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Abstract
Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.
Authors
Takashi Kadowaki, Toshimasa Yamauchi, Naoto Kubota, Kazuo Hara, Kohjiro Ueki, Kazuyuki Tobe
Response to Kadowaki et al. AdipoR2 is a 43 kDa protein
Submitter: Christa Buechler | christa.buechler@klinik.uni-regensburg.de
University of Regensburg, Internal Medicine I
Published July 17, 2006
We would like to comment on figure 2 in the review by Kadowaki et al. indicating that AdipoR2 is a shorter protein when compared to AdipoR1 (1). The original publication describing AdipoR1 and AdipoR2 also suggests a molecular weight of 42.0 kDa for AdipoR1 and 35.4 kDa for AdipoR2, respectively. (2). Analysis of human databases for AdipoR2 homology revealed an open reading frame (ORF) of 1,160 bp (REFSEQ NM_024551.2) that most likely encodes a protein of about 43 kDa. The homologous sequences from mouse (NM-197985) and rat (NM_001037979) also indicate an ORF of 1,160 bp each. RT-PCR was performed with RNA from hepatocytes and sequencing confirmed that a 1,160 ORF is encoded by the AdipoR2 mRNA. The cDNA fragment was cloned in a vector allowing in-vitro transcription and, upon immunoblot using the C-terminal V5 tag, we have published that AdipoR2 is a 43 kDa protein (3). Recombinant expression in HepG2 and COS-7 cells further confirmed that a 43 kDa protein is expressed. Bub et. al performed immunoblots with prostate cells and endogenous AdipoR2 had a similar molecular weight as AdipoR1 demonstrating that AdipoR2 is longer than initially described (4). These data demonstrate that an N-terminaly extended AdipoR2 protein exists. This receptor is by 75 amino acids larger when compared to the initial description of AdipoR2. These additional amino acids show no homology to AdipoR1 although the rest of these proteins are highly homologous (http://www.expasy.ch/tools/sim-prot.html).
Taken together these findings indicate that AdipoR2 is similar in size to AdipoR1. The N-terminal portion of AdipoR2 is unique for this receptor indicating that AdipoR2 may have distinct functions.
The study was supported by a grant from the Deutsche Forschungsgemeinschaft (BU 1141/3-2).
References
1.Kadowaki, T., Yamauchi, T., Kubota, N., Hara, K., Ueki, K., and Tobe, K. 2006. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116:1784-1792.
2.Yamauchi, T., Kamon, J., Ito, Y., Tsuchida, A., Yokomizo, T., Kita, S., Sugiyama, T., Miyagishi, M., Hara, K., Tsunoda, M., et al. 2003. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423:762-769.
3.Neumeier, M., Weigert, J., Schaffler, A., Weiss, T., Kirchner, S., Laberer, S., Scholmerich, J., and Buechler, C. 2005. Regulation of adiponectin receptor 1 in human hepatocytes by agonists of nuclear receptors. Biochem Biophys Res Commun 334:924-929.
4.Bub, J.D., Miyazaki, T., and Iwamoto, Y. 2006. Adiponectin as a growth inhibitor in prostate cancer cells. Biochem Biophys Res Commun 340:1158-1166.
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