title: Novel hormone-regulated genes in visceral adipose tissue: cloning and identification of proinflammatory cytokine-like mouse and human MEDA-7: implications for obesity, insulin resistance and the metabolic syndrome.
abstract: OBJECTIVE
  We sought to characterise novel genes dysregulated by sex hormonal imbalances that induce obesity and metabolic disorder in a setting of oestrogen deficiency and androgen dominance in follicle-stimulating hormone receptor (For [also known as Fshr]) knockout female mice.
  
  
  METHODS
  Transcriptome analysis of mesenteric adipose tissue (MAT) of mutants revealed novel genes. One novel gene named Meda-7 was selected for study. Meda-7 was cloned from mouse and human adipose tissue; its expression, hormonal regulation and function were characterised.
  
  
  RESULTS
  Mouse Meda-7 is richly expressed in deep visceral adipose tissue and encodes a 22 kDa secreted protein with 71% homology to human mesenteric oestrogen-dependent adipose gene- 7 (MEDA-7) protein. Both have six conserved cysteines like many cytokines. In obese patients, MEDA-7 is more abundant in omental than subcutaneous fat. Meda-7 is downregulated in For-knockout female MAT at 5 months (obese state) followed by steep upregulation at 9 months (prediabetic condition) when mutants progress towards the metabolic syndrome. Meda-7 is expressed predominantly in the stromal-vascular cell fraction. In this fraction,M1-proinflammatorymacrophages are rich in Meda-7. Meda-7 dysregulation in 5-month-old For-knockout MAT is restored by oestrogen, but treatment has no effect in older mutants. Overabundance of MEDA-7 in HEK-293 cells enhances cell proliferation via p42/44 mitogen-activated protein kinases. Secreted MEDA-7 attenuates insulin-stimulated glucose uptake in 3T3-L1 adipocytes, while downregulating glucose transporter-4 and upregulating both monocyte chemotactic protein-1 and suppressor of cytokine signalling-3. Downstream activity of the insulin signalling mediator, phospho-AKT, is also downregulated.
  
  
  CONCLUSIONS
  MEDA-7 is a hormone-regulated adipokine/proinflammatory cytokine that is implicated in causing chronic inflammation, affecting cellular expansion and blunting insulin response in adipocytes.
authors.affiliation: Molecular Endocrinology Laboratory, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montréal, QC, Canada H2W 1R7.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: M R
authors.initials: MR
authors.lastname: Sairam
mesh_terms: D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001706:Biopsy; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D050152:Intra-Abdominal Fat / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D011962:Receptors, FSH / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D050151:Subcutaneous Fat / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C570497:MEDA-7 protein, mouse; C434482:MZB1 protein, human; D011962:Receptors, FSH; D011994:Recombinant Proteins; D005947:Glucose