title: CCL5/RANTES contributes to hypothalamic insulin signaling for systemic insulin responsiveness through CCR5.
abstract: Many neurodegenerative diseases are accompanied by metabolic disorders. CCL5/RANTES, and its receptor CCR5 are known to contribute to neuronal function as well as to metabolic disorders such as type 2 diabetes mellitus, obesity, atherosclerosis and metabolic changes after HIV infection. Herein, we found that the lack of CCR5 or CCL5 in mice impaired regulation of energy metabolism in hypothalamus. Immunostaining and co-immunoprecipitation revealed the specific expression of CCR5, associated with insulin receptors, in the hypothalamic arcuate nucleus (ARC). Both ex vivo stimulation and in vitro tissue culture studies demonstrated that the activation of insulin, and PI3K-Akt pathways were impaired in CCR5 and CCL5 deficient hypothalamus. The inhibitory phosphorylation of insulin response substrate-1 at Ser302 (IRS-1S302) but not IRS-2, by insulin was markedly increased in CCR5 and CCL5 deficient animals. Elevating CCR5/CCL5 activity induced GLUT4 membrane translocation and reduced phospho-IRS-1S302through AMPKα-S6 Kinase. Blocking CCR5 using the antagonist,MetCCL5, abolished the de-phosphorylation of IRS-1S302and insulin signal activation. In addition, intracerebroventricular delivery ofMetCCL5 interrupted hypothalamic insulin signaling and elicited peripheral insulin responsiveness and glucose intolerance. Taken together, our data suggest that CCR5 regulates insulin signaling in hypothalamus which contributes to systemic insulin sensitivity and glucose metabolism.
authors.affiliation: The PhD Program for Neural Regenerative Medicine, College of Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes (NHRI), 250 Wuxing St. Taipei, Taiwan, 110.|Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|Center for Neurotrauma and Neuroregeneration, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Szu-Yi
authors.initials: SY
authors.lastname: Chou
authors.affiliation: The PhD Program for Neural Regenerative Medicine, College of Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes (NHRI), 250 Wuxing St. Taipei, Taiwan, 110.|Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Reni
authors.initials: R
authors.lastname: Ajoy
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan.|Core Facility, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun Austin
authors.initials: CA
authors.lastname: Changou
authors.affiliation: The PhD Program for Neural Regenerative Medicine, College of Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes (NHRI), 250 Wuxing St. Taipei, Taiwan, 110.|Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Hsieh
authors.affiliation: Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yang-Kao
authors.initials: YK
authors.lastname: Wang
authors.affiliation: The PhD Program for Neural Regenerative Medicine, College of Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes (NHRI), 250 Wuxing St. Taipei, Taiwan, 110.|Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|Center for Neurotrauma and Neuroregeneration, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Hoffer
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism / Q000473:pathology; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics*; D051275:Glucose Transporter Type 4 / Q000235:genetics; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D051275:Glucose Transporter Type 4; D007328:Insulin; C495693:Slc2a4 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin