NR1D1 and energy state regulation of the adipocyte response to obesity

This project explores how adipocytes respond to obesity. Why does adipose tissue in people with obesity become unable to store more lipid? I propose that dysfunction of the adipocytes themselves is central, with normal pathways of adipocyte metabolism shutting down as obesity develops. Specifically, I will test the idea that, through clock protein NR1D1, and changing availability of key metabolic intermediate acetyl-CoA, programmes of lipid uptake and storage become down-regulated. Crucially, both NR1D1 and acetyl-CoA affect levels of histone acetylation, a chromatin modification associated with increased transcriptional activity. I will adopt exciting experimental approaches to define how manipulation of NR1D1 and acetyl-CoA alters adipocyte function. I will use a transgenic mouse model that permits temporal control over adipocyte Nr1d1 expression, and mass spectrometry- and tagmentation-based methods to quantify acetyl-CoA and map acetylated histone distribution. I will study adipocytes from people with obesity or NR1D1 mutation, to show that this has relevance in humans. In sum, I will: 1) define the role of NR1D1 in obesity-related down-regulation of adipocyte function; 2) define the mechanism(s) mediating state-dependent control of adipocyte function; 3) determine the importance of NR1D1 and epigenetic regulation of adipocyte function in human obesity.