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Control of mouse metabolism by circadian clock-coordinated mRNA translation

Objective

The mammalian circadian clock plays a fundamental role in the liver by regulating fatty acid, glucose and xenobiotic metabolism. Impairment of this rhythm has been show to lead to diverse pathologies including metabolic syndrome. At present, it is supposed that the circadian clock regulates metabolism mostly by regulating the expression of liver enzymes at the transcriptional level. We have now collected evidence that post-transcriptional regulations play also an important role in this regulation. Particularly, recent results from our laboratory show that the circadian clock can synchronize mRNA translation in mouse liver through rhythmic activation of the Target Of Rapamycin Complex 1 (TORC1) with a 12-hours period. Based on this unexpected observation, we plan to identify the genes rhythmically translated in the mouse liver as well as the mechanisms involved in this translation. Indeed, our initial observations suggest a cap-independent translation during the day and a cap-dependent translation during the night. Identification of the different complexes involved in translation at this two different times and their correlation with the sequence, structure, and/or function of the translated genes will provide new insight into the action of the circadian clock on animal metabolism. In parallel, we will identify the signalling pathways involved in the rhythmic activation of TORC1 in mouse liver. Finally, we will study the consequences of a deregulated rhythmic translation in circadian clock-deficient mice on the metabolism and the longevity of these animals. Perturbations of the circadian clock have been linked to numerous pathologies, including obesity, type 2 diabetes and cancer. Our project on the importance of circadian clock-coordinated translation will likely reveal new findings in the field of regulation of animal metabolism by the circadian clock.

Call for proposal

ERC-2010-StG_20091118
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Host institution

NESTEC SA
Address
Epfl Innovation Park Building H
1015 Lausanne
Switzerland
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
EU contribution
€ 1 115 699,20
Principal investigator
Frédéric Bruno Martin Gachon (Dr.)
Administrative Contact
Paul Nichols (Mr.)

Beneficiaries (2)

NESTEC SA
Switzerland
EU contribution
€ 1 115 699,20
Address
Epfl Innovation Park Building H
1015 Lausanne
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Principal investigator
Frédéric Bruno Martin Gachon (Dr.)
Administrative Contact
Paul Nichols (Mr.)
UNIVERSITE DE LAUSANNE

Participation ended

Switzerland
EU contribution
€ 360 131,60
Address
Quartier Unil-centre Bâtiment Unicentre
1015 Lausanne
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Isabelle Rivier Flühmann (Ms.)