Alternative titles; symbols
FLJ21432
TEXT
DESCRIPTION
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). 
CLONING
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.
GENE FUNCTION
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.
MAPPING
Yamauchi et al. (2003) stated that the human ADIPOR2 gene maps to chromosome 12p13.31 and the mouse Adipor2 gene maps to chromosome 6F1.
ANIMAL MODEL
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.
REFERENCES
- 1. 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 ID : 12802337
- 2. 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 ID : 17268472
CONTRIBUTORS
Marla J. F. O'Neill - updated : 4/27/2007
CREATION DATE
Ada Hamosh : 7/14/2003
EDIT HISTORY
wwang : 4/27/2007
alopez : 7/21/2005
terry : 11/22/2004
mgross : 7/14/2003
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