Study of the role of Sirtuin 3 in diet-induced obesity of transgenic mice that overexpress the mitochondrial deacetylase and characterization of its role in white adipogenic 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 obesityassociated
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 adiposespecific
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 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 in response to SIRT3 modulation of
expression and/or activity.