Lipid homeostasis is exquisitely controlled by hormonal and nutritional signals. Glucocorticoids are steroid hormones that play a critical role in regulating lipid homeostasis. However, the mechanisms underlying these glucocorticoid effects are largely unclear. Glucocorticoids convey their signals through an intracellular glucocorticoid receptor (GR). GR is a transcription factor, which upon binding to ligands, can associate with genomic glucocorticoid response element (GRE) to regulate the transcription of nearby genes. Thus, one critical step to understand glucocorticoid action is to identify genes directly regulated by GR that trigger the physiological response. We have identified a GR primary target gene, fasting-induced adipose factor (FIAF, a.k.a. angiopoietin-like 4, ANGPTL4), which encodes a secreted protein that inhibits lipoprotein lipase and induces adipose tissue lipolysis. The goals of this proposal are to examine the role in glucocorticoid-regulated lipid metabolism and to elucidate the mechanisms of transcriptional regulation of FIAF gene by distinct signals that include glucocorticoids, insulin and AICAR (an AMP-activated kinase activator).
In Aim 1, we will analyze the effects of glucocorticoids on chromatin structure, and histone acetylation and methylation status of FIAF gene. We will also investigate the potential role of FOXO1 in glucocorticoid and insulin response on FIAF gene. Moreover, we will investigate whether AMP kinase mediates the inhibitory effect of AICAR on glucocorticoid-activated FIAF gene transcription.
In Aim 2, we will use mice lacking FIAF gene to explore the role of FIAF in metabolic changes induced by long-term glucocorticoid treatment and fasting. In addition to measure metabolic parameters, we will also monitor the rate of lipid metabolism using stable isotope labeling technique. Overall, this research not only will expand our understanding on mechanisms underlying glucocorticoid-regulated lipid homeostasis, but also will provide important knowledge that can be applied to develop therapeutic interventions against metabolic diseases, such as obesity and diabetes.

Public Health Relevance

Disturbance of lipid homeostasis is associated with the development of a wide variety of metabolic diseases, such as diabetes, obesity and atherosclerosis. Glucocorticoids are steroid hormones that play an important role in regulation of lipid metabolism. This proposed research is to understand the molecular mechanisms of glucocorticoid action on lipid metabolism and to provide new insights for future pharmaceutical interventions against metabolic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083591-02
Application #
7860696
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Margolis, Ronald N
Project Start
2009-07-01
Project End
2014-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$373,774
Indirect Cost
Name
University of California Berkeley
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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Kuo, Taiyi; Chen, Tzu-Chieh; Lee, Rebecca A et al. (2017) Pik3r1 Is Required for Glucocorticoid-Induced Perilipin 1 Phosphorylation in Lipid Droplet for Adipocyte Lipolysis. Diabetes 66:1601-1610
Chen, Tzu-Chieh; Benjamin, Daniel I; Kuo, Taiyi et al. (2017) The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKC?. Sci Signal 10:
Boortz, Kayla A; Syring, Kristen E; Dai, Chunhua et al. (2016) G6PC2 Modulates Fasting Blood Glucose In Male Mice in Response to Stress. Endocrinology 157:3002-8
Kuo, Taiyi; Liu, Patty H; Chen, Tzu-Chieh et al. (2016) Transcriptional regulation of FoxO3 gene by glucocorticoids in murine myotubes. Am J Physiol Endocrinol Metab 310:E572-85
Boortz, Kayla A; Syring, Kristen E; Lee, Rebecca A et al. (2016) G6PC2 Modulates the Effects of Dexamethasone on Fasting Blood Glucose and Glucose Tolerance. Endocrinology 157:4133-4145
Kuo, Taiyi; McQueen, Allison; Chen, Tzu-Chieh et al. (2015) Regulation of Glucose Homeostasis by Glucocorticoids. Adv Exp Med Biol 872:99-126
Ou, Chen-Yin; Chen, Tzu-Chieh; Lee, Joyce V et al. (2014) Coregulator cell cycle and apoptosis regulator 1 (CCAR1) positively regulates adipocyte differentiation through the glucocorticoid signaling pathway. J Biol Chem 289:17078-86
Poole, Daniel P; Lee, Mike; Tso, Patrick et al. (2014) Feeding-dependent activation of enteric cells and sensory neurons by lymphatic fluid: evidence for a neurolymphocrine system. Am J Physiol Gastrointest Liver Physiol 306:G686-98
Kuo, Taiyi; Chen, Tzu-Chieh; Yan, Stephanie et al. (2014) Repression of glucocorticoid-stimulated angiopoietin-like 4 gene transcription by insulin. J Lipid Res 55:919-28

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