Identification of cofactor network, including SIRT1 and SRC-3, which converges on energy expenditure through PGC-1a

Organisms respond to variations in hormonal, metabolic, and nutritional signaling by altering the expression of their genetic information, allowing metabolic adaptation. Transcriptional control is achieved through an interwoven and redundant molecular circuitry that involves individual transcription factors, the basal transcriptional machinery, and multiprotein coregulator complexes, which fine-tune metabolic homeostasis. Most of the coregulators interact directly with transcription factors and can either repress or enhance their transcriptional activities. Aberrant signaling by coregulators is known to generate abnormalities of cellular metabolism, and hence can contribute to abnormalities of systemic metabolic pathways and to the pathogenesis of several common disorders, such as obesity and type 2 diabetes. We first demonstrated that an in vivo pharmacological activation of SIRT1, a member of the evolutionary conserved family of NAD-dependant deacetylases named sirtuins, protects the mice against the development of obesity and linked pathophysiologies, through an increased energy expenditure. At the molecular level, the in vivo effects of the sirtuinactivating compounds were associated with an induction of the expression of genes involved in mitochondrial biogenesis, oxidative phosphorylation and fatty acid oxidation in metabolic tissues such as the skeletal muscle and the brown adipose tissue and were explained by a the SIRT1-mediated deacetylation, and subsequent activation, of PGC-1a, a master regulator of mitochondrial function. In parallel, through a genetical approach, we demonstrated that not only deacetylases but also acetyltransferases impact in a major fashion on energy homeostasis. In fact, we have shown that, through promoting the expression the PGC-1a acetyltransferase GCN5, SRC-3 facilitates PGC-1a acetylation in muscle and brown adipose tissue and consequently inhibits PGC-1a activity. Interestingly, the expression levels of SIRT1, the major PGC-1a deacetylase, mirror those of SRC-3 and GCN5 in various physiological situations such as fasting and high fat feeding. This results in a convergent regulation of PGC-1a acetylation by both acetyltransferases and deacetylases and lead us to consider theses enzymes as members of coregulator network that informs PGC-1a about the cellular energy status, which then adapts cellular energy production through its commanding role of master regulator of mitochondrial function. It is therefore tempting to speculate that this converging cofactor network, including SRC-3, GCN5 and SIRT1 can be exploited to design new preventive and therapeutic strategies to combat obesity and associated metabolic disorders such as type 2 diabetes.Pas de résum