Feeding behavior in mammals is both episodic and circadian. Accordingly, mammals have developed mechanisms to temporally regulate liver gluconeogenesis to maintain glucose homeostasis. The CREB/CRTC2 pathway regulates transcription of gluconeogenic genes via cis-acting cAMP Response Elements (CREs) in response to fasting and feeding bouts. In parallel, the self sustaining hepatic circadian clock mediates circadian rhythm in expression of metabolic genes- a number of which are regulated by CREB and CRTC2- with peak levels aligned to appropriate time of the day. Although molecular interactions between the circadian clock and the CREB/CRTC2 pathway are thought to shape the overall adaptation to feeding regimen, these interactions are not well defined. The core circadian clock is based on a transcriptional feedback loop in which Clock/Bamal1 transcriptional activators bind to cis acting E-box in the promoters of Per and Cry genes, whose protein products in turn inhibit Clock/Bmal1 function, thus producing circadian rhythms in Per and Cry proteins. The current application tests the hypothesis that the circadian clock and CREB pathway promote metabolic adaptation to environmental changes through reciprocal regulatory interactions between the Per/CRY inhibitors and CREB/CRTC2 activators.
Aims 1 to 3 address the role of Cry proteins in the circadian modulation of hepatic CREB and CRTC2 activities in response to episodic feeding. In particular, we will evaluate the proposed role of Crys in attenuating glucagon-dependent increases in cAMP production. Does cytoplasmic Cry interfere with G protein coupled receptor signaling? Aims 4-6 address counter-regulatory effects of the CREB/CRTC2 pathway on clock activity. In particular, we will examine the regulatory importance of CREB binding sites on Per genes, which offer a node for synchronizing Per transcription and consequently the circadian clock with the daily feeding rhythms. Finally, we will test how these interactions shape long term adaptation of the organism to feeding regimens.

Public Health Relevance

The circadian clock is thought to promote energy homeostasis by modulating the expression of fasting and feeding programs in metabolically active tissues. Disturbances in clock function have been associated with an increased risk of insulin resistance and the metabolic syndrome, most notably in shift workers. The current application tests the importance of a newly identified interaction between the circadian clock and a cell surface receptor signaling pathway in maintaining glucose homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK091618-01
Application #
8087954
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Silva, Corinne M
Project Start
2011-04-15
Project End
2016-03-31
Budget Start
2011-04-15
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$752,763
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Chaix, Amandine; Zarrinpar, Amir; Panda, Satchidananda (2016) The circadian coordination of cell biology. J Cell Biol 215:15-25
Chaix, Amandine; Panda, Satchidananda (2016) Ketone Bodies Signal Opportunistic Food-Seeking Activity. Trends Endocrinol Metab 27:350-2
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Gill, Shubhroz; Panda, Satchidananda (2015) A Smartphone App Reveals Erratic Diurnal Eating Patterns in Humans that Can Be Modulated for Health Benefits. Cell Metab 22:789-98
Luan, Bing; Goodarzi, Mark O; Phillips, Naomi G et al. (2014) Leptin-mediated increases in catecholamine signaling reduce adipose tissue inflammation via activation of macrophage HDAC4. Cell Metab 19:1058-65
Chaix, Amandine; Zarrinpar, Amir; Miu, Phuong et al. (2014) Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab 20:991-1005

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