Research over the past decade has uncovered a connection between circadian clocks and metabolic homeostasis. Mice lacking components of the molecular clock develop dramatic metabolic abnormalities, including obesity, disrupted glucoregulation, elevated free fatty acids and metabolic myopathy. Although the molecular mechanisms underlying these phenotypes remain poorly understood, many of these defects point to disruptions in mitochondrial oxidative metabolic pathways, including fatty acid oxidation and respiration. A major clue concerning the cause of mitochondrial dysfunction in circadian mutants stems from the recent discovery that the clock transcription factor loop regulates cellular levels of NAD+, and in turn, controls activity of the sirtuin family of NAD+-dependent deacetylases, key factors in oxidative metabolism. In exciting new results, we also now show that circadian mutant mice exhibit hyperacetylation of several mitochondrial enzymes that are rate-limiting in the urea cycle, ketone production, fatty acid oxidation and ATP synthesis. My research proposal will thus build upon my previous studies of oxygen-dependent control of metabolic transcription factor pathways and specifically test the hypothesis that circadian gene disruption leads to impaired oxidative metabolism due to dysregulation of NAD+ synthesis and activity of mitochondrial-localized sirtuin enzymes. The proposed experiments will exploit experimental genetic, biochemical and cell physiological approaches and will serve as an invaluable vehicle in my development as an independent investigator in metabolism research.

Public Health Relevance

The increased prevalence of metabolic diseases, including diabetes and obesity, underscore the need for a deeper understanding of human metabolism. It is clear that in addition to diet and exercise, circadian rhythms play an important role in maintaining metabolic homeostasis. The goal of this proposal is to elucidate the connection between circadian regulation and metabolic pathways to advance our knowledge of metabolic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK092034-03
Application #
8448333
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (J1))
Program Officer
Castle, Arthur
Project Start
2011-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$53,942
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Peek, Clara Bien; Affinati, Alison H; Ramsey, Kathryn Moynihan et al. (2013) Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science 342:1243417
Marcheva, Biliana; Ramsey, Kathryn M; Peek, Clara B et al. (2013) Circadian clocks and metabolism. Handb Exp Pharmacol :127-55