The Journal of Practical Medicine >

2025 , Vol. 41 >Issue 3: 330 - 338

DOI: https://doi.org/10.3969/j.issn.1006-5725.2025.03.004

Basic Research

Protective effect of exenatide on oxidative stress in hypothalamus of diabetes mice and its mechanism

  • Lu ZHENG ,
  • Haohao ZHANG ,
  • Feifei WU ,
  • Jiaqi GUO ,
  • Youqin WANG ,
  • Ruimin HAO ,
  • Lihui FENG ,
  • Yan. LI
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  • *.Department of Endocrinology，Heping Hospital Affiliated to Changzhi Medical College，Changzhi 046000，Shanxi，China

Received date: 2024-10-06

  Online published: 2025-02-19

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Abstract

Objective To explore the effect of exenatide on oxidative stress in the hypothalamus of diabetes mice and its potential mechanism. Methods After one week of adaptive feeding， C57BL/6J mice were randomly divided into the CON group （normal chaw diet）， the T2DM group （high-fat diet， HFD）， and the T2DM+Exe group （HFD+ exenatide）. After 8 weeks of HFD， mice in the T2DM+Exe group were intraperitoneally injected with exenatide ［24 nmol/（kg·d）］ for 8 weeks.The weight and glucose and lipid metabolism levels of the mice were measured， and the levels of inflammatory and adipokine factors in mice were detected using the ELISA method. Western Blot was used to detect the expression of melanocortin receptor-4 （MC4R） and proopiomelanocortin （POMC） in the hypothalamus. Hypothalamic mitochondria were extracted， and the content of mitochondrial reactive oxygen species （ROS） was measured using a flow cytometer. The content of malondialdehyde （MDA） and the activities of superoxide dismutase （SOD） in the mitochondria were detected using assay kits. Changes in the ultrastructure of mitochondria were observed using a transmission electron microscope. In vitro experiments， palmitic acid （PA） and exenatide were used to treat hypothalamic GT1-7 cells， and short hairpin RNA （shRNA） was used to silence the melanocortin 4 receptor （MC4R）， and observe the cellular oxidative stress and lipid deposition. Results Compared with the CON group， the T2DM group mice showed a significant increase in glucose and lipid metabolism indicators， pro-inflammatory factors， and adipose factor levels （P < 0.05）， the expression of MC4R and POMC proteins in the hypothalamus were decreased （P < 0.05）， and the mitochondrial ROS and MDA content in the hypothalamus significantly were increased （P < 0.05）， while SOD and CAT activities were decreased （P < 0.05）. Mitochondrial morphology was abnormal. After intervention with exenatide， the above indicators were significantly improved. After inhibiting MC4R expression in vitro experiments， compared with the intervention group with exenatide， the ROS and MDA content was significantly increased （P < 0.05）， SOD activity was decreased （P < 0.05）， and lipid deposition occurred in the cells. Conclusions Exenatide exhibits a protective effect on hypothalamic oxidative stress injury in diabetic mice， and this mechanism may be associated with the upregulation of MC4R expression.

Key words： exenatide; diabetes mellitus; hypothalamic oxidative stress; melanocortin receptor-4

Cite this article

Lu ZHENG , Haohao ZHANG , Feifei WU , Jiaqi GUO , Youqin WANG , Ruimin HAO , Lihui FENG , Yan. LI . Protective effect of exenatide on oxidative stress in hypothalamus of diabetes mice and its mechanism[J]. The Journal of Practical Medicine, 2025 , 41(3) : 330 -338 . DOI: 10.3969/j.issn.1006-5725.2025.03.004

References

1 NCD Risk Factor Collaboration （NCD-RisC）.Worldwide trends in diabetes prevalence and treatment from 1990 to 2022： A pooled analysis of 1108 population-representative studies with 141 million participants ［J］. Lancet， 2024， 404（10467）： 2077-2093.
2 PANG D， YANG C， LUO Q， et al. Soy isoflavones improve the oxidative stress induced hypothalamic inflammation and apoptosis in high fat diet-induced obese male mice through PGC1-alpha pathway ［J］. Aging （Albany NY）， 2020， 12（9）： 8710-8727. doi:10.18632/aging.103197
3 JO D， YOON G， SONG J. Role of Exendin-4 in Brain Insulin Resistance， Mitochondrial Function， and Neurite Outgrowth in Neurons under Palmitic Acid-Induced Oxidative Stress ［J］. Antioxidants （Basel）， 2021， 10（1）：78. doi:10.3390/antiox10010078
4 MALONE J I， HANSEN B C. Does obesity cause type 2 diabetes mellitus （T2DM）？Or is it the opposite？ ［J］. Pediatr Diabetes， 2019， 20（1）： 5-9. doi:10.1111/pedi.12787
5 马刚，孙家忠. GLP-1 RAs联合恩格列净对2型糖尿病患者的治疗效果及对胰岛素抵抗的影响［J］. 实用医学杂志，2020，36（18）：2500-2504.
6 DE SOUZA CORDEIRO L M， ELSHEIKH A， DEVISETTY N， et al. Hypothalamic MC4R regulates glucose homeostasis through adrenaline-mediated control of glucose reabsorption via renal GLUT2 in mice ［J］. Diabetologia， 2021， 64（1）： 181-194. doi:10.1007/s00125-020-05289-z
7 POLENI P E， AKIEDA-ASAI S， KODA S， et al. Possible involvement of melanocortin-4-receptor and AMP-activated protein kinase in the interaction of glucagon-like peptide-1 and leptin on feeding in rats ［J］. Biochem Biophys Res Commun， 2012， 420（1）： 36-41. doi:10.1016/j.bbrc.2012.02.109
8 TANAKA T， MASUZAKI H， YASUE S， et al. Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphorylation in mice fed a high-fat diet ［J］. Cell Metab， 2007， 5（5）： 395-402. doi:10.1016/j.cmet.2007.04.004
9 GOKUL P R， APPERLEY L， PARKINSON J， et al. Semaglutide， A Long-Acting GLP-1 Analogue， for the management of early onset obesity due to MC4R defect-A case report ［J］. Horm Res Paediatr， 2024. doi： 10.1159/000537921 .
10 LAMBADIARI V， PAVLIDIS G， KOUSATHANA F， et al. Effects of 6-month treatment with the glucagon like peptide-1 analogue liraglutide on arterial stiffness， left ventricular myocardial deformation and oxidative stress in subjects with newly diagnosed type 2 diabetes ［J］. Cardiovasc Diabetol， 2018， 17（1）： 8. doi:10.1186/s12933-017-0646-z
11 YAGISHITA Y， URUNO A， FUKUTOMI T， et al. Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress ［J］. Cell Rep， 2017， 18（8）： 2030-2044. doi:10.1016/j.celrep.2017.01.064
12 LIN M H， CHENG P C， HSIAO P J， et al. 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 ［J］. Int Immunopharmacol， 2023， 115： 109653. doi:10.1016/j.intimp.2022.109653
13 STENLID R， CERENIUS S Y， WEN Q， et al. Adolescents with obesity treated with exenatide maintain endogenous GLP-1， reduce DPP-4， and improve glycemic control ［J］. Front Endocrinol （Lausanne）， 2023， 14： 1293093. doi:10.3389/fendo.2023.1293093
14 BAI C， WANG Y， NIU Z， et al. Exenatide improves hepatocyte insulin resistance induced by different regional adipose tissue［J］. Front Endocrinol （Lausanne）， 2022， 13： 1012904. doi:10.3389/fendo.2022.1012904
15 XU Q， ZHANG X， LI T， et al. Exenatide regulates Th17/Treg balance via PI3K/Akt/FoxO1 pathway in db/db mice ［J］. Mol Med， 2022， 28（1）： 144. doi:10.1186/s10020-022-00574-6
16 XU F， CAO H， CHEN Z， et al. Short-term GLP-1 receptor agonist exenatide ameliorates intramyocellular lipid deposition without weight loss in ob/ob mice ［J］. Int J Obes （Lond）， 2020， 44（4）： 937-947. doi:10.1038/s41366-019-0513-y
17 ADRIAENSSENS A E， BIGGS E K， DARWISH T， et al. Glucose-Dependent Insulinotropic Polypeptide Receptor-Expressing Cells in the Hypothalamus Regulate Food Intake ［J］. Cell Metab， 2019， 30（5）：987-996.e6. doi:10.1016/j.cmet.2019.07.013
18 HUANG Z， LIU L， ZHANG J， et al. Glucose-sensing glucagon-like peptide-1 receptor neurons in the dorsomedial hypothalamus regulate glucose metabolism ［J］. Sci Adv， 2022， 8（23）： eabn5345. doi:10.1126/sciadv.abn5345
19 HAVEL P J， HAHN T M， SINDELAR D K， et al. Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats ［J］. Diabetes， 2000， 49（2）： 244-252. doi:10.2337/diabetes.49.2.244
20 DONG Y， CARTY J， GOLDSTEIN N， et al. Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo ［J］. Mol Metab， 2021， 54： 101352. doi:10.1016/j.molmet.2021.101352
21 SPEZANI R， MARINHO T S， REIS T S， et al. Cotadutide （GLP-1/Glucagon dual receptor agonist） modulates hypothalamic orexigenic and anorexigenic neuropeptides in obese mice ［J］. Peptides， 2024， 173： 171138. doi:10.1016/j.peptides.2023.171138
22 GONZáLEZ P， LOZANO P， ROS G， et al. Hyperglycemia and Oxidative Stress： An Integral， Updated and Critical Overview of Their Metabolic Interconnections ［J］. Int J Mol Sci， 2023， 24（11）：9352. doi:10.3390/ijms24119352
23 XIA B， DING J， LI Q， et al. Loganin protects against myocardial ischemia-reperfusion injury by modulating oxidative stress and cellular apoptosis via activation of JAK2/STAT3 signaling ［J］. Int J Cardiol， 2024， 395： 131426. doi:10.1016/j.ijcard.2023.131426
24 PANDEY S， MANGMOOL S， MADREITER-SOKOLOWSKI C T， et al. Exendin-4 protects against high glucose-induced mitochondrial dysfunction and oxidative stress in SH-SY5Y neuroblastoma cells through GLP-1 receptor/Epac/Akt signaling ［J］. Eur J Pharmacol， 2023， 954： 175896. doi:10.1016/j.ejphar.2023.175896
25 WANG Y， FANG N， WANG Y， et al. Activating MC4R Promotes Functional Recovery by Repressing Oxidative Stress-Mediated AIM2 Activation Post-spinal Cord Injury ［J］. Mol Neurobiol， 2024， 61（8）：6101-6118. doi:10.1007/s12035-024-03936-9
26 ZHANG H H， LIU J， QIN G J， et al. Melanocortin 4 Receptor Activation Attenuates Mitochondrial Dysfunction in Skeletal Muscle of Diabetic Rats ［J］. J Cell Biochem， 2017， 118（11）： 4072-4079. doi:10.1002/jcb.26062
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