PhD Defense: Matthew Heckman

The Circadian Clock and Nr2f2 (COUP-TF) Regulation of Adipogenesis

Abstract

The circadian clock is being recognized as a significant mechanism regulating mammalian metabolism and energy balance; however, the relative importance of systemic versus tissue specific clock dysfunction remains to be elucidated. I demonstrate that modulating the activity of the circadian clock in pre-adipocytes affects some aspects of adipogenesis and lipid accumulation in a manner consistent with the obese phenotype observed in the Clock mutant mouse model.

In this work I identified the transcription factor COUP-TF to be a putative clock controlled gene that can act as a mediator of differentiation in various contexts, and I demonstrate that the Nr2f1 (Coup-TF1) and Nr2f2 (Coup-TF2) paralogs code for proteins that act as redundant, negative regulators of adipogenesis. My results also indicate that relatively small changes in expression of these genes may cause significant changes in adiposity correlated with its apparent regulation by the circadian clock.

The Clock mutation in mice of the C57BL/6 background results in increased weight gain with age and are susceptible to obesity and metabolic syndrome, particularly when challenged with a high-fat diet. I present data demonstrating significant attenuation of Coup-TF2 gene expression in adipose tissue associated with mutation of Clocks and circadian clock dysfunction, with novel anomalies in mRNA processing detected. My results suggest the novel concept that circadian clock dysfunction may influence gene expression at the level of splicing in addition to regulation of transcription, and that reduced expression of COUP-TF in adipose tissue may increase susceptibility to obesity and metabolic syndrome.