Circadian misalignment has deleterious effects on metabolism, and contributes to the obesity and diabetes epidemics in the United States. REV-ERB nuclear receptors link the circadian clock and metabolism, and the present proposal combines tissue-specific, genome-wide analysis of cistromes, transcriptomes, and the epigenome in novel mouse genetic models with sophisticated metabolic phenotyping to understand the physiological role of REV-ERBa and b in the generation and systemic coordination of central and hepatic circadian rhythms and metabolism.
Specific Aim 1 is to determine the cell autonomous and non-cell autonomous roles of hepatic REV-ERBa and b in liver circadian rhythms and metabolism. We hypothesize that REV-ERBs have cell-autonomous as well as non-cell autonomous functions in hepatocytes. Preliminary characterization of adult mice after hepatocyte REV-ERB double knockout (HepDKO) has demonstrated the cell-autonomous role of REV-ERBs in liver circadian rhythms and also revealed genes that do not lose circadian rhythmicity upon REV-ERB deletion. The underlying mechanisms and specialized metabolic functions will be determined using integrative functional genomics, proteomics, and metabolic phenotyping.
Specific Aim 2 is to elucidate the molecular mechanisms by which hepatocyte REV-ERBs control circadian rhythms in non-hepatocytic liver cells. In addition to hierarchical (cell-autonomous and non-cell autonomous) regulation of peripheral clocks, we hypothesize that there is communication between peripheral clocks in difference cell types with an organ. Preliminary data demonstrate that hepatocyte REV-ERBs control circadian rhythms in non-hepatocytes. The scope and underlying mechanisms will be determined using integrative genomics and metabolomics.
In Specific Aim 3 we will determine the role of hypothalamic REV-ERBs in the regulation of circadian behavior and metabolism. We hypothesize that hypothalamic REV-ERBs centrally control circadian behavior as well as peripheral metabolism, and this is borne out by preliminary analysis of mice with deletion of REV-ERBs in the suprachiasmatic nucleus (SCN) as well as other mice with REV-ERB deletion in non-SCN neurons. Cistromic, transcriptomic, and epigenomic analysis will be used to determine the underlying molecular mechanisms. We will also utilize novel mouse models to test the desyncrony hypothesis of metabolic stress resulting from lack of coordination between biological clocks and environmental zeitgeberes. Together, the studies will lead to a more fundamental understanding of the links between circadian rhythm and metabolism that underlie the mechanism by which circadian misalignment exacerbates metabolic dysfunction, obesity, and diabetes.
People who work on night shifts or have circadian disruption have an increased likelihood of developing metabolic diseases including obesity and diabetes. REV-ERBs are key components of biological clocks and have important implications for understanding the links between circadian rhythm and metabolism that underlie the mechanism by which circadian misalignment exacerbates metabolic dysfunction, obesity, diabetes, and cardiovascular diseases.
Showing the most recent 10 out of 76 publications
