Molecular and structural pharmacology of adiponectin receptor: towards innovative treatments of obesity-related diseases.

Project Information

ADIPOR

Grant agreement ID: 647687

DOI

10.3030/647687

Project closed

EC signature date 26 June 2015

Start date 1 July 2015

End date 31 December 2020

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 989 518,00

EU contribution

€ 1 989 518,00

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 4 - ADIPOR (Molecular and structural pharmacology of adiponectin receptor: towards innovative treatments of obesity-related diseases.)

Reporting period: 2020-01-01 to 2020-12-31

Summary of the context and overall objectives of the project

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 was 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 from the beginning of the project to the end of the period covered by the report and main results achieved so far

This ERC grant focused on the molecular and structural pharmacology of adiponectin receptors (ADIPORs). ADIPORs are promising targets for ORD (T2D etc..) but, so far, drug discovery programs have failed, most likely due to the lack of structural and functional knowledge on this membrane protein and to the absence of an efficient technology to screen for molecules that can modify their activity.
During our ERC ADIPOR, we have discovered a novel enzymatic activity of adiponectin receptors as well as their structural identity/relationships with alkaline ceramidases (ACER3) (Nature and Nature comm papers). ACER3 has been implicated in human diseases (Leukodystrophy E33G mutant and AML cancers).
Those two enzymes modulate the level of ceramide, a key bioactive lipid implicated in many pathophysiological conditions (insulin sensitivity, apoptosis).
Importantly, we have succeeded in developing an innovative biophysical assay to monitor the ceramidase enzymatic activity in a high-throughput manner (IP protection undergoing with INSERM-transfert).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

In conclusion of the action, the biochemical and structural data obtained during this grant 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. The three most significant achievements are the discovery of structures and enzymatic activities of Adiponectin receptors, the discovery of structures of AdipoRs analogs involved in human diseases and the development of key technologies to enable drug discovery to treat diseases involving ADIPORs and ceramidases.

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