New Transcriptional Regulators of Non-shivering Thermogenesis

Unlike white adipose tissue (WAT), which stores excess energy as triglycerides, brown adipose tissue (BAT) burns fatty acids and glucose to produce heat. The thermogenic ability of BAT is due to the specialized inner mitochondrial proton transporter named uncoupling protein 1 (UCP1), which dissipates the proton motive force generated by the electron transport chain to create heat instead of ATP. Despite data suggesting that increasing BAT activity may be a promising antiobesity therapy, an inclusive model of the transcriptional regulation of thermogenic genes remain unclear. The aim of this dissertation work was to identify and characterize novel regulators of the UCP1 promoter and nonshivering thermogenesis./nChapter 1 reviews BAT in both mice and human, profiling the basic mechanism of uncoupled respiration and cold-induced nonshivering thermogenesis. Unlike classical BAT, which has constitutive UCP1 expression, brown adipocyte-like cells arise in WAT depots following prolonged cold exposure and contribute to whole body thermogenic capacity. While having similar functions, these cells arise from different precursor populations, having unique gene signatures and potentially depot specific regulation. Human BAT resembles either classical BAT or brown adipocyte-like cells in a depot specific manner, with differing levels of basal UCP1 expression and expression profiles./nFinally, known transcriptional and hormonal regulators of BAT are discussed./nChapter 2 profiles my screening efforts to identify novel transcriptional regulators of the UCP1. Briefly, a library of over 1100 transcription factors was screened for activation of the UCP1 promoter. Expression profiling of the positive factors identified 6 novel, brown fat enriched transcriptional activators of UCP1. The first such transcription factor identified was the previously uncharacterized C2H2 type zinc-finger protein, Zfp516. Zfp516 is induced by cold where it binds and activates a brown fat gene program. Zfp516 ablation is embryonic lethal, but Zfp516 knockout embryos have little to no UCP1 expression and aberrant morphology. On the other hand, adipose specific transgenic overexpression in aP2-Zfp516 resulted in marked browning of inguinal WAT, increased body temperature and whole body energy expenditure, and prevention of diet-induced obesity./nChapter 3 profiles a second transcription factor identified in my screening efforts, the CCCH-type zinc finger protein, Zc3h10. Zc3h10, together with multiple cofactors, binds and activates the distal UCP1 promoter. Ablation of Zc3h10 results in defective BAT differentiation in cells, while adipose specific transgenic overexpression in aP2-Zc3h10 mice results in a lean phenotype./nFinally, chapter 4 concludes this work, discussing my findings in the context of the field of brown adipocyte biology and presents future directions and remaining questions./nThis study has identified novel transcriptional regulators of UCP1, contributing significantly to the understanding of brown adipocyte biology and nonshivering thermogenesis, and providing new targets for future antiobesity therapeutics.

Advisor: Sul, Hei Sook