Targeting hepatic CREB to reduce glucose output as a treatment option for diabetes is a highly controversial notion. Inhibition of CREB activity in the liver using a dominant-negative approach caused increased hepatic triglyceride content, suggesting that CREB is a poor target. In contrast, a recent report using antisense oligonucleotides (ASO) suggested that CREB inhibition prevented hepatic steatosis and insulin resistance However, given the systemic application of the ASO, and the repression of CREB in other metabolic tissues such as adipose tissue, this report did not directly address the function of CREB in the liver. During the past grant cycle, we have completed a systematic, genome-wide evaluation of CREB binding in the mammalian liver using ChlP-Seq analysis. Strikingly, four genes central to circadian regulation are direct CREB targets, suggesting a novel role for CREB in the maintenance of the peripheral clock in the liver. This is relevant, because night-shift work and other disruptions of circadian rhythms increase the risk of """"""""metabolic syndrome"""""""", including obesity, insulin resistance, and dyslipidemia in humans. Based on the above, we propose three specific aims.
In AIM 1, we will determine if CREB ablation in hepatocytes can be used to alleviate hepatic insulin resistance and steatosis. We have derived two new models that will enable us to analyze CREB function in a precise, cell-type specific manner, a conditional null allele for CREB (CREB[loxp), and a conditional CREB Ser133 to Ala133 mutation (CREB][loxp](S133A)). These two alleles allow us to dissociate the contribution of CREB phosphorylation by protein kinase A versus all CREB functions.
In AIM 2, we will determine the contribution of CREB to the control of the peripheral clock in the liver. Mice will also be subjected to restricted feeding to study the contribution of CREB to shifting part of the liver's circadian clock in this paradigm.
In AIM 3, we will determine the role of CREB in nutritional control of the neuroendocrine axis. We will ablate CREB in the hypothalamus to assess its contribution to the regulation of TRH, and its role in feeding-dependent thermogenesis.
Treatment options for type 2 diabetes are limited, and inhibition of hepatic glucose production is a very attractive target. Therefore, we will investigate whether ablation of CREB or its phosphorylation can be used for this purpose. In addition, circadian control of metabolism is essential for human health, and we will determine the contribution of CREB to this process with multiple approaches.
| Juliana, Christine A; Yang, Juxiang; Cannon, Corey E et al. (2018) A PDX1-ATF transcriptional complex governs ? cell survival during stress. Mol Metab 17:39-48 |
| Barnoud, Thibaut; Budina-Kolomets, Anna; Basu, Subhasree et al. (2018) Tailoring Chemotherapy for the African-Centric S47 Variant of TP53. Cancer Res 78:5694-5705 |
| Kim, Yong Hoon; Marhon, Sajid A; Zhang, Yuxiang et al. (2018) Rev-erb? dynamically modulates chromatin looping to control circadian gene transcription. Science 359:1274-1277 |
| Plikus, Maksim V; Guerrero-Juarez, Christian F; Ito, Mayumi et al. (2017) Regeneration of fat cells from myofibroblasts during wound healing. Science 355:748-752 |
| Juliana, Christine A; Yang, Juxiang; Rozo, Andrea V et al. (2017) ATF5 regulates ?-cell survival during stress. Proc Natl Acad Sci U S A 114:1341-1346 |
| Ediger, Benjamin N; Lim, Hee-Woong; Juliana, Christine et al. (2017) LIM domain-binding 1 maintains the terminally differentiated state of pancreatic ? cells. J Clin Invest 127:215-229 |
| Jang, Jessica C; Li, Jiang; Gambini, Luca et al. (2017) Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction. Proc Natl Acad Sci U S A 114:E10399-E10408 |
| Carr, Rotonya M; Dhir, Ravindra; Mahadev, Kalyankar et al. (2017) Perilipin Staining Distinguishes Between Steatosis and Nonalcoholic Steatohepatitis in Adults and Children. Clin Gastroenterol Hepatol 15:145-147 |
| Park, Hyeong Kyu; Kwak, Mi Kyung; Kim, Hye Jeong et al. (2017) Linking resistin, inflammation, and cardiometabolic diseases. Korean J Intern Med 32:239-247 |
| Ackermann, Amanda M; Zhang, Jia; Heller, Aryel et al. (2017) High-fidelity Glucagon-CreER mouse line generated by CRISPR-Cas9 assisted gene targeting. Mol Metab 6:236-244 |
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