Circadian regulation of molecular and systemic adipose tissue function in humans

Project Summary The mammalian circadian system regulates metabolic processes over a 24-hour cycle and molecular circadian clocks control functional tissue specific and cell autonomous oscillations. Adipocytes, the primary cell type in adipose tissue, are central to regulating free fatty acid metabolism; dysregulation of free fatty acid release from adipocytes (i.e. lipolysis) is central to the pathophysiology of obesity and contributes to lipotoxicity in other tissues such as pancreas, liver, and muscle. Shift workers have disruptions in the circadian system and are at increased risk of obesity and metabolic disease. Adipocytes have a cell autonomous cycling molecular circadian clock and the literature suggests that adipocyte metabolism and lipolysis pathways are regulated by cell intrinsic circadian rhythms that are altered in obesity. However, adipocytes are highly responsive to both nutrient delivery and systemic hormonal signals driven by intermittent meal intake, making many secreted adipocyte products appear rhythmic over a 24 h fasting/feeding cycle. Therefore, the relative control of adipose tissue by feeding versus molecular clock driven mechanisms in humans is not understood. As such, the overall goal of this application is to define the molecular and systemic role of intrinsic adipocyte molecular circadian clock and how this is impacted by obesity in humans. In this context, Aim 1 will establish whether human subcutaneous adipose tissue exhibits autonomous systemic and molecular circadian rhythmicity independent of diurnal nutrient delivery in vivo in normal weight humans. Aim 2 will interrogate whether obesity alters adipocyte specific rhythms in circadian and lipolysis genes and is related to measures of systemic adipose tissue function. Finally, Aim 3 will interrogate the impact of feeding regime and obesity on the adipocyte specific cistrome of core circadian clock transcription factors allowing a more complete understanding of genomic regulation of adipocyte clock. This work will be the first work to address the relative contribution of intrinsic adipocyte circadian clock during continuous feeding versus adipocyte function driven by intermittent food intake in humans and interrogate circadian clock in the context of obesity. Answering these fundamental questions is essential to understanding whether disruptions in circadian molecular clocks contribute to metabolic abnormalities in obesity and these studies will provide a regulatory paradigm for circadian clock in adipocytes. Importantly, these proposed research activities with an outstanding mentorship team and the intellectually enriching environment at Mayo Clinic will build upon the applicant’s training and provide opportunities to expand her clinical translational knowledge and skillset culminating in the development of a research niche for the applicant.