TY - JOUR
T1 - The GLP-1 receptor agonist exenatide ameliorates neuroinflammation, locomotor activity, and anxiety-like behavior in mice with diet-induced obesity through the modulation of microglial M2 polarization and downregulation of SR-A4
AU - Lin, Ming Hong
AU - Cheng, Po Ching
AU - Hsiao, Pi Jung
AU - Chen, Szu Chia
AU - Hung, Chih Hsing
AU - Kuo, Chao Hung
AU - Huang, Shau Ku
AU - Clair Chiou, Hsin Ying
N1 - Funding Information:
This work is supported by Kaohsiung Medical University Chung-Ho Memorial Hospital (KMUH105-M534), the Ministry of Sciences and Technology (MOST), Taiwan (MOST109-2314-B-037–034-MY3; MOST110-2314-B-037–027-MY3; MOST110-2320-B-037–009-), Kaohsiung Municipal Siaogang Hospital (H-110–008), and NSYSU-KMU Joint Research Project, Kaohsiung City, Taiwan (NSYSU-KMU109-I004-2; NSYSU-KMU 110-P023).
Funding Information:
This work was supported by the National Science and Technology Concil (reorganized from Ministry of Sciences and Technology, MOST109-2314-B-037–034-MY3; MOST110-2314-B-037–027-MY3; MOST110-2320-B-037–009-) and Kaohsiung Municipal Siaogang Hospital (H-110-008), All animal work was performed in an Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC)-an accredited facility, the Center for Experimental Animals of Kaohsiung Medical University. We highly appreciate the technical support for the open-field test from Professor Shiou-Lan Chen, Graduate Institute of Medicine, KMU, Taiwan.
Funding Information:
This work was supported by the National Science and Technology Concil (reorganized from Ministry of Sciences and Technology , MOST109-2314-B-037–034-MY3 ; MOST110-2314-B-037–027-MY3 ; MOST110-2320-B-037–009 -) and Kaohsiung Municipal Siaogang Hospital ( H-110-008 )
Publisher Copyright:
© 2022 The Authors
PY - 2023/2
Y1 - 2023/2
N2 - Obesity is associated with multiple comorbidities, such as metabolic abnormalities and cognitive dysfunction. Moreover, accumulating evidence indicates that neurodegenerative disorders are associated with chronic neuroinflammation. GLP-1 receptor agonists (RAs) have been extensively studied as a treatment for type 2 diabetes. Emerging evidence has demonstrated a protective effect of GLP-1 RAs on neurodegenerative disease, which is independent of its glucose-lowering effects. In this study, we aimed to examine the effects of a long-acting GLP-1 RA, exenatide, on high-fat diet (HFD)-induced neuroinflammation and related brain function impairment. First, mice treated with exenatide exhibited significantly reduced HFD-increased body weight and blood glucose. In an open field test, exenatide treatment ameliorated the reduction in local motor activity and anxiety in HFD-fed mice. Moreover, HFD induced astrogliosis, microgliosis, and upregulation of IL-1β, IL-6 and TNF-α in hippocampus and cortex. Exenatide treatment reduced HFD-induced astrogliosis and IL-1β and TNF-α expressions. Moreover, exenatide increased phosphor-ERK and M2-type microglia marker arginase-1 expression in the hippocampus and cortex. In addition, we found that scavenger receptor-A4 protein expression was induced by HFD and was subsequently inhibited by exenatide. SR-A4 knockout reversed the locomotor activity impairment but not the anxiety behavior caused by HFD consumption. SR-A4 knockout also reduced HFD-induced neuroinflammation, as shown by the reduced expression of GFAP and IBA-1 compared with that in wild-type control mice. These results demonstrate that exenatide decreases HFD-increased neuroinflammation and promotes anti-inflammatory M2 differentiation. The inhibition of SR-A4 by exenatide exerts anti-inflammatory activity.
AB - Obesity is associated with multiple comorbidities, such as metabolic abnormalities and cognitive dysfunction. Moreover, accumulating evidence indicates that neurodegenerative disorders are associated with chronic neuroinflammation. GLP-1 receptor agonists (RAs) have been extensively studied as a treatment for type 2 diabetes. Emerging evidence has demonstrated a protective effect of GLP-1 RAs on neurodegenerative disease, which is independent of its glucose-lowering effects. In this study, we aimed to examine the effects of a long-acting GLP-1 RA, exenatide, on high-fat diet (HFD)-induced neuroinflammation and related brain function impairment. First, mice treated with exenatide exhibited significantly reduced HFD-increased body weight and blood glucose. In an open field test, exenatide treatment ameliorated the reduction in local motor activity and anxiety in HFD-fed mice. Moreover, HFD induced astrogliosis, microgliosis, and upregulation of IL-1β, IL-6 and TNF-α in hippocampus and cortex. Exenatide treatment reduced HFD-induced astrogliosis and IL-1β and TNF-α expressions. Moreover, exenatide increased phosphor-ERK and M2-type microglia marker arginase-1 expression in the hippocampus and cortex. In addition, we found that scavenger receptor-A4 protein expression was induced by HFD and was subsequently inhibited by exenatide. SR-A4 knockout reversed the locomotor activity impairment but not the anxiety behavior caused by HFD consumption. SR-A4 knockout also reduced HFD-induced neuroinflammation, as shown by the reduced expression of GFAP and IBA-1 compared with that in wild-type control mice. These results demonstrate that exenatide decreases HFD-increased neuroinflammation and promotes anti-inflammatory M2 differentiation. The inhibition of SR-A4 by exenatide exerts anti-inflammatory activity.
KW - Exenatide
KW - Neuroinflammation
KW - Obesity
KW - SR-A4
KW - T2DM
UR - http://www.scopus.com/inward/record.url?scp=85145269874&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85145269874&partnerID=8YFLogxK
U2 - 10.1016/j.intimp.2022.109653
DO - 10.1016/j.intimp.2022.109653
M3 - Article
AN - SCOPUS:85145269874
SN - 1567-5769
VL - 115
JO - International Immunopharmacology
JF - International Immunopharmacology
M1 - 109653
ER -
