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Endocrinology Vol. 145, No. 1 367-383
Copyright © 2004 by The Endocrine Society

A Transgenic Mouse with a Deletion in the Collagenous Domain of Adiponectin Displays Elevated Circulating Adiponectin and Improved Insulin Sensitivity

Terry P. Combs, Utpal B. Pajvani, Anders H. Berg, Ying Lin, Linda A. Jelicks, Mathieu Laplante, Andrea R. Nawrocki, Michael W. Rajala, Albert. F. Parlow, Laurelle Cheeseboro, Yang-Yang Ding, Robert G. Russell, Dirk Lindemann, Adam Hartley, Glynn R. C. Baker, Silvana Obici, Yves Deshaies, Marian Ludgate, Luciano Rossetti and Philipp E. Scherer

Departments of Cell Biology (T.P.C., U.B.P., A.H.B., Y.L., A.R.N., M.W.R., L.C., Y.Y.D., P.E.S.), Physiology and Biophysics (L.A.J.), Pathology (R.G.R.), Neuroscience (A.H.), Medicine (S.O., L.R.), and Molecular Pharmacology (S.O., L.R.); Institute for Animal Studies (R.G.R.); Department of Medicine, Division of Endocrinology, Diabetes Research and Training Center (S.O., L.R., P.E.S.), Albert Einstein College of Medicine, Bronx, New York 10461; Department of Anatomy and Physiology, Laval Hospital Research Center, School of Medicine, Laval University (M.La., Y.Y.D.), Québec, Canada; National Hormone and Peptide Program, Harbor-University of California-Los Angeles Medical Center (A.F.P.), Torrance, California 90509; Institute for Virology, Technical University Dresden (D.L.), 01307 Dresden, Germany; and Department of Medicine, University of Wales College of Medicine (G.R.C.B., M.Lu.), Heath Park, Cardiff, United Kingdom CF14 4XN

Address all correspondence and requests for reprints to: Dr. Philipp E. Scherer, Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461. E-mail: scherer{at}aecom.yu.edu

Adiponectin is a plasma protein expressed exclusively in adipose tissue. Adiponectin levels are linked to insulin sensitivity, but a direct effect of chronically elevated adiponectin on improved insulin sensitivity has not yet been demonstrated. We identified a dominant mutation in the collagenous domain of adiponectin that elevated circulating adiponectin values in mice by 3-fold. Adiponectinemia raised lipid clearance and lipoprotein lipase activity, and suppressed insulin-mediated endogenous glucose production. The induction of adiponectin during puberty and the sexual dimorphism in adult adiponectin values were preserved in these transgenic animals. As a result of elevated adiponectin, serum PRL values and brown adipose mass both increased. The effects on carbohydrate and lipid metabolism were associated with elevated phosphorylation of 5'-AMP-activated protein kinase in liver and elevated expression of peroxisomal proliferator-activated receptor {gamma}2, caveolin-1, and mitochondrial markers in white adipose tissue. These studies strongly suggest that increasing endogenous adiponectin levels has direct effects on insulin sensitivity and may induce similar physiological responses as prolonged treatment with peroxisomal proliferator-activated receptor {gamma} agonists.




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