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Crucial Role of the SH2B1 PH Domain for the Control of Energy Balance

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Crucial Role of the SH2B1 PH Domain for the Control of Energy Balance Diabetes Volume 68, November 2019 2049 Crucial Role of the SH2B1 PH Domain for the Control of Energy Balance Anabel Flores,1 Lawrence S. Argetsinger,2 Lukas K.J. Stadler,3 Alvaro E. Malaga,2 Paul B. Vander,2 Lauren C. DeSantis,2 Ray M. Joe,1,2 Joel M. Cline,2 Julia M. Keogh,3 Elana Henning,3 Ines Barroso,4 Edson Mendes de Oliveira,3 Gowri Chandrashekar,2 Erik S. Clutter,2 Yixin Hu,2 Jeanne Stuckey,5 I. Sadaf Farooqi,3 Martin G. Myers Jr.,1,2,6 and Christin Carter-Su1,2,6 Diabetes 2019;68:2049–2062 | https://doi.org/10.2337/db19-0608 Disruption of the adaptor protein SH2B1 (SH2-B, PSM) is obesity and glucose intolerance of otherwise Sh2b1-null associated with severe obesity, insulin resistance, and mice (6), suggesting the importance of brain SH2B1 for neurobehavioral abnormalities in mice and humans. Here, the control of energy balance and glucose homeostasis. SH2B1 we identify 15 variants in severely obese children. At the cellular level, SH2B1 is an intracellular adaptor Four obesity-associated human SH2B1 variants lie in protein that is recruited to phosphorylated tyrosine res- OBESITY STUDIES the Pleckstrin homology (PH) domain, suggesting that idues on specific membrane receptor tyrosine kinases (e.g., the PH domain is essential for SH2B1’s function. We gen- receptors for brain-derived neurotrophic factor [BDNF], erated a mouse model of a human variant in this domain (P322S). P322S/P322S mice exhibited substantial prenatal nerve growth factor [NGF], insulin) and cytokine receptor/ lethality. Examination of the P322S/1 metabolic phenotype Janus kinase (JAK) complexes (e.g., leptin receptor/JAK2) – revealed late-onset glucose intolerance. To circumvent and enhances the function of these receptors (7 13). The P322S/P322S lethality, mice containing a two-amino acid exact mechanism(s) by which it does so is unclear, although deletion within the SH2B1 PH domain (DP317, R318 [DPR]) a variety of mechanisms have been proposed. These include were studied. Mice homozygous for DPR were born at the enhanced dimerization causing increased activation of the expected Mendelian ratio and exhibited obesity plus insulin kinase itself (14), stabilization of the active state of the resistance and glucose intolerance beyond that attribut- kinase (15), decreased dephosphorylation or increased com- able to their increased adiposity. These studies demon- plex formation of insulin receptor substrate (IRS) proteins strate that the PH domain plays a crucial role in how SH2B1 bound to receptors or receptor/JAK2 (16,17), regulation of controls energy balance and glucose homeostasis. the actin cytoskeleton (18), and activation of specificpath- ways, including extracellular signal–regulated kinases (ERKs), Akt, and/or phospholipase Cg (10,19). Some of these Hyperphagia, severe obesity, insulin resistance, and neuro- receptors, including the leptin, BDNF, and insulin recep- behavioral abnormalities have been reported in individuals tors, play important roles in the central control of energy with rare coding variants in the gene encoding SH2B1 (SH2- expenditure and/or glucose homeostasis (20). SH2B1b B, PSM) (1,2). Consistently, mice null for Sh2b1 exhibit has been shown to enhance BDNF- and NGF-stimulated obesity, impaired glucose homeostasis, and often, aggressive neurite outgrowth in PC12 cells (13,21). behavior (3–5). Transgenic expression of the b-isoform The four isoforms of SH2B1 (a, b, g, d), which differ of SH2B1 (SH2B1b) in the brain largely corrects the only in their COOH termini, share 631 NH2-terminal 1Cell and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI Corresponding author: Christin Carter-Su, [email protected] 2 Department of Molecular and Integrative Physiology, University of Michigan, Ann Received 21 June 2019 and accepted 12 August 2019 Arbor, MI This article contains Supplementary Data online at http://diabetes 3University of Cambridge Metabolic Research Laboratories and NIHR Cambridge .diabetesjournals.org/lookup/suppl/doi:10.2337/db19-0608/-/DC1. Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, U.K. L.S.A. and L.K.J.S. contributed equally to this work. 4MRC Epidemiology Unit, Wellcome Trust-MRC Institute of Metabolic Science, © 2019 by the American Diabetes Association. Readers may use this article as Addenbrooke’s Hospital, Cambridge, U.K. long as the work is properly cited, the use is educational and not for profit, and the 5Life Sciences Institute and Departments of Biological Chemistry and Biophysics, work is not altered. More information is available at http://www.diabetesjournals University of Michigan, Ann Arbor, MI .org/content/license. 6Department of Internal Medicine, University of Michigan, Ann Arbor, MI 2050 Role of SH2B1 PH Domain in Energy Balance Diabetes Volume 68, November 2019 amino acids. These amino acids possess a dimerization access to food and tap water except as noted. Mice were fed domain, Pleckstrin homology (PH) domain, src-homology standard chow (20% protein, 9% fat [PicoLab Mouse Diet 2 (SH2) domain, nuclear localization sequence (NLS), and 20 5058, #0007689]) or, as described in Fig. 2H–M and nuclear export sequence (NES) (22–24) (Fig. 1A). The SH2 Supplementary Fig. 2F–K, a high-fat diet (HFD) (20% pro- domain enables SH2B1 recruitment to specificphosphory- tein, 20% carbohydrate, 60% fat [D12492; Research Diets]). lated tyrosine residues in activated tyrosine kinases (25). The NLS and NES are essential for SH2B1 to shuttle Mouse Models, Genotyping, and Gene Expression among the nucleus, the cytosol, and the plasma mem- CRISPR/Cas9 genome editing was used to insert the P322S brane (22,23). The NLS combined with the dimerization mutation into mice. The reverse complement of the geno- Sh2b1 domain enables SH2B1 to associate with the plasma mic sequence in C57BL/6J mice (accession number membrane (26). However, the function and importance NC_000073, GRC m38) was used to design the reagents for of the SH2B1 PH domain remains largely unknown. Four CRISPR. The guides were designed using the website de- human obesity-associated variants lie in the SH2B1 PH scribed in Ran et al. (36). The mutations in the donor are C domain (Fig. 1A), suggesting the importance of the PH summarized in Fig. 1 (details in the Supplementary Data). domain in SH2B1 function. The PH domains of some After testing, each guide/donor combination was injected proteins bind inositol phospholipids to mediate mem- into C57BL/6J oocytes by the University of Michigan Trans- brane localization (27,28). However, 90–95% of all human genic Animal Model Core. P322S and DPR founders were PH domains do not bind strongly to phosphoinositides and backcrossed to C57BL/6J mice. The mice were genotyped presumably mediate other functions (29). Indeed, the PH as described in Truett et al. (37) using primers listed in domain of SH2B1 neither localizes to the plasma membrane Supplementary Table 1. The P322S and DPR PCR products fi Sh2b1 nor is required to localize SH2B1b to the plasma membrane were digested with XbaI or puri ed and sequenced. (23,30). Here, we tested the importance of the PH domain knockout (KO) mice were obtained from Dr. Liangyou of SH2B1 in vivo by generating and studying mice con- Rui (University of Michigan) and genotyped according taining human obesity-associated (P322S) or engineered (in- to Duan et al. (3). C57BL/6J mice used to invigorate our frame deletion of P317 and R318 [DPR]) mutations in the C57BL/6J colony came from The Jackson Laboratory. Sh2b1 SH2B1 PH domain. Our results demonstrate that the SH2B1 Relative levels of gene expression were deter- PH domain plays multiple crucial roles in vivo, including mined using RT-PCR (details in the Supplementary Data). for the control of energy balance and glucose homeo- Mouse Body Weight and Food Intake stasis, and in in vitro studies, changes the subcellular Mice were individually housed, and body weight and food distribution of SH2B1b and enhances NGF-stimulated consumption were assessed weekly. neurite outgrowth in PC12 cells. Mouse Glucose Tolerance Tests, Insulin Tolerance RESEARCH DESIGN AND METHODS Tests, and Hormone Levels Human Studies Mice were fasted 0900–1300 h for glucose tolerance tests The Genetics of Obesity Study (GOOS) is a cohort of .7,000 (GTTs) or 0800–1400 h for insulin tolerance tests (ITTs). individuals with severe obesity with age of onset of ,10 Glucose or human insulin was injected intraperitoneally, years (31,32). Severe obesity is defined as a BMI (kg/m2)SD and blood was collected from the tail vein. Blood glucose score .3 (U.K. reference population). Whole-exome se- levels were assessed using a Bayer Contour glucometer. For quencing and targeted resequencing were performed as in plasma insulin levels, mice were fasted 0800–1400 h, and Hendricks et al. (33). All variants were confirmed by Sanger tail blood was assayed using an Ultra Sensitive Mouse Insulin sequencing (1). HOMA of insulin resistance (HOMA-IR) was ELISA kit (#90080; Crystal Chem). Tail blood (0900–1000 h) calculated using the equation HOMA-IR score 5 [(fasting (Figs. 2F and 4G) or trunk blood after sacrifice (1000–1300 insulin in mU/mL) 3 (fasting glucose in mg/dL)] / 405, h) (Fig. 6B) from fed mice was tested for leptin using a Mouse which estimates steady-state b-cell function and insulin Leptin ELISA kit (#90030; Crystal Chem). sensitivity (34,35). All human studies were approved by the Cambridge local research ethics committee. Each Mouse Body Composition, Metabolic Assessment, and subject (or parent
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