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.