? Obesity and diabetes have reached epidemic levels in the United States. Diabetes and its associated complications are becoming one of the leading causes of morbidity in this country. Although several hypotheses link obesity and insulin resistance, the role of circadian rhythm in the pathogenesis of diabetes has not been well addressed. Interestingly, there is a clear circadian variation in fasting glucose, insulin sensitivity and glucose tolerance, which is severely dampened in the condition of obesity and diabetes. ? The orphan nuclear receptor Rev-erb( emerged as a core circadian gene. By repressing gene expression of another clock gene, Bma1, Rev-erb( functions as a negative regulator of circadian rhythm. We showed GSK3(-dependent phosphorylation is required for maintaining the protein stability of Rev-erb( and is crucial for synchronizing the circadian oscillation of Bma1 gene in vitro. To extend our knowledge on GSK3(-dependent regulation of Rev-erb(, we propose two specific aims in the first phase of this application (K99 phase), including:
Aim 1. Elucidate the signal pathways upstream of GSK3( mediating Rev-erb( degradation in hepatocytes;
and Aim 2. Determine in vivo roles of Rev-erb( phosphorylation by GSK3( in circadian rhythm and metabolism. A mouse model expressing Rev-erb( mutant which mimics GSK3( phosphorylation in liver will be created to address these questions. This will be the first analysis to determine the role of Rev-erb( as a clock protein in liver circadian rhythm and glucose metabolism. This study will be carried out in the Penn Diabetes Center at University of Pennsylvania under the supervision of Dr. Mitchell Lazar. The center has expertise in diabetes and obesity research, and is an outstanding environment in which to conduct the proposed project. Meanwhile, the project will provide superb training for the principle investigator, Dr. Lei Yin, to develop an academic career in the field of diabetes and obesity. ? The role of the ubiquitin-proteasome pathway (UPP) has not been well-studied in the process of metabolism and energy homeostasis. We recently discovered that Cullin 4A-based E3 ligase regulates protein stability of Rev-erb( as well as gene expression important for gluconeogenesis, suggesting Cullin 4A is a novel modulator functioning in both circadian rhythm and metabolism. Therefore, the specific aim 3 proposed during the R00 phase will be focused on unraveling roles of the Cullin 4A E3 ubiquitin ligase in regulating circadian rhythm, insulin signaling and glucose metabolism. We expect this work will provide a panel of evidences for the functional importance of the ubiquitin-proteasome system in the regulation of metabolism. In addition, this work may shed the new light on identifying new therapeutic targets for treating insulin resistance and diabetes. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Career Transition Award (K99)
Project #
1K99DK077449-01A1
Application #
7318559
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Margolis, Ronald N
Project Start
2007-07-20
Project End
2009-06-30
Budget Start
2007-07-20
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$72,781
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tong, Xin; Zhang, Deqiang; Charney, Nicholas et al. (2017) DDB1-Mediated CRY1 Degradation Promotes FOXO1-Driven Gluconeogenesis in Liver. Diabetes 66:2571-2582
Russo, Lucia; Ghadieh, Hilda E; Ghanem, Simona S et al. (2016) Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte-hepatocyte axis. J Lipid Res 57:2163-2175
Tong, Xin; Li, Pei; Zhang, Deqiang et al. (2016) E4BP4 is an insulin-induced stabilizer of nuclear SREBP-1c and promotes SREBP-1c-mediated lipogenesis. J Lipid Res 57:1219-30
Tong, Xin; Zhang, Deqiang; Guha, Anirvan et al. (2015) CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activity by Promoting Ubiquitination-Dependent Degradation of the Mammalian CRY1. PLoS One 10:e0139725
Zhang, Deqiang; Tong, Xin; Arthurs, Blake et al. (2014) Liver clock protein BMAL1 promotes de novo lipogenesis through insulin-mTORC2-AKT signaling. J Biol Chem 289:25925-35
Tong, Xin; Zhang, Deqiang; Buelow, Katie et al. (2013) Recruitment of histone methyltransferase G9a mediates transcriptional repression of Fgf21 gene by E4BP4 protein. J Biol Chem 288:5417-25
Tong, Xin; Yin, Lei (2013) Circadian rhythms in liver physiology and liver diseases. Compr Physiol 3:917-40
Yin, Lei; Wu, Nan; Lazar, Mitchell A (2010) Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism. Nucl Recept Signal 8:e001
Tong, Xin; Muchnik, Marina; Chen, Zheng et al. (2010) Transcriptional repressor E4-binding protein 4 (E4BP4) regulates metabolic hormone fibroblast growth factor 21 (FGF21) during circadian cycles and feeding. J Biol Chem 285:36401-9
Yin, Lei; Joshi, Shree; Wu, Nan et al. (2010) E3 ligases Arf-bp1 and Pam mediate lithium-stimulated degradation of the circadian heme receptor Rev-erb alpha. Proc Natl Acad Sci U S A 107:11614-9

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