.forename: Michael
authors.initials: M
authors.lastname: Kruse
authors.forename: Anne-Cathrin
authors.initials: AC
authors.lastname: Seltmann
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Mosig
authors.forename: Natalia
authors.initials: N
authors.lastname: Rudovich
authors.forename: Michael
authors.initials: M
authors.lastname: Nauck
authors.forename: Andreas F H
authors.initials: AF
authors.lastname: Pfeiffer
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D018592:Cross-Over Studies; D004032:Diet; D005749:Gastric Inhibitory Polypeptide / Q000097:blood / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D018932:Chemokine CCL2; D007328:Insulin; D005749:Gastric Inhibitory Polypeptide