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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3283-3298.e6 |
| Journal | Cell reports |
| Volume | 25 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 18 2018 |
Funding
We thank J. Bass, C. Peek, N. Chandel, and D. Chakravarti for helpful discussion, the UC Davis Mouse Biology Program for generating Bcl6 floxed mice, and the Vanderbilt MMPC for performing clamps. We are also grateful to Northwestern University's Center for Translational Imaging, Comprehensive Metabolic Core, and Mouse Histology and Phenotyping Laboratory supported by NCI P30-CA060553; the Mass Spectrometry Core Facility at the UT Health Science Center at San Antonio and the Case Western Reserve University Research Institute for Children's Health Analytical Core for services; and Illumina for support with sequencing. This work was supported by HHMI and NIH grants DK057978 and HL105278 (R.M.E.), as well as R01DK108987, P30DK020595, and K08HL092298 (G.D.B.). We thank J. Bass, C. Peek, N. Chandel, and D. Chakravarti for helpful discussion, the UC Davis Mouse Biology Program for generating Bcl6 floxed mice, and the Vanderbilt MMPC for performing clamps. We are also grateful to Northwestern University\u2019s Center for Translational Imaging, Comprehensive Metabolic Core, and Mouse Histology and Phenotyping Laboratory supported by NCI P30-CA060553 ; the Mass Spectrometry Core Facility at the UT Health Science Center at San Antonio and the Case Western Reserve University Research Institute for Children\u2019s Health Analytical Core for services; and Illumina for support with sequencing. This work was supported by HHMI and NIH grants DK057978 and HL105278 (R.M.E.), as well as R01DK108987 , P30DK020595 , and K08HL092298 (G.D.B.).
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
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
