SIRT3 controls brown fat thermogenesis by deacetylation regulation of pathways upstream of UCP1.

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 ß3-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.

ß-Adrenoceptor Blockade for Infantile Hemangioma Therapy: Do ß3-Adrenoceptors Play a Role?

Infantile hemangiomas (IH) are frequent (4-5% of the childhood population) benign vascular tumors that involve accumulation, proliferation, and differentiation of aberrant vascular cells. Typically, IH are innocuous and spontaneously disappear, but they represent a potential risk for harmful effects in the body (e.g., permanent disfigurement) and health (e.g., ulcerations) in some patients. From a serendipitous discovery, the nonselective ß-adrenoceptor blocker propranolol (which blocks ß1-adrenoceptors, ß2-adrenoceptors, and ß3-adrenoceptors) emerged as an alternative therapy to treat this pathology and it quickly became a first-line treatment for IH. Nevertheless, its specific mechanisms of action remain thus far unknown. In this respect, several studies have suggested that ß1-adrenoceptors and ß2-adrenoceptors play a role in proliferative and angiogenic mechanisms. However, current basic research studies suggest that ß3-adrenoceptors could be also involved. Notably, ß3-adrenoceptors stimulate multiple intracellular pathways related to vascular function (e.g., blood flow, angiogenesis, etc.). This review compiles some lines of evidence suggesting that ß3-adrenoceptors may: (1) play a role in the pathophysiology of IH and (2) represent a potential therapeutic target for IH treatment. Hence, clinical evidence is mandatory to decide whether incorporation of ß3-adrenoceptor blockers into the therapeutic armamentarium may increase effectiveness in the treatment of IH and other vascular anomalies.