Liangyou Rui, Ph.D. ~Assistant Professor of Physiology Ph.D., University of Michigan, 1998 7810 Med. Sci. II (734) 615-7542 ruily@umich.edu

Current Research: 

I am interested in cell signaling and mechanisms of obesity and type 2 diabetes.  Leptin is an adipose hormone that regulates appetite and energy balance primarily by activating its receptor LEPRb in the brain.  Deficiency of either leptin or LEPRb causes morbid obesity in both animals and humans.  Obesity is a primary risk factor for type 2 diabetes, which affects more than 17 million people in the US alone. Type 2 diabetes is caused by a combination of impaired insulin production from pancreatic b cells and impaired insulin action (insulin resistance) in liver, muscle and fat.  Insulin is a polypeptide hormone that regulates blood glucose metabolism through binding and activating its receptor tyrosine kinase. We have identified SH2B1 (also known as SH2-B) as a signaling protein for both leptin and insulin in cultured cells.  We generated SH2B1 knockout mice, and demonstrated that SH2B1-deficient mice develop obesity and type 2 diabetes.  We specifically restored SH2B1 expression in neurons in SH2B1 knockout mice, and showed that neuron-specific restoration of SH2B1 rescues leptin resistant and obese phenotypes. Moreover, neuron-specific overexpression of SH2B1 protects against high fat-induced leptin resistance and obesity. We conclude that neuronal SH2B1 controls energy balance and body weight by enhancing leptin sensitivity.  We also showed that SH2B1 regulates glucose metabolism both indirectly by regulating body weight and directly by enhancing insulin signaling in liver, adipose tissue and muscle. SH2B1 also regulates the ability of pancreatic b cells to produce and secrete insulin. We have recently generated conditional SH2B1 knockout mice. Using these animal models, we plan to identify key subpopulations of neurons in the brain that control energy balance, body weight and glucose metabolism, and elucidate the underlying molecular mechanisms.  Additionally, we are studying molecular mechanisms by which SH2B1 directly modulates insulin signaling and physiological responses in peripheral tissues (e.g. liver and adipose tissue) and regulates islet b cell function.
In addition to SH2B1, we are working on multiple signaling molecules that are involved in regulation of body weight and cell metabolism. Our goals are to elucidate molecular mechanisms of insulin and leptin resistance, obesity and type 2 diabetes, and to identify potential drug targets for therapeutic intervention of obesity and type 2 diabetes.

Recent Publications:

Decheng Ren, Yingjiang Zhou, David Morris, Minghau Li, Zhiqin Li, and Liangyou Rui. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. Journal of Clinical Investigation. 117: 397-406; 2007

Minghua Li, Zhiqin Li, David Morris and Liangyou Rui. Identification of SH2B2b as an inhibitor for SH2B1- and SH2B2a-promoted Janus Kinase-2 activation and insulin signaling. Endocrinology.148(4): 1615-1621; 2007

Minghua Li, Decheng Ren, Masanori Iseki, Satoshi Takaki, and Liangyou Rui. Differential Role of SH2-B and APS in Regulating Energy and Glucose Homeostasis. Endocrinology. 147(5):2163-2170; 2006

Decheng Ren, Minghua Li, Chaojun Duan, and Liangyou Rui. Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Cell Metabolism. 2:95-104; 2005

Chaojun Duan, Minghua Li, Liangyou Rui. SH2-B promotes insulin receptor 1 (IRS1)- and IRS2-mediated activation of the PI 3-kinase pathway in response to leptin. Journal of Biological Chemistry. 279(42):43684-91; 2004

Chaojun Duan, Hongyan Yang, Morris F. White, Liangyou Rui. Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. Molecular and Cellular Biology. 24(17): 7435-7443; 2004

Liangyou Rui, Minsheng Yuan, Dan Frantz, Steven Shoelson, Morris F. White. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. Journal of Biological Chemistry 277(44):42394-42398; 2002

Liangyou Rui, Tracey L. Fisher, Jeffrey Thomas and Morris F. White. Regulation of insulin/Insulin-like growth factor signaling by proteasome-mediated degradation of Insulin receptor substrate-2. Journal of Biological Chemistry 276(43):40362-40367; 2001

Liangyou Rui, Vincent Aguirre, Jason K. Kim, Gerald I. Shulman, Anna Lee, Anne Corbould, Andrea Dunaif, and Morris F. White. Insulin/IGF-1 and TNF- stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. Journal of Clinical Investigation 107: 181-189; 2001

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