Phd in MOLECULAR MEDICINE

Thesis title: Sirt5 inhibition induces brown fat-like phenotype in 3T3L1 preadipocytes

Brown adipose tissue (BAT) activity plays a key role in regulating systemic energy. Activation of BAT results in increased energy expenditure, making this tissue an attractive pharmacological target for therapies against obesity and type 2 diabetes. Sirtuin 5 (SIRT5) affects BAT function by regulating adipogenic transcription factors expression and mitochondrial respiration. Here we treated 3T3-L1 preadipocytes and mouse primary preadipocyte cultures with the SIRT5 inhibitor MC3482 and investigated the effects of this compound on adipose differentiation and function. Administration of MC3482 during the early stages of differentiation promoted expression of brown adipocyte and mitochondrial biogenesis markers. Upon treatment with MC3482, 3T3-L1 adipocytes showed increased activation of AMP-activated protein kinase (AMPK), which potentially stimulates brown adipocyte differentiation. Such effect was paralleled by an increase in autophagic/mitophagic flux and a reduction in lipid droplet size mediated by a higher lipolityc rate. Of note, MC3482 increased expression and activity of adipose triglyceride lipase, without modulating hormone-sensitive lipase. Our findings reveal that SIRT5 inhibition stimulates brown adipogenesis in vitro and may be considered as a strategy to stimulate BAT and counteract obesity.