Glucose and lipid homeostasis are normally maintained through a network of hormonal and nutrient signaling pathways that operate between insulin sensitive tissues. Indeed, disruptions in inter-tissue communication are often associated with type II diabetes, although initiating events that trigger this process have not been characterized. In recent studies, obesity was found to stimulate the phosphorylation and activation of the cAMP responsive factor CREB in adipose;mice deficient in adiposity CREB activity remained insulin sensitive in the context of dietary or genetic obesity. The current proposal addresses the importance of the CREB coactivator CRTC3 in mediating the metabolic effects of CREB in adipose.
Three Aims are proposed;
In Aim 1, the mechanism by which disruption of the CRTC3 gene confers insulin sensitivity and resistance to diet induced obesity will be characterized. Effects of nutritional and dietary status in triggering CRTC3-dependent changes in energy expenditure, food intake, and physical activity will be determined. And potential regulatory contributions from other CRTC family members will be explored.
In Aim 2, the relative importance of CRTC3 in modulating energy expenditure through its effects on catecholamine signaling and adipogenesis will be evaluated.
In Aim 3, the role of the nucleosome remodeling and deacetylase complex (NuRD) in silencing cAMP responsive genes through an association with CREB and CRTC3 will be characterized. These studies will provide insight into the importance of the CREB:CRTC3 pathway in triggering early changes in adipose that lead to the development of systemic insulin resistance in obesity.

Public Health Relevance

Obesity is a major risk factor in the development of type II diabetes, a disease that affects more than 20 million individuals in the United States. The current application addresses how a fasting switch called CRTC3 promotes insulin resistance in the context of diet induced obesity. The studies will provide insight into molecular mechanisms by which increases in adiposity lead to systemic changes in insulin sensitivity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Salk Institute for Biological Studies
La Jolla
United States
Zip Code
Tsai, Wen-Wei; Matsumura, Shigenobu; Liu, Weiyi et al. (2015) ATF3 mediates inhibitory effects of ethanol on hepatic gluconeogenesis. Proc Natl Acad Sci U S A 112:2699-704
Hernandez, Jeniffer B; Chang, Christina; LeBlanc, Mathias et al. (2015) The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation. Nat Commun 6:7216
Blanchet, Emilie; Van de Velde, Sam; Matsumura, Shigenobu et al. (2015) Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance. Cell Rep 10:1149-57
Paz, Jose C; Park, Sangho; Phillips, Naomi et al. (2014) Combinatorial regulation of a signal-dependent activator by phosphorylation and acetylation. Proc Natl Acad Sci U S A 111:17116-21
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
Ravnskjaer, Kim; Hogan, Meghan F; Lackey, Denise et al. (2013) Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects. J Clin Invest 123:4318-28
Tsai, Wen-Wei; Niessen, Sherry; Goebel, Naomi et al. (2013) PRMT5 modulates the metabolic response to fasting signals. Proc Natl Acad Sci U S A 110:8870-5
Luo, Qianyi; Viste, Kristin; Urday-Zaa, Janny Concha et al. (2012) Mechanism of CREB recognition and coactivation by the CREB-regulated transcriptional coactivator CRTC2. Proc Natl Acad Sci U S A 109:20865-70
Wang, Yiguo; Li, Gang; Goode, Jason et al. (2012) Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature 485:128-32
Wang, Biao; Moya, Noel; Niessen, Sherry et al. (2011) A hormone-dependent module regulating energy balance. Cell 145:596-606

Showing the most recent 10 out of 23 publications