Sexually Dimorphic Diet-Induced Insulin Resistance in Obese Tissue Inhibitor of Metalloproteinase-2 (TIMP-2)-Deficient Mice (original) (raw)

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1Department of Anatomy and Neurobiology (D.M.J., H.M.S., G.D.L.), University of Vermont College of Medicine, Burlington, Vermont 05405

*Address all correspondence and requests for reprints to: Dr. Diane M. Jaworski, Department of Anatomy and Neurobiology, University of Vermont College of Medicine, 149 Beaumont Avenue, HSRF 418, Burlington, Vermont 05405.

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2Department of Medicine (O.S., A.H., B.S., W.G.T., J.L., K.L., T.L.J., M.P., R.E.P.), Division of Endocrinology, Diabetes and Metabolism, Colchester Research Facility, University of Vermont College of Medicine, Colchester, Vermont 05446

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1Department of Anatomy and Neurobiology (D.M.J., H.M.S., G.D.L.), University of Vermont College of Medicine, Burlington, Vermont 05405

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1Department of Anatomy and Neurobiology (D.M.J., H.M.S., G.D.L.), University of Vermont College of Medicine, Burlington, Vermont 05405

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2Department of Medicine (O.S., A.H., B.S., W.G.T., J.L., K.L., T.L.J., M.P., R.E.P.), Division of Endocrinology, Diabetes and Metabolism, Colchester Research Facility, University of Vermont College of Medicine, Colchester, Vermont 05446

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2Department of Medicine (O.S., A.H., B.S., W.G.T., J.L., K.L., T.L.J., M.P., R.E.P.), Division of Endocrinology, Diabetes and Metabolism, Colchester Research Facility, University of Vermont College of Medicine, Colchester, Vermont 05446

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2Department of Medicine (O.S., A.H., B.S., W.G.T., J.L., K.L., T.L.J., M.P., R.E.P.), Division of Endocrinology, Diabetes and Metabolism, Colchester Research Facility, University of Vermont College of Medicine, Colchester, Vermont 05446

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2Department of Medicine (O.S., A.H., B.S., W.G.T., J.L., K.L., T.L.J., M.P., R.E.P.), Division of Endocrinology, Diabetes and Metabolism, Colchester Research Facility, University of Vermont College of Medicine, Colchester, Vermont 05446

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2Department of Medicine (O.S., A.H., B.S., W.G.T., J.L., K.L., T.L.J., M.P., R.E.P.), Division of Endocrinology, Diabetes and Metabolism, Colchester Research Facility, University of Vermont College of Medicine, Colchester, Vermont 05446

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2Department of Medicine (O.S., A.H., B.S., W.G.T., J.L., K.L., T.L.J., M.P., R.E.P.), Division of Endocrinology, Diabetes and Metabolism, Colchester Research Facility, University of Vermont College of Medicine, Colchester, Vermont 05446

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Received:

03 September 2010

Accepted:

23 December 2010

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Diane M. Jaworski, Olga Sideleva, Holly M. Stradecki, Garret D. Langlois, Aida Habibovic, Basanthi Satish, William G. Tharp, James Lausier, Kyla LaRock, Thomas L. Jetton, Mina Peshavaria, Richard E. Pratley, Sexually Dimorphic Diet-Induced Insulin Resistance in Obese Tissue Inhibitor of Metalloproteinase-2 (TIMP-2)-Deficient Mice, Endocrinology, Volume 152, Issue 4, 1 April 2011, Pages 1300–1313, https://doi.org/10.1210/en.2010-1029
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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.

Copyright © 2011 by The Endocrine Society

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