Breast Cancer 1 (BrCa1) May Be behind Decreased Lipogenesis in Adipose Tissue from Obese Subjects

Francisco J Ortega,José M Moreno-Navarrete,Francisco J Tinahones,José I Rodriguez-Hermosa,Gema Frühbeck,José M Fernández-Real,María Gómez-Serrano,Bartomeu Ruiz,Belen Peral,Eva García-Santos,Dolores Mayas,Wifredo Ricart

doi:10.1371/journal.pone.0033233

Abstract

ContextExpression and activity of the main lipogenic enzymes is paradoxically decreased in obesity, but the mechanisms behind these findings are poorly known. Breast Cancer 1 (BrCa1) interacts with acetyl-CoA carboxylase (ACC) reducing the rate of fatty acid biosynthesis. In this study, we aimed to evaluate BrCa1 in human adipose tissue according to obesity and insulin resistance, and in vitro cultured adipocytes.Research Design and MethodsBrCa1 gene expression, total and phosphorylated (P-) BrCa1, and ACC were analyzed in adipose tissue samples obtained from a total sample of 133 subjects. BrCa1 expression was also evaluated during in vitro differentiation of human adipocytes and 3T3-L1 cells.Results BrCa1 gene expression was significantly up-regulated in both omental (OM; 1.36-fold, p = 0.002) and subcutaneous (SC; 1.49-fold, p = 0.001) adipose tissue from obese subjects. In parallel with increased BrCa1 mRNA, P-ACC was also up-regulated in SC (p = 0.007) as well as in OM (p = 0.010) fat from obese subjects. Consistent with its role limiting fatty acid biosynthesis, both BrCa1 mRNA (3.5-fold, p<0.0001) and protein (1.2-fold, p = 0.001) were increased in pre-adipocytes, and decreased during in vitro adipogenesis, while P-ACC decreased during differentiation of human adipocytes (p = 0.005) allowing lipid biosynthesis. Interestingly, BrCa1 gene expression in mature adipocytes was restored by inflammatory stimuli (macrophage conditioned medium), whereas lipogenic genes significantly decreased.ConclusionsThe specular findings of BrCa1 and lipogenic enzymes in adipose tissue and adipocytes reported here suggest that BrCa1 might help to control fatty acid biosynthesis in adipocytes and adipose tissue from obese subjects.

Highlights

The complex process of differentiation by which new fat cells are developed from pre-adipocytes is known as adipogenesis
Breast Cancer 1 (BrCa1) gene expression was significantly up-regulated in both omental (OM; 1.36-fold, p = 0.002) and subcutaneous (SC; 1.49-fold, p = 0.001) adipose tissue from obese subjects
Consistent with its role limiting fatty acid biosynthesis, both BrCa1 mRNA (3.5-fold, p,0.0001) and protein (1.2-fold, p = 0.001) were increased in pre-adipocytes, and decreased during in vitro adipogenesis, while P-acetyl-CoA carboxylase (ACC) decreased during differentiation of human adipocytes (p = 0.005) allowing lipid biosynthesis

Summary

Introduction

The complex process of differentiation by which new fat cells are developed from pre-adipocytes is known as adipogenesis. During this process, the most dramatic changes are observed in relation to structural changes that allow the biosynthesis of lipids (or lipogenesis). Fatty acid synthase (FASN; EC 2.3.1.85) and acetyl-CoA carboxylase (ACC; EC 6.4.1.2) are examples of master enzymes in lipogenesis [1,2]. The later, ACC, catalyses the formation of malonyl-CoA, an essential substrate for FASN and the chain elongation systems [2,3]. The acute control of ACC activity is the product of integrated changes such as the phosphorylation of multiple serine residues and interactions with other proteins [see [3] for references]

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