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SH2B1 Enhances Insulin Sensitivity by Both Stimulating the Insulin Receptor and Inhibiting Tyrosine Dephosphorylation of IRS Proteins

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SH2B1 Enhances Insulin Sensitivity by Both Stimulating the Insulin Receptor and Inhibiting Tyrosine Dephosphorylation of IRS Proteins Diabetes Publish Ahead of Print, published online June 19, 2009 SH2B1 Regulation of Insulin Sensitivity SH2B1 Enhances Insulin Sensitivity by Both Stimulating the Insulin Receptor and Inhibiting Tyrosine Dephosphorylation of IRS Proteins Running title: SH2B1 Regulation of Insulin Sensitivity David L. Morris, Kae Won Cho, Yingjiang Zhou and Liangyou Rui Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-5622 Address Correspondence to: Liangyou Rui, Ph.D. E-mail: [email protected] Submitted 8 October 2009 and accepted 2 June 2009. This is an uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association, publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http://diabetes.diabetesjournals.org. Copyright American Diabetes Association, Inc., 2009 SH2B1 Regulation of Insulin Sensitivity Objective-SH2B1 is a SH2 domain-containing adaptor protein expressed in both the central nervous system and peripheral tissues. Neuronal SH2B1 controls body weight; however, the functions of peripheral SH2B1 remain unknown. Here we studied peripheral SH2B1 regulation of insulin sensitivity and glucose metabolism. Research Design and Methods-We generated TgKO mice expressing SH2B1 in the brain but not peripheral tissues. Various metabolic parameters and insulin signaling were examined in TgKO mice fed a high fat diet (HFD). The effect of SH2B1 on the insulin receptor (IR) catalytic activity and IRS-1/IRS-2 dephosphorylation was examined using in vitro kinase assays and in vitro dephosphorylation assays, respectively. SH2B1 was coexpressed with PTP1B, and IR- mediated phosphorylation of IRS-1 was examined. Results-Deletion of peripheral SH2B1 markedly exacerbated HFD-induced hyperglycemia, hyperinsulinemia and glucose intolerance in TgKO mice. Insulin signaling was dramatically impaired in muscle, liver and adipose tissue in TgKO mice. Deletion of SH2B1 impaired insulin signaling in primary hepatocytes, whereas SH2B1 overexpression stimulated IR autophosphorylation and tyrosine phosphorylation of IR substrates. Purified SH2B1 stimulated IR catalytic activity in vitro. The SH2 domain of SH2B1 was both required and sufficient to promote IR activation. Insulin stimulated the binding of SH2B1 to IRS-1 or IRS-2. This physical interaction inhibited tyrosine dephosphorylation of IRS-1 or IRS-2 and increased the ability of IRS proteins to activate the PI 3-kinase pathway. Conclusions-SH2B1 is an endogenous insulin sensitizer. It directly binds to IR, IRS-1 and IRS-2, and enhances insulin sensitivity by promoting IR catalytic activity and by inhibiting tyrosine dephosphorylation of IRS proteins. 2 SH2B1 Regulation of Insulin Sensitivity nsulin decreases blood glucose terminal Src homology 2 (SH2) domain. The both by promoting glucose uptake DD domain mediates homodimerization or I into skeletal muscle and adipose heterodimerization between different SH2B tissue and by suppressing hepatic glucose proteins (27). SH2B1 and SH2B2 bind via production. In type 2 diabetes, the ability of their SH2 domains to a variety of tyrosine insulin to reduce blood glucose is impaired phosphorylated proteins, including JAK2 and (insulin resistance) due to a combination of IR, in cultured cells (28). Genetic deletion of genetic and environmental factors, resulting SH2B1 results in marked leptin resistance, in hyperglycemia. Insulin resistance is not obesity, insulin resistance and type 2 diabetes only the hallmark but also a determinant of in mice, demonstrating that SH2B1 is type 2 diabetes. required for the maintenance of normal body Insulin binds to and activates the weight, insulin sensitivity and glucose insulin receptor (IR). IR tyrosyl metabolism (29-32). Surprisingly, SH2B2 phosphorylates insulin receptor substrates null mice have normal body weight and (IRS-1, -2, -3 and -4). IRS proteins, slightly improved insulin sensitivity (32; 33), particularly IRS-1 and IRS-2, initiate and suggesting that SH2B1 and SH2B2 have coordinate multiple downstream pathways, distinct functions in vivo. However, it including the PI 3-kinase/Akt pathway (1). remains unclear whether SH2B1 cell- Genetic deletion of IRS-1, IRS-2 or Akt2 autonomously regulates insulin sensitivity in causes insulin resistance in mice, indicating peripheral insulin target tissues because that the IRS protein/PI 3-kinase/Akt2 pathway systemic deletion of SH2B1 causes obesity, is required for regulation of glucose which may cause insulin resistance in SH2B1 homeostasis by insulin (2-5). IR and IRS null mice. proteins are negatively regulated by various We generated a mouse model in which intracellular molecules, including PTP1B, recombinant SH2B1 is specifically expressed Grb10, Grb14, SOCS1, SOCS3, JNK, PKCθ, in the brain of SH2B1 null mice (TgKO) S6K and IKKβ (6-23). The relative using transgenic approaches (31). Neuron- contribution of these negative regulators to specific restoration of SH2B1 corrects both the progression of insulin resistance has been leptin resistance and obesity, suggesting that extensively studied (6-24). However, insulin neuronal SH2B1 regulates energy balance and signaling is likely to also be modulated by body weight by enhancing leptin sensitivity positive regulators. In this study, we (31). Consistent with these conclusions, demonstrate that SH2B1 is a novel polymorphisms in the SH2B1 loci are linked endogenous insulin sensitizer. to leptin resistance and obesity in humans SH2B1 is a member of the SH2B (34-36). In this work, we demonstrate that family of adapter proteins that also includes deletion of SH2B1 in peripheral tissues SH2B2 (APS) and SH2B3 (Lnk). SH2B1 and impairs insulin sensitivity independent of SH2B2 are expressed in multiple tissues, obesity in TgKO mice. Moreover, we including insulin target tissues (e.g. skeletal demonstrate that SH2B1 directly promotes muscle, adipose tissue, liver and the brain); by insulin responses by stimulating IR catalytic contrast, SH2B3 expression is restricted to activity and by protecting IRS proteins from hematopoietic tissue (25; 26). Structurally, tyrosine dephosphorylation. SH2B family members have an N-terminal dimerization domain (DD), a central RESEARCH DESIGN AND METHODS pleckstrin homology (PH) domain and a C- 3 SH2B1 Regulation of Insulin Sensitivity Animal Studies. SH2B1 KO and hamster ovary (CHOIR and CHOIR/IRS-1) cells TgKO mice have been described previously were cultured in Ham’s F-12 media (29; 31), and were backcrossed for 6 supplemented with 8% FBS. Cells were generations onto a C57BL/6 genetic deprived of serum for 16-h in DMEM (Cos7 background. Mice were housed on a 12-h and HEK293) or F-12 (CHO) containing light/dark cycle in the Unit for Laboratory 0.6% BSA before being treated. Primary liver Animal Medicine at the University of cells were isolated from male mice (8 weeks) Michigan, and fed either normal rodent chow by perfusion of the liver with type II (9% fat; Lab Diet) or HFD (45% fat; collagenase (Worthington Biochem), and Research Diets) ad libitum with free access to plated on collagen coated plates in M199 water. Fat content was measured by dual containing 10% FBS, 100 units/ml penicillin energy x-ray absorptiometry (Norland and 100 µg/ml streptomycin. After 2-h, Medical System). Blood glucose levels were primary cells were rinsed in PBS and cultured determined using glucometers (Bayer Corp). for an additional 16-h in Williams’ Medium E Plasma insulin was measured using a rat (Sigma) supplemented with 0.6% BSA, 100 insulin ELISA kit (Crystal Chem). Glucose units/ml penicillin and 100 µg/ml tolerance tests (GTT) (2 g D-glucose/kg of streptomycin. body weight) and insulin tolerance tests (ITT) Immunoprecipitation and (1 IU/kg of body weight; Eli Lilly) were Immunoblotting. Immunoprecipitation and conducted as previously described (29-31). immunoblotting were conducted as described To analyze insulin signaling, mice (fasted 16- previously (29; 37). Proteins were visualized h) were anesthetized with Averin (0.5 g of using the Odyssey Infrared Imaging System tribromoethanol and 0.25 g or tert-amyl (Li-Cor Biosciences) or ECL (Amersham), alcohol in 39.5 ml of water; 0.02 ml/g of body and quantified using Odyssey 1.2 software weight), and treated with phosphate buffered (Li-Cor). Actin, phosphoAkt (Thr308), Akt, saline (PBS) or human insulin (3 U per insulin receptor β, Myc, Shc and tubulin mouse; Eli Lilly) via inferior vena cava antibodies were from Santa Cruz. The injection. Five minutes after stimulation, phosphotyrosine-specific antibody was from gastrocnemius muscles, liver and epididymal Upstate. The AS160 antibody was from fat pads were dissected, frozen in liquid Millipore and phospho Akt substrate (PAS) nitrogen and stored at -80ºC. Tissues were antibody was from Cell Signaling. homogenized in ice cold lysis buffer (50 mM PhosphoAkt (Ser473) was from BioSource. Tris HCl, pH 7.5, 1.0% NP-40, 150 mM SH2B1 and IRS-1 antibodies have been NaCl, 2 mM EGTA, 1 mM Na3VO4, 100 mM described (14; 37). NaF, 10 mM Na4P2O7, 1 mM PMSF, 10 Insulin Receptor Kinase Assay. µg/ml aprotinin, 10 µg/ml leupeptin) and Cells were serum-deprived for 16-h, treated extracts were immunoblotted or with insulin and solubilized in kinase lysis immunoprecipitated with indicated buffer (50 mM Tris HCl [pH 7.5],
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