NR1D1 and energy state regulation of the adipocyte response to obesity (360G-Wellcome-225145_Z_22_Z)

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.