Thierry Arnould

CDR - SIRTUIN 3 adipocyte boil differentiation

The current and worldwide concern about overweight, obesity and their associated disorders, referred to the “metabolic syndrome”, requires a strong scientific investment to improve the current knowledge of the underlying mechanisms at the origin of obesity-associated disorders and to develop targeted therapies.

Our laboratory takes part to the study of the dysregulations/dysfunctions associated with the biology of mitochondria in white adipocytes and has recently started a novel research axis on the Sirtuin 3 (SIRT3), a mitochondrial deacetylase for energy homeostasis, metabolic adjustments and protection against oxidative stress.

The enzyme controls these fundamental processes, by the deacetylation of more than half of the proteins that compose the mitoproteome, upon NAD+ availability (used as a co-substrate) and is consequently a crucial metabolic sensor/effector. While the association between obesity and a reduction in SIRT3 expression/activity as well as acceleration of the onset of obesity associated disorders upon SIRT3 deficiency are documented, the putative beneficial effects of its overexpression in obese individuals have not been analyzed yet. Since white adipose tissues are essential for whole-body energy homeostasis and ensure a powerful endocrine function, in this project, we will characterize the local and systemic effects of an adipose-specific versus systemic SIRT3 overexpression in mice exposed to a high fat diet.

In addition, as adipogenesis is an essential component to ensure adaptive capacity to changes in nutritional status, the still unknown role of SIRT3 in white adipogenic differentiation programmes will also be characterized.

Using in vivo and in vitro works on murine and human cells/tissues, several mitochondrial features (abundance, dynamics, respiration, and acetylated mitoproteome) will be assessed (including by RNAseq) in response to SIRT3 modulation of expression and/or activity.