Alternative titles; symbols
HGNC Approved Gene Symbol: ADIPOR2
Cytogenetic location: 12p13.33 Genomic coordinates (GRCh38) : 12:1,691,070-1,788,674 (from NCBI)
The adiponectin receptors, ADIPOR1 (607945) and ADIPOR2, serve as receptors for globular and full-length adiponectin (605441) and mediate increased AMPK (see 602739) and PPAR-alpha (PPARA; 170998) ligand activities, as well as fatty acid oxidation and glucose uptake by adiponectin (Yamauchi et al., 2003).
Yamauchi et al. (2003) isolated cDNAs encoding ADIPOR1 and ADIPOR2 by expression cloning. The mouse Adipor2 protein contains 311 amino acids and has a predicted molecular mass of 35.4 kD. Human ADIPOR2 has 299 amino acids and shares 95.2% identity with the mouse protein. ADIPOR1 and ADIPOR2 are highly related structurally, and mouse Adipor1 and Adipor2 share 66.7% identity. ADIPOR1 and ADIPOR2 are 7-transmembrane domain proteins, but they are structurally, topologically, and functionally distinct from G protein-coupled receptors (GPCRs). Epitope tag labeling showed that the N terminus is internal and the C terminus is external in the ADIPORs, a topology opposite that of GPCRs. ADIPOR1 and ADIPOR2 are conserved from yeast to human, especially in the membrane-spanning regions. The authors noted that the yeast homolog has a principal role in metabolic pathways that regulate lipid metabolism, such as fatty acid oxidation. Northern blot analysis of mouse or human tissues detected a major 4.0-kb ADIPOR2 transcript that was most abundantly expressed in liver.
Tang et al. (2005) stated that ADIPOR1 and ADIPOR2 are the founding members of a 7-transmembrane domain protein family that they called the PAQR family. The deduced full-length ADIPOR2 protein, which Tang et al. (2005) called PAQR2, contains 386 amino acids. RT-PCR detected high ADIPOR2 expression in all 20 human tissues examined.
Tang et al. (2005) determined that the ADIPOR2 gene contains 7 coding exons.
Crystal Structure
Tanabe et al. (2015) reported the crystal structures of human ADIPOR1 and ADIPOR2 at 2.9- and 2.4-angstrom resolution, respectively, representing a novel class of receptor structure. The 7-transmembrane helices, conformationally distinct from those of G protein-coupled receptors, enclose a large cavity where 3 conserved histidine residues coordinate a zinc ion. The zinc-binding structure may have a role in adiponectin-stimulated AMPK phosphorylation and UCP2 (601693) upregulation. Adiponectin may broadly interact with the extracellular face, rather than the carboxy-terminal tail, of the receptors.
Vasiliauskaite-Brooks et al. (2017) described the crystal structure of ADIPOR2 bound to a free fatty acid molecule and show that ADIPOR2 possesses intrinsic basal ceramidase activity that is enhanced by adiponectin. The authors also identified a ceramide binding pose and proposed a possible mechanism for the hydrolytic activity of ADIPOR2 using computational approaches. In molecular dynamics simulations, the side chains of residues coordinating the zinc rearranged quickly to promote the nucleophilic attack of a zinc-bound hydroxide ion onto the ceramide amide carbonyl. Furthermore, Vasiliauskaite-Brooks et al. (2017) presented a revised ADIPOR1 crystal structure exhibiting a 7-transmembrane-domain architecture that is clearly distinct from that of ADIPOR2. In this structure, no free fatty acid is observed and the ceramide binding pocket and putative zinc catalytic site are exposed to the inner membrane leaflet. ADIPOR1 also possesses intrinsic ceramidase activity, so Vasiliauskaite-Brooks et al. (2017) suspected that the 2 distinct structures may represent key steps in the enzymatic activity of ADIPORs. The ceramidase activity is low, however, and the authors suggested that further studies are required to characterize fully the enzymatic parameters and substrate specificity of ADIPORs.
Yamauchi et al. (2003) stated that the human ADIPOR2 gene maps to chromosome 12p13.31 and the mouse Adipor2 gene maps to chromosome 6F1.
Yamauchi et al. (2003) showed that expression of ADIPOR1 or ADIPOR2 at the cell surface in 293T cells enhanced the binding of both globular and full-length adiponectin. In 293T cells expressing ADIPOR1, globular or full-length adiponectin had little effect on cyclic AMP, cyclic GMP, and intracellular calcium levels. In contrast, expression of ADIPOR1 enhanced increases in PPARA ligand activity by both globular and full-length adiponectin. Expression of ADIPOR1 or ADIPOR2 in myocytes demonstrated that both proteins were able to mediate binding of globular and full-length adiponectin and increases in PPARA ligand activity and fatty acid oxidation by globular and full-length adiponectin. Further expression and suppression experiments indicated that, unlike GPCRs, ADIPOR1 and ADIPOR2 do not seem to be coupled with G protein, but activate unique sets of signaling molecules, such as PPARA, AMPK, and p38 MAPK (MAPK14; 600289). Scatchard plot analysis showed that ADIPOR1 is a high-affinity receptor for globular adiponectin but a low-affinity receptor for full-length adiponectin, while ADIPOR2 is an intermediate-affinity receptor for globular and full-length adiponectin. In this respect, fatty acid oxidation mediated through ADIPOR1 was highly sensitive to globular adiponectin, but was resistant to full-length adiponectin. Fatty acid oxidation mediated through ADIPOR2 was intermediately sensitive to globular or full-length adiponectin. Thus, there was a good correlation between binding affinity and adiponectin sensitivity, and the half-maximum effective dose corresponded to 13 to 50% of the Kd on a molar basis.
Holland et al. (2011) found that mouse and human ADIPOR1 and ADIPOR2 were associated with ceramidase activity. Treatment of cells with adiponectin or overexpression of adiponectin in mice potently stimulated ceramide catabolism and formation of its antiapoptotic metabolite, sphingosine 1-phosphate (S1P). Using models of caspase-8 (CASP8; 601763)-mediated apoptosis in mouse pancreatic beta cells and cardiomyocytes, Holland et al. (2011) showed that overexpression of adiponectin decreased apoptosis, whereas ablation of adiponectin enhanced apoptosis. Ceramidase activity was impaired in Adipor1 -/- Adipor2 -/- mouse embryonic fibroblasts, leading to elevated ceramide levels and enhanced susceptibility to palmitate- or ceramide-induced cell death. Mutation of conserved histidines in mouse Adipor1 and Adipor2 reduced their ceramidase activities following transfection in HEK293 cells. The effect of adiponectin on insulin sensitivity and cell survival appeared to be positively and negatively correlated with sphingolipid and ceramide levels, respectively, and independent of AMPK activation. Holland et al. (2011) proposed that adiponectin promotes insulin sensitivity and cell survival by inducing ceramide catabolism and S1P production.
Using an adenovirus vector, Yamauchi et al. (2007) overexpressed Adipor1 and Adipor2 in the liver of Lepr (601007)-null db/db mice and observed increased AMPK activation and PPARA signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and led to an amelioration of diabetes. Targeted disruption of Adipor1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of Adipor2 resulted in decreased activity of PPARA signaling pathways. Simultaneous disruption of both Adipor1 and Adipor2 resulted in increased tissue triglyceride content, inflammation, and oxidative stress, leading to insulin resistance and marked glucose intolerance. Yamauchi et al. (2007) concluded that ADIPOR1 and ADIPOR2 are 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.
Holland, W. L., Miller, R. A., Wang, Z. V., Sun, K., Barth, B. M., Bui, H. H., Davis, K. E., Bikman, B. T., Halberg, N., Rutkowski, J. M., Wade, M. R., Tenorio, V. M., Kuo, M.-S., Brozinick, J. T., Zhang, B. B., Birnbaum, M. J., Summers, S. A., Scherer, P. E. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nature Med. 17: 55-63, 2011. [PubMed: 21186369] [Full Text: https://doi.org/10.1038/nm.2277]
Tanabe, H., Fujii, Y., Okada-Iwabu, M., Iwabu, M., Nakamura, Y., Hosaka, T., Motoyama, K., Ikeda, M., Wakiyama, M., Terada, T., Ohsawa, N., Hato, M., and 12 others. Crystal structures of the human adiponectin receptors. Nature 520: 312-316, 2015. [PubMed: 25855295] [Full Text: https://doi.org/10.1038/nature14301]
Tang, Y. T., Hu, T., Arterburn, M., Boyle, B., Bright, J. M., Emtage, P. C., Funk, W. D. PAQR proteins: a novel membrane receptor family defined by an ancient 7-transmembrane pass motif. J. Molec. Evol. 61: 372-380, 2005. [PubMed: 16044242] [Full Text: https://doi.org/10.1007/s00239-004-0375-2]
Vasiliauskaite-Brooks, I., Sounier, R., Rochaix, P., Bellot, G., Fortier, M., Hoh, F., De Colibus, L., Bechara, C., Saied, E. M., Arenz, C., Leyrat, C., Granier, S. Structural insights into adiponectin receptors suggest ceramidase activity. Nature 544: 120-123, 2017. [PubMed: 28329765] [Full Text: https://doi.org/10.1038/nature21714]
Yamauchi, T., Kamon, J., Ito, Y., Tsuchida, A., Yokomizo, T., Kita, S., Sugiyama, T., Miyagishi, M., Hara, K., Tsunoda, M., Murakami, K., Ohteki, T., and 14 others. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423: 762-769, 2003. Note: Erratum: Nature 431: 1123 only, 2004. [PubMed: 12802337] [Full Text: https://doi.org/10.1038/nature01705]
Yamauchi, T., Nio, Y., Maki, T., Kobayashi, M., Takazawa, T., Iwabu, M., Okada-Iwabu, M., Kawamoto, S., Kubota, N., Kubota, T., Ito, Y., Kamon, J. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nature Med. 13: 332-339, 2007. [PubMed: 17268472] [Full Text: https://doi.org/10.1038/nm1557]