• ISSN 1674-8301
  • CN 32-1810/R
Volume 37 Issue 3
May  2023
Turn off MathJax
Article Contents
Jubiao Zhang, Yang Chen, Lihong Yan, Xin Zhang, Xiaoyan Zheng, Junxia Qi, Fen Yang, Juxue Li. EphA3 deficiency in the hypothalamus promotes high-fat diet-induced obesity in mice[J]. The Journal of Biomedical Research, 2023, 37(3): 179-193. doi: 10.7555/JBR.36.20220168
Citation: Jubiao Zhang, Yang Chen, Lihong Yan, Xin Zhang, Xiaoyan Zheng, Junxia Qi, Fen Yang, Juxue Li. EphA3 deficiency in the hypothalamus promotes high-fat diet-induced obesity in mice[J]. The Journal of Biomedical Research, 2023, 37(3): 179-193. doi: 10.7555/JBR.36.20220168

EphA3 deficiency in the hypothalamus promotes high-fat diet-induced obesity in mice

doi: 10.7555/JBR.36.20220168
Funds:  This work was supported by National Natural Science Foundation of China (Grants No. 82070872, 92049118, and 81570774), the Jiangsu Province's Innovation Personal as well as Innovative and Entrepreneurial Team of Jiangsu Province (Grant No. JSSCTD2021), the National Key Research and Development Program of China (Grant No. 2018YFC1003504), the Junior Thousand Talents Program of China, the NJMU startup fund.
More Information
  • Corresponding author: Juxue Li, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China. Tel: +86-25-86869392, E-mail: lijuxue@njmu.edu.cn
  • Received: 2022-07-30
  • Revised: 2022-10-24
  • Accepted: 2022-11-06
  • Published: 2022-11-28
  • Issue Date: 2023-05-28
  • Erythropoietin-producing hepatocellular carcinoma A3 (EphA3) is a member of the largest subfamily of tyrosine kinase receptors—Eph receptors. Previous studies have shown that EphA3 is associated with tissue development. Recently, we have found that the expression of EphA3 is elevated in the hypothalamus of mice with diet-induced obesity (DIO). However, the role of EphA3 in hypothalamic-controlled energy metabolism remains unclear. In the current study, we demonstrated that the deletion of EphA3 in the hypothalamus by CRISPR/Cas9-mediated gene editing promotes obesity in male mice with high-fat diet feeding rather than those with normal chow diet feeding. Moreover, the deletion of hypothalamic EphA3 promotes high-fat DIO by increasing food intake and reducing energy expenditure. Knockdown of EphA3 leads to smaller intracellular vesicles in GT1-7 cells. The current study reveals that hypothalamic EphA3 plays important roles in promoting DIO.


  • CLC number: R589, Document code: A
    The authors reported no conflict of interests.
    Δ These authors contributed equally to this work.
  • loading
  • [1]
    Finucane MM, Stevens GA, Cowan MJ, et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants[J]. Lancet, 2011, 377(9765): 557–567. doi: 10.1016/S0140-6736(10)62037-5
    Dee A, Kearns K, O'Neill C, et al. The direct and indirect costs of both overweight and obesity: a systematic review[J]. BMC Res Notes, 2014, 7: 242. doi: 10.1186/1756-0500-7-242
    Dahiya DK, Renuka, Puniya M, et al. Gut microbiota modulation and its relationship with obesity using prebiotic fibers and probiotics: a review[J]. Front Microbiol, 2017, 8: 563. doi: 10.3389/fmicb.2017.00563
    Myers Jr MG, Olson DP. Central nervous system control of metabolism[J]. Nature, 2012, 491(7424): 357–363. doi: 10.1038/nature11705
    Rodriguez EM, Blázquez JL, Guerra M. The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid[J]. Peptides, 2010, 31(4): 757–776. doi: 10.1016/j.peptides.2010.01.003
    Ruan H, Dietrich MO, Liu Z, et al. O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat[J]. Cell, 2014, 159(2): 306–317. doi: 10.1016/j.cell.2014.09.010
    Ilnytska O, Argyropoulos G. The role of the Agouti-Related Protein in energy balance regulation[J]. Cell Mol Life Sci, 2008, 65(17): 2721–2731. doi: 10.1007/s00018-008-8104-4
    Zhan C, Zhou J, Feng Q, et al. Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively[J]. J Neurosci, 2013, 33(8): 3624–3632. doi: 10.1523/JNEUROSCI.2742-12.2013
    Konner AC, Klöckener T, Brüning JC. Control of energy homeostasis by insulin and leptin: targeting the arcuate nucleus and beyond[J]. Physiol Behav, 2009, 97(5): 632–638. doi: 10.1016/j.physbeh.2009.03.027
    Brown A, Yates PA, Burrola P, et al. Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling[J]. Cell, 2000, 102(1): 77–88. doi: 10.1016/S0092-8674(00)00012-X
    Miao H, Nickel CH, Cantley LG, et al. EphA kinase activation regulates HGF-induced epithelial branching morphogenesis[J]. J Cell Biol, 2003, 162(7): 1281–1292. doi: 10.1083/jcb.200304018
    Kudo C, Ajioka I, Hirata Y, et al. Expression profiles of EphA3 at both the RNA and protein level in the developing mammalian forebrain[J]. J Comp Neurol, 2005, 487(3): 255–269. doi: 10.1002/cne.20551
    Stephen LJ, Fawkes AL, Verhoeve A, et al. A critical role for the EphA3 receptor tyrosine kinase in heart development[J]. Dev Biol, 2007, 302(1): 66–79. doi: 10.1016/j.ydbio.2006.08.058
    Konstantinova I, Nikolova G, Ohara-Imaizumi M, et al. EphA-Ephrin-A-mediated β cell communication regulates insulin secretion from pancreatic islets[J]. Cell, 2007, 129(2): 359–370. doi: 10.1016/j.cell.2007.02.044
    Platt RJ, Chen S, Zhou Y, et al. CRISPR-Cas9 knockin mice for genome editing and cancer modeling[J]. Cell, 2014, 159(2): 440–455. doi: 10.1016/j.cell.2014.09.014
    Mellon PL, Windle JJ, Goldsmith PC, et al. Immortalization of hypothalamic GnRH by genetically targeted tumorigenesis[J]. Neuron, 1990, 5(1): 1–10. doi: 10.1016/0896-6273(90)90028-E
    Egawa M, Yoshimatsu H, Bray GA. Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats[J]. Am J Physiol, 1991, 260(2 Pt 2): R328–R334. https://pubmed.ncbi.nlm.nih.gov/1996720/
    Qiu J, Zhang CG, Borgquist A, et al. Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels[J]. Cell Metab, 2014, 19(4): 682–693. doi: 10.1016/j.cmet.2014.03.004
    Wauman J, Tavernier J. Leptin receptor signaling: pathways to leptin resistance[J]. Front Biosci (Landmark Ed), 2011, 16(7): 2771–2793. https://pubmed.ncbi.nlm.nih.gov/21622208/
    Sinha MK, Ohannesian JP, Heiman ML, et al. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects[J]. J Clin Invest, 1996, 97(5): 1344–1347. doi: 10.1172/JCI118551
    Licinio J, Negrão AB, Mantzoros C, et al. Sex differences in circulating human leptin pulse amplitude: clinical implications[J]. J Clin Endocrinol Metab, 1998, 83(11): 4140–4147. https://pubmed.ncbi.nlm.nih.gov/9814504/
    Saad MF, Riad-Gabriel MG, Khan A, et al. Diurnal and ultradian rhythmicity of plasma leptin: effects of gender and adiposity[J]. J Clin Endocrinol Metab, 1998, 83(2): 453–459. https://pubmed.ncbi.nlm.nih.gov/9467557/
    Carmo JMD, Da Silva AA, Gava FN, et al. Impact of leptin deficiency compared with neuronal-specific leptin receptor deletion on cardiometabolic regulation[J]. Am J Physiol Regul Integr Comp Physiol, 2019, 317(4): R552–R562. doi: 10.1152/ajpregu.00077.2019
    Binns KL, Taylor PP, Sicheri F, et al. Phosphorylation of tyrosine residues in the kinase domain and juxtamembrane region regulates the biological and catalytic activities of Eph receptors[J]. Mol Cell Biol, 2000, 20(13): 4791–4805. doi: 10.1128/MCB.20.13.4791-4805.2000
    Pitulescu ME, Adams RH. Eph/ephrin molecules-a hub for signaling and endocytosis[J]. Genes Dev, 2010, 24(22): 2480–2492. doi: 10.1101/gad.1973910
    Chiari R, Hames G, Stroobant V, et al. Identification of a tumor-specific shared antigen derived from an Eph receptor and presented to CD4 T cells on HLA class Ⅱ molecules[J]. Cancer Res, 2000, 60(17): 4855–4863. https://pubmed.ncbi.nlm.nih.gov/10987298/
    Valsesia A, Rimoldi D, Martinet D, et al. Network-guided analysis of genes with altered somatic copy number and gene expression reveals pathways commonly perturbed in metastatic melanoma[J]. PLoS One, 2011, 6(4): e18369. doi: 10.1371/journal.pone.0018369
    Breitfeld J, Kehr S, Müller L, et al. Developmentally driven changes in adipogenesis in different fat depots are related to obesity[J]. Front Endocrinol, 2020, 11: 138. doi: 10.3389/fendo.2020.00138
    Krashes MJ, Koda S, Ye CP, et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice[J]. J Clin Invest, 2011, 121(4): 1424–1428. doi: 10.1172/JCI46229
    Gropp E, Shanabrough M, Borok E, et al. Agouti-related peptide-expressing neurons are mandatory for feeding[J]. Nat Neurosci, 2005, 8(10): 1289–1291. doi: 10.1038/nn1548
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(8)  / Tables(2)

    Article Metrics

    Article views (279) PDF downloads(123) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint