CCL5/RANTES contributes to hypothalamic insulin signaling for systemic insulin responsiveness through CCR5

Szu-Yi Chou, Reni Ajoy, Chun Austin Changou, Ya Ting Hsieh, Yang Kao Wang, Barry J. Hoffer

Research output: Contribution to journalArticle

10 Citations (Scopus)

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-1S302 through AMPKα-S6 Kinase. Blocking CCR5 using the antagonist, MetCCL5, abolished the de-phosphorylation of IRS-1S302 and insulin signal activation. In addition, intracerebroventricular delivery of Met CCL5 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.

Original languageEnglish
Article number37659
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Nov 29 2016

Fingerprint

Chemokine CCL5
Insulin
Hypothalamus
Phosphorylation
CCR5 Receptors
Ribosomal Protein S6 Kinases
Arcuate Nucleus of Hypothalamus
Glucose Intolerance
Insulin Receptor
Phosphatidylinositol 3-Kinases
Immunoprecipitation
Neurodegenerative Diseases
Type 2 Diabetes Mellitus
Energy Metabolism
HIV Infections
Insulin Resistance
Atherosclerosis
Obesity
Glucose
Membranes

ASJC Scopus subject areas

  • General

Cite this

CCL5/RANTES contributes to hypothalamic insulin signaling for systemic insulin responsiveness through CCR5. / Chou, Szu-Yi; Ajoy, Reni; Changou, Chun Austin; Hsieh, Ya Ting; Wang, Yang Kao; Hoffer, Barry J.

In: Scientific Reports, Vol. 6, 37659, 29.11.2016.

Research output: Contribution to journalArticle

Chou, Szu-Yi ; Ajoy, Reni ; Changou, Chun Austin ; Hsieh, Ya Ting ; Wang, Yang Kao ; Hoffer, Barry J. / CCL5/RANTES contributes to hypothalamic insulin signaling for systemic insulin responsiveness through CCR5. In: Scientific Reports. 2016 ; Vol. 6.
@article{aec9c0c28423450883ed3201fe306630,
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-1S302 through AMPKα-S6 Kinase. Blocking CCR5 using the antagonist, MetCCL5, abolished the de-phosphorylation of IRS-1S302 and insulin signal activation. In addition, intracerebroventricular delivery of Met CCL5 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.",
author = "Szu-Yi Chou and Reni Ajoy and Changou, {Chun Austin} and Hsieh, {Ya Ting} and Wang, {Yang Kao} and Hoffer, {Barry J.}",
year = "2016",
month = "11",
day = "29",
doi = "10.1038/srep37659",
language = "English",
volume = "6",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - CCL5/RANTES contributes to hypothalamic insulin signaling for systemic insulin responsiveness through CCR5

AU - Chou, Szu-Yi

AU - Ajoy, Reni

AU - Changou, Chun Austin

AU - Hsieh, Ya Ting

AU - Wang, Yang Kao

AU - Hoffer, Barry J.

PY - 2016/11/29

Y1 - 2016/11/29

N2 - 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-1S302 through AMPKα-S6 Kinase. Blocking CCR5 using the antagonist, MetCCL5, abolished the de-phosphorylation of IRS-1S302 and insulin signal activation. In addition, intracerebroventricular delivery of Met CCL5 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.

AB - 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-1S302 through AMPKα-S6 Kinase. Blocking CCR5 using the antagonist, MetCCL5, abolished the de-phosphorylation of IRS-1S302 and insulin signal activation. In addition, intracerebroventricular delivery of Met CCL5 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.

UR - http://www.scopus.com/inward/record.url?scp=84999287840&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84999287840&partnerID=8YFLogxK

U2 - 10.1038/srep37659

DO - 10.1038/srep37659

M3 - Article

AN - SCOPUS:84999287840

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 37659

ER -