Globular Adiponectin Protected ob/ob Mice from Diabetes and ApoE-deficient Mice from Atherosclerosis*

The adipocyte-derived hormone adiponectin has been shown to play important roles in the regulation of energy homeostasis and insulin sensitivity. In this study, we analyzed globular domain adiponectin (gAd) transgenic (Tg) mice crossed with leptin-deficient ob/ob or apoE-deficient mice. Interestingly, despite an unexpected similar body weight, gAd Tg ob/ob mice showed amelioration of insulin resistance and β-cell degranulation as well as diabetes, indicating that globular adiponectin and leptin appeared to have both distinct and overlapping functions. Amelioration of diabetes and insulin resistance was associated with increased expression of molecules involved in fatty acid oxidation such as acyl-CoA oxidase, and molecules involved in energy dissipation such as uncoupling proteins 2 and 3 and increased fatty acid oxidation in skeletal muscle of gAd Tg ob/ob mice. Moreover, despite similar plasma glucose and lipid levels on an apoE-deficient background, gAd Tg apoE-deficient mice showed amelioration of atherosclerosis, which was associated with decreased expression of class A scavenger receptor and tumor necrosis factor α. This is the first demonstration that globular adiponectin can protect against atherosclerosis in vivo. In conclusion, replenishment of globular adiponectin may provide a novel treatment modality for both type 2 diabetes and atherosclerosis.

[1]  B. Spiegelman,et al.  Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue. , 1992, The Journal of biological chemistry.

[2]  G. Shulman,et al.  On Diabetes: Insulin Resistance Cellular Mechanisms of Insulin Resistance , 2022 .

[3]  C. Dina,et al.  Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. , 2002, Diabetes.

[4]  Philippe Froguel,et al.  Disruption of Adiponectin Causes Insulin Resistance and Neointimal Formation* , 2002, The Journal of Biological Chemistry.

[5]  J. Friedman,et al.  Obesity in the new millennium , 2000, Nature.

[6]  Sander Kersten,et al.  Roles of PPARs in health and disease , 2000, Nature.

[7]  M. Matsuda,et al.  Diet-induced insulin resistance in mice lacking adiponectin/ACRP30 , 2002, Nature Medicine.

[8]  S. Kihara,et al.  Adipocyte-Derived Plasma Protein, Adiponectin, Suppresses Lipid Accumulation and Class A Scavenger Receptor Expression in Human Monocyte-Derived Macrophages , 2001, Circulation.

[9]  L. Hamann,et al.  Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists , 1997, Nature.

[10]  S. Kihara,et al.  Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. , 2000, Blood.

[11]  N. Maeda,et al.  Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. , 1992, Science.

[12]  T. Funahashi,et al.  cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). , 1996, Biochemical and biophysical research communications.

[13]  M. Lazar,et al.  The hormone resistin links obesity to diabetes , 2001, Nature.

[14]  S. Aizawa,et al.  Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. , 2000, Diabetes.

[15]  R. Hammer,et al.  Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy , 1999, Nature.

[16]  P. Grimaldi,et al.  Cellular and molecular aspects of adipose tissue development. , 1992, Annual review of nutrition.

[17]  T. Saheki,et al.  Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice , 2002, Nature Genetics.

[18]  E. Rubin,et al.  Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells , 1992, Cell.

[19]  Philipp E. Scherer,et al.  A Novel Serum Protein Similar to C1q, Produced Exclusively in Adipocytes (*) , 1995, The Journal of Biological Chemistry.

[20]  Y. Yazaki,et al.  Resistance to Neointimal Hyperplasia and Fatty Streak Formation in Mice With Adrenomedullin Overexpression , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[21]  K. Hosoda,et al.  Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin. , 1999, Diabetes.

[22]  G. Hotamisligil.  The role of TNFα and TNF receptors in obesity and insulin resistance , 1999 .

[23]  B. Spiegelman,et al.  Adipogenesis and Obesity: Rounding Out the Big Picture , 1996, Cell.

[24]  Y. Terauchi,et al.  The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity , 2001, Nature Medicine.

[25]  T. Funahashi,et al.  Molecular Mechanism of Metabolic Syndrome X: Contribution of Adipocytokines · Adipocyte‐derived Bioactive Substances , 1999, Annals of the New York Academy of Sciences.

[26]  M. Matsuda,et al.  PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. , 2001, Diabetes.

[27]  B. Spiegelman,et al.  AdipoQ Is a Novel Adipose-specific Gene Dysregulated in Obesity (*) , 1996, The Journal of Biological Chemistry.

[28]  P. Scherer,et al.  The adipocyte-secreted protein Acrp30 enhances hepatic insulin action , 2001, Nature Medicine.

[29]  Richard T. Lee,et al.  Biomechanical Strain Induces Class A Scavenger Receptor Expression in Human Monocyte/Macrophages and THP-1 Cells: A Potential Mechanism of Increased Atherosclerosis in Hypertension , 2001, Circulation.