The objective of this research proposal is to further investigate the role of the Src kinase family member Fyn as a novel element of the nutrient-sensor system that regulates cellular and whole body energy homeostasis via AMPK and its upstream kinase, LKB1. In our published work (Bastie et. al. 2007 Cell Metab.), we have shown that the Fyn null animals present a marked reduction in adiposity, increased insulin sensitivity and increased AMPK activity coupled with increased fatty acid oxidation and energy expenditure. In the last 10 months, we have successfully demonstrated that LKB1, the main upstream kinase of AMPK in peripheral tissues, is a direct substrate for Fyn kinase. Moreover, LKB1 sub-cellular localization is regulated by tyrosine phosphorylation on Y261 and Y365 of LKB1 by Fyn kinase. Site directed mutagenesis of Y261 and Y365 results in re-localization of LKB1 from the nucleus into the cytoplasm, with a resultant increase in AMPK phosphorylation. These findings are consistent with the observed phenotype of the Fyn null mice. Importantly, the positive metabolic effects observed in the Fyn null mice (decreased adiposity and increased energy expenditure) are reproduced by acute pharmacological inhibition of Fyn kinase activity, resulting in weight loss via specific decrease of adiposity with no alteration of lean mass (Yamada, E., Pessin, J.E., Kurland, IJ., Schwartz, GJ., and Bastie, CC. Cell Metab. Under revision). These data place Fyn kinase and LKB1 as key potential therapeutic targets in obesity, a condition with a significant clinical unmet need. Based upon these data, we propose to further examine the novel functions of Fyn kinase as a fuel sensor. We will determine the precise mechanism (s) of Fyn kinase-dependent regulation of LKB1 using molecular and cellular tools. We will also explore the basis for upstream signals regulating Fyn kinase activity during the fed and fasted states and how this regulates LKB1 localization and subsequently AMPK activity. Finally, we will study the metabolic effects and the signaling pathways of pharmacological inhibition of Fyn function in animal models of obesity.

Public Health Relevance

Obesity and diabetes are associated with dysfunctions of glucose and lipid metabolism. Lack of Fyn kinase increases insulin sensitivity, up-regulates lipid utilization and pharmacological inhibition of Fyn promotes weight loss. Therefore, Fyn kinase is a potential target for the development of specific drugs against insulin resistance associated with obesity and type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081412-04
Application #
8520295
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
2010-09-15
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$329,070
Indirect Cost
$130,835
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Yamada, Eijiro; Bastie, Claire C (2014) Disruption of Fyn SH3 domain interaction with a proline-rich motif in liver kinase B1 results in activation of AMP-activated protein kinase. PLoS One 9:e89604
Bari, Muhammad Furqan; Weickert, Martin O; Sivakumar, Kavitha et al. (2014) Elevated soluble CD163 in gestational diabetes mellitus: secretion from human placenta and adipose tissue. PLoS One 9:e101327
Apontes, Pasha; Liu, Zhongbo; Su, Kai et al. (2014) Mangiferin stimulates carbohydrate oxidation and protects against metabolic disorders induced by high-fat diets. Diabetes 63:3626-36
Lee, Ting-Wen A; Kwon, Hyokjoon; Zong, Haihong et al. (2013) Fyn deficiency promotes a preferential increase in subcutaneous adipose tissue mass and decreased visceral adipose tissue inflammation. Diabetes 62:1537-46
Yang, Yingjuan; Tarabra, Elena; Yang, Gong-She et al. (2013) Alteration of de novo glucose production contributes to fasting hypoglycaemia in Fyn deficient mice. PLoS One 8:e81866
Sivakumar, K; Bari, M F; Adaikalakoteswari, A et al. (2013) Elevated fetal adipsin/acylation-stimulating protein (ASP) in obese pregnancy: novel placental secretion via Hofbauer cells. J Clin Endocrinol Metab 98:4113-22
Martinez-Lopez, Nuria; Athonvarangkul, Diana; Sahu, Srabani et al. (2013) Autophagy in Myf5+ progenitors regulates energy and glucose homeostasis through control of brown fat and skeletal muscle development. EMBO Rep 14:795-803
Kuliawat, Regina; Klein, Laura; Gong, Zhenwei et al. (2013) Potent humanin analog increases glucose-stimulated insulin secretion through enhanced metabolism in the β cell. FASEB J 27:4890-8
Vatish, Manu; Tesfa, Lydia; Grammatopoulos, Dimitris et al. (2012) Inhibition of Akt activity and calcium channel function coordinately drive cell-cell fusion in the BeWO choriocarcinoma placental cell line. PLoS One 7:e29353
Bastie, Claire C; Gaffney-Stomberg, Erin; Lee, Ting-Wen A et al. (2012) Dietary cholecalciferol and calcium levels in a Western-style defined rodent diet alter energy metabolism and inflammatory responses in mice. J Nutr 142:859-65

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