Diabetes Metab J.  2015 Oct;39(5):363-372. 10.4093/dmj.2015.39.5.363.

Perspective of Small-Molecule AdipoR Agonist for Type 2 Diabetes and Short Life in Obesity

• Okada-Iwabu M
• Iwabu M
• Ueki K
• Yamauchi T
• Kadowaki T

• KMID: 2174009
• DOI: http://doi.org/10.4093/dmj.2015.39.5.363

Abstract

Obesity associated with unhealthy diet and lack of exercise is shown to contribute to the onset and/or aggravation of the metabolic syndrome and diabetes, thus placing affected individuals at increased risk of cardiovascular disease and cancer. Plasma adiponectin levels are decreased in obesity, which causes insulin resistance and diabetes. Therefore, we identified adiponectin receptors (AdipoRs) as the therapeutic target. It was suggested that, similarly to caloric restriction and exercise, activation of the AdipoRs may have the potential not only to improve lifestyle-related diseases but to contribute to prolonged the shortened lifespan on a high caloric unhealthy diet. To this end, we have identified "AdipoRon" as an adiponectin receptor agonist. Indeed, AdipoRon ameliorated diabetes associated with obesity as well as to increase exercise endurance, thus prolonging shortened lifespan of obese mice fed on a high fat diet. Additionally, we have recently determined the crystal structures of the human AdipoRs. The seven-transmembrane helices of AdipoRs are structurally distinct from those of G-protein coupled receptors. It is expected that these findings will contribute not only to the elucidation of the AdipoR-related signal transduction but to the development and optimization of AdipoR-targeted therapeutics for obesity-related diseases such as diabetes.

Keyword

Adiponectin; AdipoR; Agonist; Crystal structure; Diabetes mellitus; Obesity

MeSH Terms

Adiponectin
Animals
Caloric Restriction
Cardiovascular Diseases
Diabetes Mellitus
Diet
Diet, High-Fat
GTP-Binding Proteins
Humans
Insulin Resistance
Mice
Mice, Obese
Obesity*
Plasma
Receptors, Adiponectin
Signal Transduction
Adiponectin
GTP-Binding Proteins
Receptors, Adiponectin

Figure

• 

  Fig. 1 In liver, adiponectin receptor 1 (AdipoR1) activates AMP-activated protein kinase (AMPK) pathway, whereas AdipoR2 activates peroxisome proliferator-activated receptor α (PPARα) pathway, both ameliorating insulin resistance and steatosis [3034]. AdipoRon, adiponectin receptor agonist; LKB1, liver kinase B1; PEPCK, phosphoenolpyruvate carboxykinase; SREBP1c, sterol regulatory element-binding protein 1c; TNFα, tumor necrosis factor α; MCP1, monocyte chemoattractant protein 1; ACO, acyl CoA oxidase; UCP2, uncoupling protein 2.

• 

  Fig. 2 In muscle, adiponectin receptor 1 (AdipoR1) regulates peroxisome proliferator-activated receptor α (PPARα) coactivator-1 (PGC-1α) via AMP-activated protein kinase (AMPK)-sirtuin 1 (SIRT1) and Ca2+-calcium/calmodulin-dependent protein kinase kinase (CaMKK) pathways to promote mitochondrial biogenesis [3134]. AdipoRon, adiponectin receptor agonist; NADH, nicotinamide adenine dinucleotide; CaMK, calcium/calmodulin-dependent protein kinase; LKB1, liver kinase B1.

• 

  Fig. 3 Strategy for development of first- and best-in-class adiponectin receptor (AdipoR) agonists in the treatment of obesity-related diseases such as type 2 diabetes. AdipoR1 and AdipoR2 were discovered in 2003, and they have been shown to represent a key drug target in obesity-related diseases. Small-molecule compound targeted to AdipoR (adiponectin receptor agonist [AdipoRon]) was developed and reported in 2013, and crystal structures of AdipoRs were determined in 2015. Elucidation of crystal structures of AdipoRon-AdipoR complex should be important for development of first- and best-in-class drugs for type 2 diabetes and obesity-linked diseases [2830313443].

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