title: Sexually dimorphic diet-induced insulin resistance in obese tissue inhibitor of metalloproteinase-2 (TIMP-2)-deficient mice.
abstract: Circulating levels of matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitor of metalloproteinases (TIMPs), are altered in human obesity and may contribute to its pathology. TIMP-2 exerts MMP-dependent (MMP inhibition and pro-MMP-2 activation) and MMP-independent functions. To assess the role of TIMP-2 in a murine model of nutritionally induced obesity, weight gain in wild-type and TIMP-2 deficient [knockout (KO)] mice fed a chow or high-fat diet (HFD) was determined. The effects of diet on glucose tolerance and insulin sensitivity, as well as pancreatic β-cell and adipocyte physiology, were assessed. Chow-fed TIMP-2 KO mice of both sexes became obese but maintained relatively normal glucose tolerance and insulin sensitivity. Obesity was exacerbated on the HFD. However, HFD-fed male, but not female, TIMP-2 KO mice developed insulin resistance with reduced glucose transporter 2 and pancreatic and duodenal homeobox 1 levels, despite increased β-cell mass and hyperplasia. Thus, although β-cell mass was increased, HFD-fed male TIMP-2 KO mice develop diabetes likely due to β-cell exhaustion and failure. TIMP-2 mRNA, whose expression was greatest in sc adipose tissue, was down-regulated in HFD-fed wild-type males, but not females. Furthermore, HFD increased membrane type 1-MMP (MMP-14) expression and activity in male, but not female, sc adipose tissue. Strikingly, MMP-14 expression increased to a greater extent in TIMP-2 KO males and was associated with decreased adipocyte collagen. Taken together, these findings demonstrate a role for TIMP-2 in maintaining extracellular matrix integrity necessary for normal β-cell and adipocyte physiology and that loss of extracellular matrix integrity may underlie diabetic and obesogenic phenotypes.
authors.affiliation: Department of Anatomy and Neurobiology, University of Vermont College of Medicine, 149 Beaumont Avenue, HSRF 418, Burlington, Vermont 05405, USA. diane.jaworski@uvm.edu
authors.forename: Diane M
authors.initials: DM
authors.lastname: Jaworski
authors.forename: Olga
authors.initials: O
authors.lastname: Sideleva
authors.forename: Holly M
authors.initials: HM
authors.lastname: Stradecki
authors.forename: Garret D
authors.initials: GD
authors.lastname: Langlois
authors.forename: Aida
authors.initials: A
authors.lastname: Habibovic
authors.forename: Basanthi
authors.initials: B
authors.lastname: Satish
authors.forename: William G
authors.initials: WG
authors.lastname: Tharp
authors.forename: James
authors.initials: J
authors.lastname: Lausier
authors.forename: Kyla
authors.initials: K
authors.lastname: Larock
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Jetton
authors.forename: Mina
authors.initials: M
authors.lastname: Peshavaria
authors.forename: Richard E
authors.initials: RE
authors.lastname: Pratley
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004041:Dietary Fats / Q000009:adverse effects; D005260:Female; D007124:Immunoenzyme Techniques; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012737:Sex Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain / Q000235:genetics
chemical_list: D004041:Dietary Fats; D020738:Leptin; D019716:Tissue Inhibitor of Metalloproteinase-2; D053511:Matrix Metalloproteinase 14