Brown adipose tissue (BAT) is capable of thermogenesis via uncoupling protein 1 (UCP1) and has high expression of sirtuin 3 (SIRT3), a deacetylase in the mitochondria. Much of the acetylation that occurs in mitochondria is thought to occur nonenzymatically. SIRT3 appears to play a critical role in reversing these acetylations, which are generally thought to have an inhibitory effect on enzymatic activities. The findings of Sebaa et al. suggest that SIRT3 indirectly controls BAT thermogenesis by deacetylating and promoting the function of pathways upstream of UCP1.
SIRT3 controls brown fat thermogenesis by deacetylation regulation of pathways upstream of UCP1
- Abstract
Objective: Brown adipose tissue (BAT) is important for thermoregulation in many mammals. Uncoupling protein 1 (UCP1) is the critical regulator of thermogenesis in BAT. Here we aimed to investigate the deacetylation control of BAT and to investigate a possible functional connection between UCP1 and sirtuin 3 (SIRT3), the master mitochondrial lysine deacetylase.
Methods: We carried out physiological, molecular, and proteomic analyses of BAT from wild-type and Sirt3KO mice when BAT is activated. Mice were either cold exposed for 2 days or were injected with the β3-adrenergic agonist, CL316,243 (1 mg/kg; i.p.). Mutagenesis studies were conducted in a cellular model to assess the impact of acetylation lysine sites on UCP1 function. Cardiac punctures were collected for proteomic analysis of blood acylcarnitines. Isolated mitochondria were used for functional analysis of OXPHOS proteins.
Results: Our findings showed that SIRT3 absence in mice resulted in impaired BAT lipid use, whole body thermoregulation, and respiration in BAT mitochondria, without affecting UCP1 expression. Acetylome profiling of BAT mitochondria revealed that SIRT3 regulates acetylation status of many BAT mitochondrial proteins including UCP1 and crucial upstream proteins. Mutagenesis work in cells suggested that UCP1 activity was independent of direct SIRT3-regulated lysine acetylation. However, SIRT3 impacted BAT mitochondrial proteins activities of acylcarnitine metabolism and specific electron transport chain complexes, CI and CII.
Conclusions: Our data highlight that SIRT3 likely controls BAT thermogenesis indirectly by targeting pathways upstream of UCP1.