Nuclear receptors (NRs) are transcriptional regulators of metabolism. A major goal of this laboratory is to understand the biological importance of transcriptional repression by unliganded NRs. The orphan receptor Rev-erba has been particularly enlightening because it lacks an activation domain and is a constitutive represser. Transcriptional repression by Rev-erba is a key molecular component of the negative limb of the cell autonomous circadian clock. Normal circadian rhythms are disrupted both by absence of Rev-erba, and by unregulated persistence of its function. In the prior period, we showed that Rev-erba recruitment of the N-CoR/HDAC3 corepressor complex is critical for repression of circadian genes, and that modulation of Rev- erba protein stability initiates and synchronizes cellular clocks. Here we will determine the cellular mechanisms regulating Rev-erba activity, and explore the role of Rev-erba in regulating circadian activity and metabolic functions in liver and adipocytes.
Specific Aim 1 is to determine molecular mechanisms regulating Rev-erba activity. Rev-erba protein is stabilized by GSKSp-dependent phosphorylation, and we hypothesize that this modification regulates association with a specific E3 ligase. Biochemical and molecular approaches will be taken to identify and validate the role of specific components of this complex, and determine their involvement in normal clock function. Preliminary data indicate that Rev-erba activity is also regulated by heme binding. We will test the hypothesis that this plays a critical role in regulating the normal role of Rev-erba in the cell autonomous clock.
Specific Aim 2 is to determine the role of mechanisms regulating Rev-erba activity on circadian and metabolic physiology. We hypothesize that the mechanisms regulating cellular Rev-erba activity have important effects on circadian and metabolic processes. This will be tested by expressing informative Rev-erba mutants in liver, where Rev-erba normally regulates circadian gene expression and metabolism.
Specific Aim 3 is to understand the role of Rev- erba in adipocyte biology. Rev-erba is induced during adipogenesis, and we hypothesize that it regulates not only adipocyte differentiation, but also the physiological functions of the mature adipocyte, including adipokine production and lipolysis, both of which display circadian rhythms in vivo. We will explore the role of Rev-erba activity in the basal and circadian regulation of these adipocyte genes as well as adipocyte metabolic functions. Insights gained from this work will shed new light on the transcriptional and post- transcriptional control of circadian and metabolic physiology, as well as interrelationships between circadian rhythms and metabolism. This has the potential to lead to new understanding of circadian and metabolic disorders, including obesity, diabetes, and cardiovascular disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Emmett, Matthew J; Lim, Hee-Woong; Jager, Jennifer et al. (2017) Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge. Nature 546:544-548
Lazar, Mitchell A (2017) Maturing of the nuclear receptor family. J Clin Invest 127:1123-1125
Zhang, Yuxiang; Papazyan, Romeo; Damle, Manashree et al. (2017) The hepatic circadian clock fine-tunes the lipogenic response to feeding through ROR?/?. Genes Dev :
Papazyan, Romeo; Zhang, Yuxiang; Lazar, Mitchell A (2016) Genetic and epigenomic mechanisms of mammalian circadian transcription. Nat Struct Mol Biol 23:1045-1052
Jager, Jennifer; Wang, Fenfen; Fang, Bin et al. (2016) The Nuclear Receptor Rev-erb? Regulates Adipose Tissue-specific FGF21 Signaling. J Biol Chem 291:10867-75
Zhang, Yuxiang; Fang, Bin; Damle, Manashree et al. (2016) HNF6 and Rev-erb? integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms. Genes Dev 30:1636-44
Bass, Joseph; Lazar, Mitchell A (2016) Circadian time signatures of fitness and disease. Science 354:994-999
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, Z; Lazar, M A (2015) Rev-erb? and the circadian transcriptional regulation of metabolism. Diabetes Obes Metab 17 Suppl 1:12-6
Altman, Brian J; Hsieh, Annie L; Sengupta, Arjun et al. (2015) MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells. Cell Metab 22:1009-19

Showing the most recent 10 out of 72 publications