SIRT5 Inhibition Induces Brown Fat-Like Phenotype in 3T3-L1 Preadipocytes.

Francesca Molinari,Enza Vernucci,Dante Rotili,Giada Tomaselli,Simone Mirabilii,Antonello Mai,Andrea Armani,Massimiliano Caprio,Luigi Sansone,Marco Tafani,Vincenzo Marzolla,Agostino Tafuri,Serena Saladini,Alessandra Feraco,Maria Rosaria Ricciardi,Matteo A Russo

doi:10.3390/cells10051126

Abstract

Brown adipose tissue (BAT) activity plays a key role in regulating systemic energy. The 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 factor expression and mitochondrial respiration. We analyzed the expression of SIRT5 in the different adipose depots of mice. 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. The administration of MC3482 during the early stages of differentiation promoted the expression of brown adipocyte and mitochondrial biogenesis markers. Upon treatment with MC3482, 3T3-L1 adipocytes showed an increased activation of the AMP-activated protein kinase (AMPK), which is known to stimulate brown adipocyte differentiation. This effect was paralleled by an increase in autophagic/mitophagic flux and a reduction in lipid droplet size, mediated by a higher lipolytic rate. Of note, MC3482 increased the expression and the activity of adipose triglyceride lipase, without modulating hormone-sensitive lipase. Our findings reveal that SIRT5 inhibition stimulates brown adipogenesis in vitro, supporting this approach as a strategy to stimulate BAT and counteract obesity.

Highlights

Adipose tissue can be mainly categorized into two distinct types: white and brown adipose tissue (WAT and Brown adipose tissue (BAT), respectively) showing different cell morphology and function [1]
Our study shows that pharmacological inhibition of Sirtuin 5 (SIRT5) by MC3482 treatment promotes brown adipogenesis in differentiating 3T3-L1 preadipocyte cultures
This effect was observed in primary preadipocyte cultures derived from mouse inguinal (subcutaneous) white adipose tissue (iWAT) and treated ex vivo with MC3482 (Figure 2)

Summary

Introduction

Adipose tissue can be mainly categorized into two distinct types: white and brown adipose tissue (WAT and BAT, respectively) showing different cell morphology and function [1]. A number of drug agents, metabolites and molecular pathways have been shown to regulate browning and lead to the increased thermogenic capacity of adipose tissue [3,4,5,6,7]. Both brown and beige adipocytes play a relevant role in the regulation of whole-body energy homeostasis. BAT activation and/or the emergence of beige adipocytes in mouse

Methods

Results

Conclusion