Circadian misalignment has deleterious effects on metabolism, and contributes to the obesity and diabetes epidemics in the US. Recent discoveries implicate the nuclear receptor Rev-erb1 as a transcriptional link between the circadian clock and metabolism. The present proposal combines tissue-specific, genome-wide analysis of TF binding and epigenomic modifications, novel mouse genetic models, and sophisticated metabolic phenotyping to understand the physiological role of Rev-erb1 and Rev-erb2 in the coordination of circadian rhythms and metabolism.
Specific Aim 1 is to determine the role of Rev-erb1 in the regulation of hepatic circadian rhythm and metabolism. The liver is a critical metabolic organ, and our preliminary data demonstrate fatty liver in mice lacking Rev-erb1. Genome-wide analysis of Rev-erb1 binding sites identifies lipid metabolic genes to which HDAC3 is recruited in a circadian manner. We hypothesize that this is a critical mechanism of circadian epigenomic control of hepatic lipid metabolism, and will test this by a combination of genome-wide approaches in informative and carefully phenotyped mouse genetic models.
Specific Aim 2 is to determine the role of Rev-erb1 in adipose circadian rhythm and metabolism. Preliminary data show that mice lacking Rev-erb1 have increased white adipose tissue, and genome-wide analysis reveals binding of Rev-erb1 to a distinct set of metabolic genes. We will test the hypothesis that Rev-erb1 epigenomically controls fat- specific functions together with cooperating transcription factors.
Specific Aim 3 is to determine the role of Rev- erb1 stabilization in circadian rhythm and metabolism, utilizing a novel mouse model in which Rev-erb1 is insensitive to the lithium-stimulated degradation pathway.
Specific Aim 4 is to determine the role of Rev-erb2 in the regulation of circadian rhythm and metabolism. Knockdown and knockout models will test the hypothesis that Rev-erb2 has circadian and metabolic functions that are both unique and partly redundant with Rev-erb1. These integrative studies have important implications for understanding the links between circadian rhythm and metabolism that underlie the mechanism by which circadian misalignment exacerbates metabolic dysfunction, obesity, and diabetes.

Public Health Relevance

In humans, circadian regulation is intimately linked to metabolic homeostasis, and circadian misalignment is now recognized as a risk factor for metabolic disorders including diabetes, obesity, and cardiovascular diseases that are of great significance due to their marked rise in modern societies, especially the United States. The nuclear receptor Rev-erb1 links circadian and metabolic physiology. Thus, understanding its integrative function will inform new approaches to metabolic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045586-21
Application #
8536254
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
1992-09-30
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
21
Fiscal Year
2013
Total Cost
$493,491
Indirect Cost
$175,997
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zhang, Yuxiang; Fang, Bin; Damle, Manashree et al. (2016) HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms. Genes Dev 30:1636-44
Jager, Jennifer; Wang, Fenfen; Fang, Bin et al. (2016) The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling. J Biol Chem 291:10867-75
Zhang, Yuxiang; Fang, Bin; Emmett, Matthew J et al. (2015) GENE REGULATION. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock. Science 348:1488-92
Lim, Hee-Woong; Uhlenhaut, N Henriette; Rauch, Alexander et al. (2015) Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo. Genome Res 25:836-44
Gerhart-Hines, Zachary; Lazar, Mitchell A (2015) Circadian metabolism in the light of evolution. Endocr Rev 36:289-304
Gerhart-Hines, Z; Lazar, M A (2015) Rev-erbα and the circadian transcriptional regulation of metabolism. Diabetes Obes Metab 17 Suppl 1:12-6
Fang, Bin; Everett, Logan J; Jager, Jennifer et al. (2014) Circadian enhancers coordinate multiple phases of rhythmic gene transcription in vivo. Cell 159:1140-52
Everett, Logan J; Lazar, Mitchell A (2014) Nuclear receptor Rev-erbα: up, down, and all around. Trends Endocrinol Metab 25:586-92
Jager, Jennifer; O'Brien, W Timothy; Manlove, Jessica et al. (2014) Behavioral changes and dopaminergic dysregulation in mice lacking the nuclear receptor Rev-erbα. Mol Endocrinol 28:490-8
Gerhart-Hines, Zachary; Feng, Dan; Emmett, Matthew J et al. (2013) The nuclear receptor Rev-erbα controls circadian thermogenic plasticity. Nature 503:410-3

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