HONG KONG – Japanese scientists have used an advanced high-energy radiation particle accelerator to elucidate the structure of two receptors of the adipocyte-derived hormone, adiponectin, which could lead to the development of new treatments for obesity-related diseases, in particular type 2 diabetes.

Researchers at the Riken Structural Biology Laboratory and Center for Life Science Technologies in Yokohama, in collaboration with the University of Tokyo, used the SPring-8 synchrotron facility to map the structure of the adiponectin AdipoR1 and AdipoR2 receptors, they reported in the April 8, 2015, issue of Nature.

Located in Harima and run by the Japan Synchrotron Radiation Research Group, the SPring-8 (Super Photon ring-8 Giga-Electron-Volt [GeV]) synchrotron is a circular particle accelerator facility that is one of only five such large (>5 GeV) radiation facilities in the world. Synchrotrons have valuable nanotechnology and biotechnology applications, including molecular crystallography.

Adiponectin is involved in the regulation of both glucose and fatty acid oxidation. Its levels are reduced in patients with both type 1 and type 2 diabetes, and in mouse models, the administration of the peptide hormone has been reported to improve glucose intolerance.

In addition, in mice fed on a high-fat diet, the recently discovered small-molecule adiponectin receptor agonist, Adiporon, showed very similar effects to adiponectin in muscle and liver, such as activation of the AMPK and PPAR-alfa signaling pathways, which are also involved in glucose and lipid metabolism.

"Adiponectin receptor agonists, including Adiporon, were discovered in a study led by Takashi Kadowaki, a professor in the department of metabolic diseases at the University of Tokyo," said lead researcher of the present study, Shigeyuki Yokoyama, a distinguished senior scientists with the Riken Structural Biology Laboratory and an emeritus professor at the University of Tokyo.

In that landmark study, which was published in the Nov. 28, 2013, edition of Nature, Adiporon was further shown to ameliorate insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice.

Moreover, the adiponectin receptor antagonist was demonstrated to improve diabetes in genetically obese mouse models and to prolong the shortened life spans of mice fed a high-fat diet.

Orally bioavailable small-molecule agonists of the AdipoR1 and AdipoR2 receptors, such as Adiporon, therefore, represent a promising new therapeutic approach for the treatment of obesity-related diseases, in particular the treatment of type 2 diabetes.

Since adiponectin binds to both AdipoR1 and AdipoR2, Yokoyama and colleagues reasoned that a thorough understanding of that binding could contribute to the development of agonist drugs that target those receptors. "The two receptors are the key molecules of metabolic syndrome," he told BioWorld Today.

Moreover, the genes coding for adiponectin receptors are evolutionarily conserved in many living beings and, since those genes have remained essentially unchanged by evolution, it is likely they are unique and essential, and therefore should play an important biological role.

Using a beamline at the SPring-8 synchrotron facility, the researchers obtained finely detailed crystallographic images of the two adiponectin receptors at resolutions of just 2.9 and 2.4 Ångstroms. "We used its micro-beam beam line, BL32XU, which is very powerful for the micro-crystallography of human integral membrane proteins," explained Yokoyama.

Those detailed crystallographic images revealed the important finding that the structure of the two adiponectin receptors was of a completely new type that is unlike G protein-coupled (GPC) receptors, the most common type of receptor targeted by drug therapies, as they were found to incorporate a zinc ion held in place by three histidine amino acid residues.

"As the crystal structures of AdipoR1 and AdipoR2 are completely different from those of GPC receptors, their modes of action are also highly likely to be different from those of GPC receptors," said Yokoyama.

"Analyzing the structure of these two receptors provided us with a number of interesting surprises. We believe that this new information on the structure of the adiponectin receptors will help us understand new relationships between the structure and functions of these important receptors."

Those new structural findings "are expected to be useful for the improvement and/or refinement of adiponectin receptor agonists [such as Adiporon] and contribute to rational drug design and development," he added.

The research team also discovered that the receptors had large internal cavities. "The discovery of the presence of a zinc ion in the cavity is fascinating, though more work will be required to understand its significance," said Yokoyama. "The next step for us is the elucidation of the structural mechanisms by which adiponectin and Adiporon activate AdipoR1 and AdipoR2."