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Cell Rep. 2018 Dec 18;25(12):3283-3298.e6. doi: 10.1016/j.celrep.2018.11.074.

Loss of Transcriptional Repression by BCL6 Confers Insulin Sensitivity in the Setting of Obesity.

Author information

1
Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
2
Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
3
Center for Translational Imaging, Departments of Radiology and Biomedical Engineering, Northwestern University, Chicago, IL 60611, USA.
4
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
5
Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA.
6
Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. Electronic address: grant.barish@northwestern.edu.

Abstract

Accumulation of visceral adiposity is directly linked to the morbidity of obesity, while subcutaneous body fat is considered more benign. We have identified an unexpected role for B cell lymphoma 6 (BCL6), a critical regulator of immunity, in the developmental expansion of subcutaneous adipose tissue. In adipocyte-specific knockout mice (Bcl6AKO), we found that Bcl6 deletion results in strikingly increased inguinal, but not perigonadal, adipocyte size and tissue mass in addition to marked insulin sensitivity. Genome-wide RNA expression and DNA binding analyses revealed that BCL6 controls gene networks involved in cell growth and fatty acid biosynthesis. Using deuterium label incorporation and comprehensive adipokine and lipid profiling, we discovered that ablation of adipocyte Bcl6 enhances subcutaneous adipocyte lipogenesis, increases levels of adiponectin and fatty acid esters of hydroxy fatty acids (FAHFAs), and prevents steatosis. Thus, our studies identify BCL6 as a negative regulator of subcutaneous adipose tissue expansion and metabolic health.

KEYWORDS:

BCL-6; BCL6; FAHFA; PAHSA; adipocyte; adiponectin; adipose tissue; ceramide; fatty acid esters of hydroxy fatty acids; hypertrophy; insulin sensitivity; lipogenesis; obesity; repressor; subcutaneous fat

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