Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - ADIPOR (Molecular and structural pharmacology of adiponectin receptor: towards innovative treatments of obesity-related diseases.)

Teaser

Increased ceramide levels in obese individuals have been demonstrated to correlate with insulin resistance and type II diabetes. Adiponectin receptors (ADIPORs) are integral membrane proteins possessing potent antidiabetic actions, at least partly arbitrated to...

Summary

Increased ceramide levels in obese individuals have been demonstrated to correlate with insulin resistance and type II diabetes. Adiponectin receptors (ADIPORs) are integral membrane proteins possessing potent antidiabetic actions, at least partly arbitrated to receptor-associated ceramidase activity, resulting in hydrolysis of ceramide to sphingosine and fatty acid. The recent crystal structures of two receptor subtypes, ADIPOR1 and ADIPOR2, revealed that their architecture but the molecular mechanisms of ADIPORs function were still obscure however.
The overall objectives of the project is to characterize how the adiponectin binding to the receptor ADIPORs leads to anti-diabetic, anti inflamatory and anti-proliferative actions using structural biology and pharmacology. Ultimately, this study will enable the development of treatment for obesity-related diseases such as type 2 diabetes, cardiovascular diseases ans cancer.

Work performed

The laboratory of Dr Sébastien Granier, supported by the ERC consolidator grant ADIPOR (647687), solved two crystal structures of ADIPOR2 bound to a free fatty acid molecule and demonstrate that ADIPORs possess an intrinsic ceramidase activity. This work also determined the ceramide binding pose within the internal cavity of ADIPOR2 and proposed a putative ceramide hydrolysis mechanism using computational methods. Moreover, the team presented a revised ADIPOR1 crystal structure with a different architecture in comparison with ADIPOR2. In conclusion, the biochemical and structural data demonstrated for the first time that ADIPORs have a direct ceramidase activity.
Highlighting the importance of the discovery made by the laboratory during this first period of the grant is the fact that this work was published in the most prestigious scientific journal \'Nature\'.

Final results

In conclusion, the biochemical and structural data obtained during the first period demonstrate that ADIPORs are enzymes. Since insulin resistance and type 2 diabetes correlate with increased levels of ceramides and reduced expression of ADIPORs, this study may facilitate the development of new therapeutic approaches to treating obesity-related diseases by modifying the enzymatic activity of the ADIPORs.
We hypothesize that the two different ADIPOR structures discovered during our study may represent possible conformational changes of the receptors during the enzymatic process. We also hypothesize that, to exert its function, adiponectin is increasing the enzymatic activity of the receptor by modifying the ADIPOR conformational changes. Those hyptothesis are being tested and we expect to obtain insights into the adiponectin-adiponectin receptor function during the last period of the grant.