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 Sirt3 KO 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.

Alpha-Linolenic Acid-Enriched Butter Promotes Fatty Acid Remodeling and Thermogenic Activation in the Brown Adipose Tissue

“…Taken together, our work suggests that ALA-biofortified butter could be an alternative to fish oil in activating brown thermogenesis. Emerging evidence also suggests that sirtuin 3 (SIRT3), a NAD + -dependent deacetylase in mitochondria, is a key modulator for brown thermogenesis [24]. Consistent with this study, the transcriptional levels of Sirt3 and SIRT3 protein expression levels were higher in n3Bu-fed BAT than Bu or Ma-fed BAT ( Figure 4C,D).…”

“…Conforming to the increased mitochondrial mass, the mitochondrial DNA to genomic DNA ratio (mtDNA/gDNA) was significantly higher in n3Bu-fed BAT compared to Bu-or Ma-fed BAT ( Figure 4B). Emerging evidence also suggests that sirtuin 3 (SIRT3), a NAD + -dependent deacetylase in mitochondria, is a key modulator for brown thermogenesis [24]. Consistent with this study, the transcriptional levels of Sirt3 and SIRT3 protein expression levels were higher in n3Bu-fed BAT than Bu or Ma-fed BAT ( Figure 4C,D).…”

Comprehensive proteomics and functional annotation of mouse brown adipose tissue

“…Previous study showed SIRT3 absence in mice resulted in impaired BAT lipid use, whole body thermoregulation, and respiration in BAT mitochondria without affecting UCP1 expression. Further analysis indicated SIRT3 controlled brown fat thermogenesis by deacetylation regulation of pathways upstream of UCP1 [64].…”

Influenza infection rewires energy metabolism and induces browning features in adipose cells and tissues

“…inflammation and WAT browning, the latter through deacetylation regulation of pathways upstream of UCP1 32,33 . It is noteworthy that opposite regulation directions of the OXPHOS pathway and the sirtuin signaling pathway have been recently reported 34 .…”