Peripheral clocks in metabolism and diabetes

DESCRIPTION (provided by applicant): The immediate goals of Radu Daniel Rudic, Ph.D. are to expand his experience and knowledge to the area of diabetes research. Ultimately his plan is to develop a niche that will facilitate his transition as an independent investigator in academia. The proposed research will be performed at the University of Pennsylvania. The proposal examines the relationship between circadian rhythms, metabolism, and diabetes. Circadian rhythms are daily variations in physiology and function. Metabolism, including glucose and lipid homeostasis, is known to exhibit circadian variation. However, the mechanisms governing these rhythms are not known. Analysis of gene expression of aortic tissue revealed that the adipokines leptin, adiponectin, and resistin followed circadian rhythmicity. Regulatory control of these secreted peptides and proteins which are important in glucose and lipid homeostasis is still not fully understood. In specific aim 1, adipokine release will be assessed in mice with a defective circadian clock. In Specific Aim 2, the impact of molecular clock dysfunction on lipid homeostasis will be assessed by measuring lipid profiles, triglyceride clearance, secretion, and lipid metabolizing activity. Moreover, though the molecular clock is known to be perturbed in models of diabetes, if and how the molecular clock impacts the evolution of diabetes is unknown. In Specific Aim 3, the influence of a disrupted molecular clock will be examined in diabetes by implementing mouse models of diabetes. In summary, though light may be the dominant signal to set circadian rhythms in the central nervous system, other environmental factors may preside in the periphery. While environmental influences may dominate in the constitution of diabetes, they may interact with oscillating gene function under control of the metabolic clock in a way that amplifies or diminishes their influence.