Zbtb7b engages the long noncoding RNA Blnc1 to drive brown and beige fat development and thermogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 34; pp. E7111 - E7120
• Main Authors: Li, Siming, Mi, Lin, Yu, Lei, Yu, Qi, Liu, Tongyu, Wang, Guo-Xiao, Zhao, Xu-Yun, Wu, Jun, Lin, Jiandie D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22-08-2017
• Series: PNAS Plus
• Subjects: Activation; Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; Adipose tissue; Adipose Tissue, Beige - growth & development; Adipose Tissue, Beige - metabolism; Adipose Tissue, Brown - growth & development; Adipose Tissue, Brown - metabolism; Animal tissues; Animals; Biological Sciences; Biology; Browning; Cells, Cultured; Chemical energy; Cofactors; Cold; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Energy metabolism; Fats; Female; Gene expression; Genomes; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; PNAS Plus; Protein turnover; Proteomics; Ribonucleic acid; RNA; RNA, Long Noncoding; Rodents; Studies; Thermogenesis; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Zinc; Zinc finger proteins; lncRNA; brown fat; Blnc1; Zbtb7b; beige fat
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1703494114

Brown and beige adipocytes convert chemical energy into heat through uncoupled respiration to defend against cold stress. Beyond thermogenesis, brown and beige fats engage other metabolic tissues via secreted factors to influence systemic energy metabolism. How the protein and long noncoding RNA (lncRNA) regulatory networks act in concert to regulate key aspects of thermogenic adipocyte biology remains largely unknown. Here we developed a genome-wide functional screen to interrogate the transcription factors and cofactors in thermogenic gene activation and identified zinc finger and BTB domain-containing 7b (Zbtb7b) as a potent driver of brown fat development and thermogenesis and cold-induced beige fat formation. Zbtb7b is required for activation of the thermogenic gene program in brown and beige adipocytes. Genetic ablation of Zbtb7b impaired cold-induced transcriptional remodeling in brown fat, rendering mice sensitive to cold temperature, and diminished browning of inguinal white fat. Proteomic analysis revealed a mechanistic link between Zbtb7b and the lncRNA regulatory pathway through which Zbtb7b recruits the brown fat lncRNA 1 (Blnc1)/heterogeneous nuclear ribonucleoprotein U (hnRNPU) ribonucleoprotein complex to activate thermogenic gene expression in adipocytes. These findings illustrate the emerging concept of a protein–lncRNA regulatory network in the control of adipose tissue biology and energy metabolism.