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Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro , and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr −/− mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-α signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-α signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo .

We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a choline-deficient l -amino acid-defined diet containing 45% fat (HF-CDAA). The mice fed HF-CDAA diets for 16 weeks were divided into four groups: the no treatment (HF-CDAA), HF-CDAA containing 1000 mg/kg metformin, HF-CDAA containing 10 mg/kg GW7647, and HF-CDAA with both metformin and GW7647 groups. Metformin alone slightly deteriorated the aspartate and alanine aminotransferase (AST/ALT) values, whereas co-treatment with GW7647 and metformin greatly suppressed liver injury and fibrosis via activation of the AMP-activated protein kinase (AMPK) pathway. Further study revealed that co-treatment decreased the expression of inflammatory-, fibrogenesis-, and endoplasmic reticulum (ER) stress-related genes and increased the oxidized nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, suggesting the superiority of co-treatment due to restoration of mitochondrial function. The additive benefits of a PPARα agonist and metformin in a HF-CDAA diet-induced advanced NASH model was firstly demonstrated, possibly through restoration of mitochondrial function and AMPK activation, which finally resulted in suppression of hepatic inflammation, ER stress, then, fibrosis.

Pioglitazone Reduces Islet Triglyceride Content and Restores Impaired Glucose-Stimulated Insulin Secretion in Heterozygous Peroxisome Proliferator–Activated Receptor-γ–Deficient Mice on a High-Fat Diet Junji Matsui 1 , Yasuo Terauchi 2 , Naoto Kubota 1 2 , Iseki Takamoto 1 2 , Kazuhiro Eto 1 2 , Tokuyuki Yamashita 1 , Kajuro Komeda 3 , Toshimasa Yamauchi 1 2 , Junji Kamon 1 , Shunbun Kita 1 , Mitsuhiko Noda 2 4 and Takashi Kadowaki 1 2 1 Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan 2 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Kawaguchi, Japan 3 Division of Laboratory Animal Science, Animal Research Center, Tokyo Medical University, Tokyo, Japan 4 Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan Address correspondence and reprint requests to Takashi Kadowaki, MD, PhD, Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp Abstract Heterozygous peroxisome proliferator–activated receptor-γ (PPAR-γ)-deficient ( PPARγ +/− ) mice were protected from high-fat diet–induced insulin resistance. To determine the impact of systemic reduction of PPAR-γ activity on β-cell function, we investigated insulin secretion in PPARγ +/− mice on a high-fat diet. Glucose-induced insulin secretion in PPARγ +/− mice was impaired in vitro. The tissue triglyceride (TG) content of the white adipose tissue, skeletal muscle, and liver was decreased in PPARγ +/− mice, but it was unexpectedly increased in the islets, and the increased TG content in the islets was associated with decreased glucose oxidation. Administration of a PPAR-γ agonist, pioglitazone, reduced the islet TG content in PPARγ +/− mice on a high-fat diet and ameliorated the impaired insulin secretion in vitro. Our results demonstrate that PPAR-γ protects islets from lipotoxicity by regulating TG partitioning among tissues and that a PPAR-γ agonist can restore impaired insulin secretion under conditions of islet fat accumulation. FFA, free fatty acid KRBB, Krebs-Ringer bicarbonate buffer PPAR, peroxisome proliferator–activated receptor TG, triglyceride WAT, white adipose tissue Footnotes M.N. is currently affiliated with the Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan. Accepted March 20, 2003. Received February 5, 2003. DIABETES

The CBP protein (cAMP response element binding protein (CREB) binding protein) 1 is a co-activator 2 for several transcription factors with a wide range of important biological functions, such as sterol regulatory element binding proteins (SREBPs) 3 , CCAAT/enhancer-binding proteins (C/EBPs) 4 , nuclear receptors 5 , 6 (including peroxisome proliferator–activated receptors, PPARs) 7 , and signal transducers and activators of transcription (STATs) 8 . In contrast to these individual transcription factors, the biological roles of CBP are poorly understood. CBP enhances transcriptional activities via histone acetylation and the recruitment of additional co-activators such as SRC (steroid coactivator)−1 (ref. 9 ). To identify its physiological functions using a loss-of-function mutant, we analyzed CBP-deficient mice 10 , 11 , 12 . As Crebbp null mice ( Crebbp −/− ) died during embryogenesis 10 , 11 , 12 , we used Crebbp +/− mice 12 . Unexpectedly, Crebbp +/− mice showed markedly reduced weight of white adipose tissue (WAT) but not of other tissues. Despite this lipodystrophy, Crebbp +/− mice showed increased insulin sensitivity and glucose tolerance and were completely protected from body weight gain induced by a high-fat (HF) diet. We observed increased leptin sensitivity and increased serum adiponectin levels in Crebbp +/− mice. These increased effects of insulin-sensitizing hormones secreted from WAT may explain, at least in part, the phenotypes of Crebbp +/− mice. This study demonstrates that CBP may function as a 'master-switch' between energy storage and expenditure.

Increased Serum Leptin Protects From Adiposity Despite the Increased Glucose Uptake in White Adipose Tissue in Mice Lacking p85α Phosphoinositide 3-Kinase Yasuo Terauchi 1 2 , Junji Matsui 1 , Junji Kamon 1 , Toshimasa Yamauchi 1 2 , Naoto Kubota 1 2 3 , Kajuro Komeda 4 , Shinichi Aizawa 5 , Yasuo Akanuma 2 6 , Motowo Tomita 7 and Takashi Kadowaki 1 2 3 1 Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan 2 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Kawaguchi, Japan 3 National Institute of Health and Nutrition, Tokyo, Japan 4 Division of Laboratory Animal Science, Animal Research Center, Tokyo Medical University, Tokyo, Japan 5 Laboratory for Vertebrate Body Plan, Center for Developmental Biology, RIKEN, Kobe, Japan 6 Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan 7 Department of Physiological Chemistry, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan Address correspondence and reprint requests to Takashi Kadowaki, MD, PhD, Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp Abstract Mice lacking the p85α regulatory subunit of phosphoinositide (PI) 3-kinase (Pik3r1 −/− ) showed increased glucose uptake in white adipose tissue (WAT) and skeletal muscle due to increased phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P3] production and on a normal diet had a body weight and fat mass similar to wild-type mice. After 3 months on a high-fat diet, Pik3r1 −/− mice still had increased insulin sensitivity and better glucose tolerance than wild-type mice, but showed markedly greater increases in body weight and WAT mass than wild-type mice. On the normal diet, serum leptin levels of Pik3r1 −/− mice were significantly higher than in wild-type mice as a result of increased leptin secretion from adipocytes, presumably due to the increased PtdIns(3,4,5)P3 production in adipocytes. Leptin (5 μg/g body wt per day) caused a reduction in food intake and decrease in body weight by the wild-type mice as well as Pik3r1 −/− mice, suggesting Pik3r1 −/− mice having leptin sensitivity similar to wild-type mice. The slightly increased serum leptin compensated for the increased glucose uptake by adipocytes in Pik3r1 −/− mice, thereby preventing adiposity on the normal diet. On the high-fat diet, leptin (5 μg/g body wt per day) failed to decrease food intake or body weight in either genotype, indicating that both genotypes had indeed become severely leptin resistant. Consequently, leptin secretion was unable to sufficiently compensate for the severe leptin resistance caused by the high-fat diet, thereby failing to prevent obesity in Pik3r1 −/− mice. Our findings suggest that primary increase in serum leptin on the normal diet play a role in the protection from adiposity in Pik3r1 −/− mice. GFAT, glutamine:fructose-6-phosphate amidotransferase GTT, glucose tolerance test HPLC, high-performance liquid chromatography IRS, insulin receptor substrate KRBH, Krebs Ringer bicarbonate buffer PI, phosphoinositide PMSF, phenylmethylsulfonyl fluoride PtdIns(3,4,5)P3, phosphatidylinositol (3,4,5)-triphosphate WAT, white adipose tissue Footnotes Accepted May 20, 2004. Received May 1, 2003. DIABETES

Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.

Mice lacking the p85alpha regulatory subunit of phosphoinositide (PI) 3-kinase (Pik3r1(-/-)) showed increased glucose uptake in white adipose tissue (WAT) and skeletal muscle due to increased phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P3] production and on a normal diet had a body weight and fat mass similar to wild-type mice. After 3 months on a high-fat diet, Pik3r1(-/-) mice still had increased insulin sensitivity and better glucose tolerance than wild-type mice, but showed markedly greater increases in body weight and WAT mass than wild-type mice. On the normal diet, serum leptin levels of Pik3r1(-/-) mice were significantly higher than in wild-type mice as a result of increased leptin secretion from adipocytes, presumably due to the increased PtdIns(3,4,5)P3 production in adipocytes. Leptin (5 microg/g body wt per day) caused a reduction in food intake and decrease in body weight by the wild-type mice as well as Pik3r1(-/-) mice, suggesting Pik3r1(-/-) mice having leptin sensitivity similar to wild-type mice. The slightly increased serum leptin compensated for the increased glucose uptake by adipocytes in Pik3r1(-/-) mice, thereby preventing adiposity on the normal diet. On the high-fat diet, leptin (5 microg/g body wt per day) failed to decrease food intake or body weight in either genotype, indicating that both genotypes had indeed become severely leptin resistant. Consequently, leptin secretion was unable to sufficiently compensate for the severe leptin resistance caused by the high-fat diet, thereby failing to prevent obesity in Pik3r1(-/-) mice. Our findings suggest that primary increase in serum leptin on the normal diet play a role in the protection from adiposity in Pik3r1(-/-) mice.

Mice lacking the p85[alpha] regulatory subunit of phosphoinositide (PI) 3-kinase (Pik3r[1.sup.-/-]) showed increased glucose uptake in white adipose tissue (WAT) and skeletal muscle due to increased phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P3] production and on a normal diet had a body weight and fat mass similar to wild-type mice. After 3 months on a high-fat diet, Pik3r[1.sup.-/-] mice still had increased insulin sensitivity and better glucose tolerance than wild-type mice, but showed markedly greater increases in body weight and WAT mass than wild-type mice. On the normal diet, serum leptin levels of Pik3r[1.sup.-/-] mice were significantly higher than in wild-type mice as a result of increased leptin secretion from adipocytes, presumably due to the increased PtdIns(3,4,5)P3 production in adipocytes. Leptin (5 [micro]g/g body wt per day) caused a reduction in food intake and decrease in body weight by the wild-type mice as well as Pik3r[1.sup.-/-] mice, suggesting Pik3r[1.sup.-/-] mice having leptin sensitivity similar to wild-type mice. The slightly increased serum leptin compensated for the increased glucose uptake by adipocytes in Pik3r[1.sup.-/-] mice, thereby preventing adiposity on the normal diet. On the high-fat diet, leptin (5 [micro]g/g body wt per day) failed to decrease food intake or body weight in either genotype, indicating that both genotypes had indeed become severely leptin resistant. Consequently, leptin secretion was unable to sufficiently compensate for the severe leptin resistance caused by the high-fat diet, thereby failing to prevent obesity in Pik3r[1.sup.-/-] mice. Our findings suggest that primary increase in serum leptin on the normal diet play a role in the protection from adiposity in Pik3r[1.sup.-/-] mice.