Endocrine Abstracts

Dysfunctional mitochondrial oxidative phosphorylation and diminished aerobic capacity are associated with metabolic, cardiovascular and neurodegenerative diseases that eventually alter life span. We will discuss two distinct signalling pathways to control energy expenditure that converge on the coactivator PGC-1α. In a first study we focussed on the polyphenol resveratrol, an activator of the class III HDAC SIRT1, the mammalian Sir2 homolog. Resveratrol significantly increased aerobic capacity as evidenced by the doubling of time that mice run on a treadmill and by the increased oxidative capacity in muscle fibers ex vivo. This enhanced muscle performance was associated with an increase in expression of genes encoding for oxidative phosphorylation and mitochondrial biogenesis. These molecular events were largely explained by the resveratrol-mediated increase in PGC-1α activity, both through an increase in its expression level and a decrease in PGC-1α acetylation, fitting with the fact that resveratrol activates SIRT1. Importantly, the improved mitochondrial activity induced by resveratrol treatment protected mice against diet induced obesity and insulin resistance. In a second study, we characterized the role of SRC-3 in energy metabolism. SRC-1 and -2, two members of the p160 cofactor family were previously shown by us to affect energy homeostasis. Differently from SRC-1 and -2 KO mice, SRC-3^−/− animals weigh less under basal conditions, an effect which is accentuated by a high fat diet. This lean phenotype of SRC-3^−/− mice is associated with increased energy expenditure in BAT and skeletal muscle subsequent to enhanced mitochondrial activity. The effect on energy expenditure in the SRC-3^−/− mice is dependent on the increase in both PGC-1α expression and activity, subsequent to its decreased acetylation. In combination, these data suggest that SRC-3 and SIRT-1 are critical links in a complex cofactor network that is governed by PGC-1α and that controls energy homeostasis. This work opens up new perspectives for therapeutic and preventive strategies for metabolic diseases.