Opposing Effects of Adiponectin Receptors 1 and 2 on Energy Metabolism

Opposing Effects of Adiponectin Receptors 1 and 2 on Energy Metabolism Mikael Bjursell 1 2 , Andrea Ahnmark 1 , Mohammad Bohlooly-Y 1 2 , Lena William-Olsson 1 , Magdalena Rhedin 1 , Xiao-Rong Peng 1 , Karolina Ploj 1 , Anna-Karin Gerdin 1 , Gunnel Arnerup 3 , Anders Elmgren 1 , Anna-Lena Berg 3 , Jan Oscarsson 1 2 4 and Daniel Lindén 1 4 1 AstraZeneca R&D, Mölndal, Sweden 2 Department of Physiology/Endocrinology, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden 3 Safety Assessment Sweden, AstraZeneca R&D, Södertälje, Sweden 4 Wallenberg Laboratory for Cardiovascular Research, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden Address correspondence and reprint requests to Daniel Lindén, AstraZeneca R&D, Department of Integrative Pharmacology, SE-431 83 Mölndal, Sweden. E-mail: daniel.linden{at}astrazeneca.com Abstract The adipocyte-derived hormone adiponectin regulates glucose and lipid metabolism and influences the risk for developing obesity, type 2 diabetes, and cardiovascular disease. Adiponectin binds to two different seven-transmembrane domain receptors termed AdipoR1 and AdipoR2. To study the physiological importance of these receptors, AdipoR1 gene knockout mice ( AdipoR1 −/− ) and AdipoR2 gene knockout mice ( AdipoR2 −/− ) were generated. AdipoR1 −/− mice showed increased adiposity associated with decreased glucose tolerance, spontaneous locomotor activity, and energy expenditure. However, AdipoR2 −/− mice were lean and resistant to high-fat diet–induced obesity associated with improved glucose tolerance and higher spontaneous locomotor activity and energy expenditure and reduced plasma cholesterol levels. Thus, AdipoR1 and AdipoR2 are clearly involved in energy metabolism but have opposing effects. ABCA1, ATP binding cassette transporter-1 AGRP, agouti-related peptide AMPK, AMP-activated protein kinase apoAI, apolipoprotein AI BAT, brown adipose tissue CPT-1, carnitine palmitoyl transferase-1 CRH, corticotrophin-releasing hormone DEXA, dual-energy X-ray absorptiometry HFD, high-fat diet NPY, neuropeptide Y PPARα, peroxisome proliferator–activated receptor α SNP, single nucleotide polymorphism WAT, white adipose tissue Footnotes Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1432 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18