Abstract
The transcriptional repressor B-cell Lymphoma 6 (Bcl6) was recently identified in a profile of genes regulated in adipocytes, suggesting a relationship between Bcl6 and metabolic regulation. As a representative target gene repressed by Bcl6, Suppressor of Cytokine Signaling (Socs) 2 expression was elevated in Bcl6 deficient (KO) mice, including metabolic tissues liver, adipose tissue and muscle, as well as in spleen and thymus. Bcl6 occupied the Socs2 promoter in wild-type, but not Bcl6 KO mice, suggesting direct regulation of Socs2 by Bcl6 in vivo. Mice deficient in Bcl6 were found to exhibit multiple features of dysregulated lipid metabolism. Adipose tissue mass was dramatically reduced or absent in Bcl6 KO mice. Further, hepatic and serum triglycerides were low. Bcl6 deficiency was accompanied by decreased hepatic expression of Stearoyl-CoA desaturase 1 (Scd1) and Fatty acid synthase (Fasn) genes which encode lipogenic enzymes. Expression of the gene for the transcription factor Carbohydrate-Responsive Element Binding Protein (Chrebp), which regulates expression of lipogenic genes, was also reduced in liver of Bcl6 KO mice. Bcl6 deficiency disrupted fasting-induced increases in hepatic triglyceride deposition, but not decreases in lipogenic gene expression. Taken together, these findings suggest that in addition to its well-recognized roles in immune regulation, Bcl6 plays a role in regulatory events of lipid metabolism, and that in the absence of Bcl6, lipid metabolism in liver and adipose tissue is dysregulated.
Highlights
B-cell Lymphoma 6 (Bcl6) (B-cell lymphoma 6) is a transcriptional repressor protein known for its ability to inhibit gene expression during B-cell responses in germinal centers [1,2,3]
The present study provides evidence consistent with endogenous Bcl6 repressing Suppressor of Cytokine Signaling 2 (Socs2) expression, since mesenchymal stem cells isolated from Bcl6deficient mice exhibit a marked, cell autonomous increase in the expression of endogenous Socs2 mRNA
In addition to stimulating Socs2 expression, Growth Hormone (GH) is a potent inhibitor of Bcl6 expression; the latter suggests that the phenotype of Bcl6 KO mice in some ways reflects enhanced GH responses mediated by activation of GH target genes, such as those related to metabolic regulation
Summary
Bcl (B-cell lymphoma 6) is a transcriptional repressor protein known for its ability to inhibit gene expression during B-cell responses in germinal centers [1,2,3]. Chromosomal translocations in the Bcl gene and mutations in the Bcl gene promoter can cause deregulation of Bc6 expression by preventing its down-regulation in post-germinal center B cells [1,3,4,5]. Bcl was recently found to be expressed and inhibited in adipocytes treated with Growth Hormone (GH) [13], raising the possibility that Bcl has unrecognized functions in adipocytes and may be a player in the regulation of lipid metabolism
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