Atsushi Tsuchida

Cloning of adiponectin receptors that mediate antidiabetic metabolic effects

Corrigendum (2004)10.1038/nature03091Adiponectin (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-α. 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-α ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.

Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions

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.

Infrared Transmission Spectrum and Lattice Vibration Analysis of Some Perovskite Fluorides

Infrared absorption spectra of the perovskite fluorides KMF3(M:Ni, Mg, and Zn) and NaNiF3 have been measured in the region 700 to 50 cm−1 at room temperature and liquid‐nitrogen temperature. Three absorption bands for KMF3 were observed and these have been assigned to the f1u lattice modes. A normal‐coordinate analysis of the crystal as a whole has been performed and the interatomic force constants in the crystal have been obtained. The forms of the normal modes of the lattice vibrations have been fully described on the basis of the normal‐coordinate treatment. Vibrational assignments have been supported from the experimental ground (temperature effect) and the theoretical side. The compound NaNiF3 reveals a much more complicated spectrum than those of KMF3, which suggests a structure of an appreciable deformation from the regular cubic perovskite. The analysis of the lattice vibrations for the rutile counterparts has been made based on the normal‐coordinate treatment by the use of the force constants tra...

Peroxisome Proliferator-activated Receptor γ Agonist Rosiglitazone Increases Expression of Very Low Density Lipoprotein Receptor Gene in Adipocytes

Apolipoprotein E (apoE) and its receptor, very low density lipoprotein receptor (VLDLR), are involved in fat accumulation in adipocytes. Here, we investigated the effect of a peroxisome proliferator-activated receptor (PPAR) γ agonist, rosiglitazone, on regulation of VLDLR expression both in white adipose tissue (WAT) of obese mice and in cultured adipocytes. Furthermore, to determine whether rosiglitazone directly regulates transcription of the VLDLR gene, we carried out luciferase assay with a reporter gene containing mouse VLDLR promoter region, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. Four-day treatment with rosiglitazone increased the expression of VLDLR in WAT of ob/ob mice. Moreover, rosiglitazone increased the expression of VLDLR in cultured adipocytes. The PPAR-responsive element (PPRE)-directed mutagenesis analyses revealed that the PPRE motif in the VLDLR promoter region plays a significant role in transcriptional activation of the VLDLR gene in adipocytes. In addition, electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that endogenous PPARγ directly binds to this functional PPRE motif in the VLDLR promoter region. We also investigated the effects of rosiglitazone on insulin sensitivity and lipid accumulation in both ob/ob mice and apoE-deficient ob/ob mice. Rosiglitazone ameliorated insulin sensitivity in both ob/ob mice and apoE-deficient ob/ob mice, possibly through decreasing the expression of monocyte chemoattractant protein-1 (MCP-1), increasing the expression of superoxide dismutase 1 (SOD1) in WAT, and increasing plasma adiponectin concentration. In ob/ob mice, body weight and WAT weight were significantly higher in the mice treated with rosiglitazone than those treated with vehicle. However, in apoE-deficient ob/ob mice, no significant difference in body weight or WAT weight was observed between the vehicle-treated group and the rosiglitazone-treated group. Moreover, rosiglitazone did not increase body weight and WAT weight in VLDLR-deficient mice. These findings indicate that rosiglitazone directly increases VLDLR expression, thereby enhancing apoE-VLDLR-dependent lipid accumulation in adipocytes.

Influence of Magnetic Ordering on the Lattice Vibration of KNiF3

Lattice vibration of KNiF 3 was measured in the far-infrared region as a function of temperature covering the Neel point. There exist three modes of vibration, ν 1 , ν 2 and ν 3 . A positive shift due to the antiferromagnetic ordering has been observed in the second mode. The analysis of the shift has given the second derivatives of the exchange integral with respect to the fluorine displacement: ∂ 2 J /∂ v x 2 / J ≃-5/A 2 and ∂ 2 J /∂ v z 2 / J ≃0.8/A 2 , in which x and z are perpendicular and parallel to the Ni-F-Ni bond direction, respectively. These values show the 180° directionality of the superexchange interaction which is responsible for the antiferromagnetism of KNiF 3 . In addition, a slight change in the temperature coefficient of frequency has been observed at the Neel point in the highest mode ν 1 , which has been compared with the volume magnetostriction measured by the strain gauge and X-ray techniques.

Lattice Vibration and Cubic‐to‐Tetragonal Transformation in Spinel‐Type Chromites

Infrared transmission of NiCr2O4 and MnCr2O4 powder was measured from 15 to 500 μ and at 100°–400°K. Four absorption peaks were discovered at ∼600, ∼500, ∼400, and ∼200 cm−1. The peak near 200 cm−1 of NiCr2O4 showed a shift with temperature which is apparently proportional to the change of c/a, while the width remained constant. This fact seems difficult to interpret by the localized limit theory of cubic‐to‐tetragonal transition of crystals.

Phonon-Induced Spin-Dependent Infrared Absorption in KNiF3

A temperature-dependent absorption band was observed in the infrared region for KNiF 3 below the Neel temperature ( T N =275°K). The peak is located at 1230 cm -1 at 100°K and shifts to the longer wave-length side with increasing temperature. This band can be attributed to a phonon-induced electric dipole transition of the spin system which has been discussed by Mizuno and Koide. The exchange parameter for KNiF 3 is determined from the peak position to be J =52.3°K or 55.3°K.