[The mechanisms by which PPARgamma and adiponectin regulate glucose and lipid metabolism].

Obesity, a state of increased adipose tissue mass, is a major cause for type 2 diabetes, hyperlipidemia, and hypertension, resulting in clustering of risk factors for atherosclerosis. Heterozygous PPARgamma knockout mice and KKA(y) mice administered with a PPARgamma antagonist were protected from high-fat diet-induced adipocyte hypertrophy and insulin resistance. Moderate reduction of PPARgamma activity prevented adipocyte hypertrophy, thereby diminution of TNFalpha, resistin, and FFA and upregulation of adiponectin and leptin. These alterations led to reduction of tissue TG content in muscle/liver, thereby ameliorating insulin resistance. Insulin resistance in the lipoatrophic mice and KKA(y) mice were ameliorated by replenishment of adiponectin. Moreover, adiponectin transgenic mice ameliorated insulin resistance and diabetes, but not the obesity of ob/ob mice. Furthermore, targeted disruption of the adiponectin gene caused moderate insulin resistance and glucose intolerance. In muscle, adiponectin activated AMP kinase and PPARgamma pathways, thereby increasing beta-oxidation of lipids, leading to decreased TG content, which ameliorated muscle insulin resistance. In the liver, adiponectin also activated AMPK, thereby downregulating PEPCK and G6Pase, leading to decreased glucose output from the liver. In conclusion, PPARgamma plays a central role in the regulation of adipocyte hypertrophy and insulin sensitivity. The upregulation of the adiponectin pathway by PPARgamma may play a role in the increased insulin sensitivity of heterozygous PPARgamma knockout mice, and activation of adiponectin pathway may provide novel therapeutic strategies for obesity-linked disorders such as type 2 diabetes and metabolic syndrome.

[1]  Philippe Froguel,et al.  Cloning of adiponectin receptors that mediate antidiabetic metabolic effects , 2003, Nature.

[2]  T Nakamura,et al.  Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. , 1999, Circulation.

[3]  Y. Nakano,et al.  Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. , 1996, Journal of biochemistry.

[4]  T. Kadowaki,et al.  The Pro12Ala Polymorphism in PPAR γ2 May Confer Resistance to Type 2 Diabetes , 2000 .

[5]  K. Umesono,et al.  Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. , 1998, The Journal of clinical investigation.

[6]  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.

[7]  T Nakamura,et al.  Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[8]  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.

[9]  S. Uchida,et al.  Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature Medicine.

[10]  S. Kihara,et al.  Adiponectin, an Adipocyte-Derived Plasma Protein, Inhibits Endothelial NF-&kgr;B Signaling Through a cAMP-Dependent Pathway , 2000, Circulation.

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

[12]  P. Froguel,et al.  Globular Adiponectin Protected ob/ob Mice from Diabetes and ApoE-deficient Mice from Atherosclerosis* , 2003, The Journal of Biological Chemistry.

[13]  T Nakamura,et al.  Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. , 1999, Biochemical and biophysical research communications.

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

[15]  Satoshi Tanaka,et al.  PPARγ Mediates High-Fat Diet–Induced Adipocyte Hypertrophy and Insulin Resistance , 1999 .

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

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

[18]  Y. Terauchi,et al.  The Mechanisms by Which Both Heterozygous Peroxisome Proliferator-activated Receptor γ (PPARγ) Deficiency and PPARγ Agonist Improve Insulin Resistance* , 2001, The Journal of Biological Chemistry.

[19]  A. Itai,et al.  Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes. , 2001, The Journal of clinical investigation.