The prevalence of type 2 diabetes and nonalcoholic fatty liver disease continues to rise, devastating millions of American life. In the past funding period, we discovered that genetic deletion of SH2B1 causes obesity, type 2 diabetes, hyperlipidemia and NAFLD in mice. Importantly, SH2B1 is similarly produced in humans, suggesting that the dysfunction of human SH2B1 is also a primary risk factor for hyperlipidemia, nonalcoholic fatty liver disease, and type 2 diabetes. We discovered that central SH2B1, mainly in the brain, controls body weight, whereas peripheral SH2B1 controls fuel substrate metabolism (e.g. glucose and lipids). In the current proposal, we will identify the metabolic functions of SH2B1 in fat and liver, two essential tissues that control the levels of glucose and lipids in the circulation. We have generated genetically-modified mice which do not produce SH2B1 only in fat or in the liver, respectively. We will determine whether lack of SH2B1 in fat or in the liver disrupts normal functions of these two organs, thereby causing, or predisposing to, nonalcoholic fatty liver disease and type 2 diabetes. We will identify the underlying molecular mechanisms. The findings in this project will provide guidance for the development of new therapies for the treatment of nonalcoholic fatty liver disease and type 2 diabetes. We have four specific Aims:
Aim 1. Determine whether SH2B1 mediates insulin- stimulated glucose uptake in adipocytes by promoting GLUT4 trafficking.
Aim 2. Determine whether adipose SH2B1 regulates systemic insulin sensitivity and energy substrate metabolism in mice.
Aim. 3. Determine whether SH2B1 cell-autonomously regulates the gluconeogenic, lipogenic and 2-oxidation programs in hepatocytes.
Aim 4. Determine whether hepatic SH2B1 regulates hepatic metabolism, systemic insulin sensitivity and energy substrate homeostasis in mice.

Public Health Relevance

The prevalence of type 2 diabetes and nonalcoholic fatty liver disease continues to rise, devastating millions of American life. In the past funding period, we discovered that genetic deletion of SH2B1 causes obesity, type 2 diabetes, hyperlipidemia and nonalcoholic fatty liver disease in mice. We further demonstrated that brain SH2B1 controls body weight, whereas SH2B1 in peripheral tissues controls fuel substrate metabolism (e.g. glucose and lipids). Importantly, SH2B1 is also produced in humans and may perform similar functions. In this project, we will identify the metabolic functions of SH2B1 in fat and the liver, two essential tissues that control levels of glucose and lipids in the circulation. We will also determine whether lack of SH2B1 in fat or in the liver causes hyperlipidemia, nonalcoholic fatty liver disease and type 2 diabetes in mice. The findings in this project will provide guidance for the development of new therapies for the treatment of hyperlipidemia, nonalcoholic fatty liver disease 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 #
5R01DK065122-07
Application #
7807059
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Abraham, Kristin M
Project Start
2003-07-01
Project End
2013-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
7
Fiscal Year
2010
Total Cost
$396,795
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Rui, Liangyou (2014) SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes 5:511-26
Pearce, Laura R; Joe, Ray; Doche, Michael E et al. (2014) Functional characterization of obesity-associated variants involving the ? and ? isoforms of human SH2B1. Endocrinology 155:3219-26
Hu, Jun; Jiang, Lin; Low, Malcolm J et al. (2014) Glucose rapidly induces different forms of excitatory synaptic plasticity in hypothalamic POMC neurons. PLoS One 9:e105080
Chen, Zheng; Morris, David L; Jiang, Lin et al. (2014) SH2B1 in ?-cells regulates glucose metabolism by promoting ?-cell survival and islet expansion. Diabetes 63:585-95
Rui, Liangyou (2014) Energy metabolism in the liver. Compr Physiol 4:177-97
Chen, Zheng; Morris, David L; Jiang, Lin et al. (2014) SH2B1 in ?-cells promotes insulin expression and glucose metabolism in mice. Mol Endocrinol 28:696-705
Rui, Liangyou (2013) Brain regulation of energy balance and body weight. Rev Endocr Metab Disord 14:387-407
Zhou, Yingjiang; Rui, Liangyou (2013) Leptin signaling and leptin resistance. Front Med 7:207-22
Zhou, Yingjiang; Rui, Liangyou (2013) Lipocalin 13 regulation of glucose and lipid metabolism in obesity. Vitam Horm 91:369-83
Sheng, Liang; Liu, Yan; Jiang, Lin et al. (2013) Hepatic SH2B1 and SH2B2 regulate liver lipid metabolism and VLDL secretion in mice. PLoS One 8:e83269

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