Skip to main content

Advertisement

SpringerLink
Log in

Diosmetin Ameliorates HFD-induced Cognitive Impairments via Inhibiting Metabolic Disorders, Mitochondrial Dysfunction and Neuroinflammation in Male SD Rats

  • Original Article
  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Currently, accumulating evidence has indicated that overnutrition-associated obesity may result in not only metabolic dysregulations, but also cognitive impairments. This study aimed to investigate the protective effects of Diosmetin, a bioflavonoid compound with multiple biological functions, on cognitive deficits induced by a high fat diet (HFD) and the potential mechanisms. In the present study, oral administration of Diosmetin (25, 50 and 100 mg/kg) for 12 weeks significantly reduced the body weight, restored glucose tolerance and normalized lipid profiles in the serum and liver in HFD-induced obese rats. Diosmetin also significantly ameliorated depression-like behaviors and impaired spatial memory in multiple behavioral tests, including the open field test, elevated plus-maze and Morris water maze, which was in accordance with the decreased pathological changes and neuronal damage in different regions of hippocampus as suggested by H&E and Nissl staining. Notably, our results also indicated that Diosmetin could significantly improve mitochondrial dysfunction induced by HFD through upregulating genes involved in mitochondrial biogenesis and dynamics, increasing mitochondrial ATP levels and inhibiting oxidative stress. Moreover, the levels of key enzymes involved in the TCA cycle were also significantly increased upon Diosmetin treatment. Meanwhile, Diosmetin inhibited HFD-induced microglial overactivation and down-regulated inflammatory cytokines both in the serum and hippocampus. In conclusion, these results indicated that Diosmetin might be a novel nutritional intervention to prevent the occurrence and development of obesity-associated cognitive dysfunction via metabolic regulation and anti-inflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data Availability

The data that supports the findings of this study are available on reasonable request from the corresponding author.

Abbreviations

Bax:

pro-apoptotic protein Bcl-2 Associated X

Bcl-2:

B-cell lymphoma-2

BDNF:

brain-derived neurotrophic factor

CA1:

cornuammonis region 1

CA3:

cornuammonis region 3

CAT:

catalase

COX2:

cyclooxygenase-2

CS:

citrate synthase

cycs:

cytochrome c

DAPI:

40,60-diamidino-2-phenylindole

DG:

dentate gyrus region

EPM:

elevated plus-maze

HDL-C:

high-density lipoprotein cholesterol

HFD:

high fat diet

IBA-1:

Ionized calcium binding adapter molecule 1

IL-1β:

interleukin-1β

IL-6:

interleukin-6

iNOS:

inducible nitric oxide synthase

LDL-C:

low-density lipoprotein cholesterol

MDA:

malondialdehyde

Mfn1:

Mitofusin 1

Mfn2:

Mitofusin 2

MMP3:

matrix metalloproteinase-3

MMP9:

matrix metalloproteinase-9

MWM:

Morris water maze

NGF:

nerve growth factor

Nrf1:

nuclear respiratory factor-1

Nrf2:

Nuclear factor erythroid2-related factor 2

NT-3:

neurotrophin-3

NT-4:

neurotrophin-4

OFT:

open field test

OGDH:

α-ketoglutarate dehydrogenase

OGTT:

Oral glucose tolerance test

PDH:

pyruvate dehydrogenase

PDK:

pyruvate dehydrogenase kinase

PGC-1α:

peroxisome proliferator activated receptor co-activator-1α

PSD95:

postsynaptic density protein-95

SD:

Sprague-Dawley

SIRT1:

Sirtuin1

SNAP25:

synaptosome associated protein 25

SOD:

superoxide dismutase

TC:

total cholesterol

TCA:

tricarboxylic acid

TNF-α:

Tumor necrosis factor-α

Tfam:

transcription factor A

TG:

triglyceride

References

  1. Bluher M (2019) Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol 15:288–298

    Article  PubMed  Google Scholar 

  2. Popkin BM, Ng SW (2022) The nutrition transition to a stage of high obesity and noncommunicable disease prevalence dominated by ultra-processed foods is not inevitable. Obes Rev 23:e13366

    Article  PubMed  Google Scholar 

  3. Ruze R, Liu T, Zou X, Song J, Chen Y, Xu R et al (2023) Obesity and type 2 diabetes mellitus: connections in epidemiology, pathogenesis, and treatments. Front Endocrinol (Lausanne) 14:1161521

    Article  PubMed  Google Scholar 

  4. Koliaki C, Liatis S, Kokkinos A (2019) Obesity and cardiovascular disease: revisiting an old relationship. Metabolism 92:98–107

    Article  CAS  PubMed  Google Scholar 

  5. Duan Y, Zhang W, Li Z, Niu Y, Chen Y, Liu X et al (2022) Predictive ability of obesity- and lipid-related indicators for metabolic syndrome in relatively healthy Chinese adults. Front Endocrinol (Lausanne) 13:1016581

    Article  PubMed  Google Scholar 

  6. Li H, Ren J, Li Y, Wu Q, Wei J (2023) Oxidative stress: the nexus of obesity and cognitive dysfunction in diabetes. Front Endocrinol (Lausanne) 14:1134025

    Article  PubMed  Google Scholar 

  7. Wieckowska-Gacek A, Mietelska-Porowska A, Wydrych M, Wojda U (2021) Western diet as a trigger of Alzheimer’s disease: from metabolic syndrome and systemic inflammation to neuroinflammation and neurodegeneration. Ageing Res Rev 70:101397

    Article  CAS  PubMed  Google Scholar 

  8. Qu Y, Hu HY, Ou YN, Shen XN, Xu W, Wang ZT et al (2020) Association of body mass index with risk of cognitive impairment and dementia: a systematic review and meta-analysis of prospective studies. Neurosci Biobehav Rev 115:189–198

    Article  PubMed  Google Scholar 

  9. Fares J, Bou DZ, Nabha S, Fares Y (2019) Neurogenesis in the adult hippocampus: history, regulation, and prospective roles. Int J Neurosci 129:598–611

    Article  CAS  PubMed  Google Scholar 

  10. Fado R, Molins A, Rojas R, Casals N (2022) Feeding the brain: effect of nutrients on cognition, synaptic function, and AMPA receptors. Nutrients.;14

  11. Wang Q, Yuan J, Yu Z, Lin L, Jiang Y, Cao Z et al (2018) FGF21 attenuates high-Fat Diet-Induced Cognitive Impairment via Metabolic Regulation and anti-inflammation of obese mice. Mol Neurobiol 55:4702–4717

    Article  CAS  PubMed  Google Scholar 

  12. Mulati A, Zhang X, Zhao T, Ren B, Wang L, Liu X et al (2021) Isorhamnetin attenuates high-fat and high-fructose diet induced cognitive impairments and neuroinflammation by mediating MAPK and NFkappaB signaling pathways. Food Funct 12:9261–9272

    Article  CAS  PubMed  Google Scholar 

  13. Wang D, Yan J, Chen J, Wu W, Zhu X, Wang Y (2015) Naringin improves neuronal insulin signaling, brain mitochondrial function, and cognitive function in High-Fat Diet-Induced obese mice. Cell Mol Neurobiol 35:1061–1071

    Article  CAS  PubMed  Google Scholar 

  14. Schmitt LO, Gaspar JM (2023) Obesity-Induced Brain Neuroinflammatory and mitochondrial changes. Metabolites.;13

  15. Cheng CF, Ku HC, Lin H (2018) PGC-1alpha as a pivotal factor in lipid and metabolic regulation. Int J Mol Sci.;19

  16. Wang CS, Kavalali ET, Monteggia LM (2022) BDNF signaling in context: from synaptic regulation to psychiatric disorders. Cell 185:62–76

    Article  CAS  PubMed  Google Scholar 

  17. Lang X, Zhao N, He Q, Li X, Li X, Sun C et al (2020) Treadmill exercise mitigates neuroinflammation and increases BDNF via activation of SIRT1 signaling in a mouse model of T2DM. Brain Res Bull 165:30–39

    Article  CAS  PubMed  Google Scholar 

  18. Hao S, Dey A, Yu X, Stranahan AM (2016) Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity. Brain Behav Immun 51:230–239

    Article  PubMed  Google Scholar 

  19. Salas-Venegas V, Flores-Torres RP, Rodriguez-Cortes YM, Rodriguez-Retana D, Ramirez-Carreto RJ, Concepcion-Carrillo LE et al (2022) The obese brain: mechanisms of systemic and local inflammation, and interventions to reverse the cognitive deficit. Front Integr Neurosci 16:798995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Patel K, Gadewar M, Tahilyani V, Patel DK (2013) A review on pharmacological and analytical aspects of diosmetin: a concise report. Chin J Integr Med 19:792–800

    Article  CAS  PubMed  Google Scholar 

  21. Mei Z, Du L, Liu X, Chen X, Tian H, Deng Y et al (2022) Diosmetin alleviated cerebral ischemia/reperfusion injury in vivo and in vitro by inhibiting oxidative stress via the SIRT1/Nrf2 signaling pathway. Food Funct 13:198–212

    Article  CAS  PubMed  Google Scholar 

  22. Choi J, Lee DH, Park SY, Seol JW (2019) Diosmetin inhibits tumor development and block tumor angiogenesis in skin cancer. Biomed Pharmacother 117:109091

    Article  CAS  PubMed  Google Scholar 

  23. Lee DH, Park JK, Choi J, Jang H, Seol JW (2020) Anti-inflammatory effects of natural flavonoid diosmetin in IL-4 and LPS-induced macrophage activation and atopic dermatitis model. Int Immunopharmacol 89:107046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Si Q, Shi Y, Huang D, Zhang N (2020) Diosmetin alleviates hypoxia–induced myocardial apoptosis by inducing autophagy through AMPK activation. Mol Med Rep 22:1335–1341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Saghaei E, Nasiri BS, Safavi P, Borjian BZ, Bijad E (2020) Diosmetin mitigates cognitive and memory impairment provoked by chronic unpredictable mild stress in mice. Evid Based Complement Alternat Med 2020:5725361

    Article  PubMed  PubMed Central  Google Scholar 

  26. Shi M, Wang J, Bi F, Bai Z (2022) Diosmetin alleviates cerebral ischemia-reperfusion injury through Keap1-mediated Nrf2/ARE signaling pathway activation and NLRP3 inflammasome inhibition. Environ Toxicol 37:1529–1542

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Luo N, Yang C, Zhu Y, Chen Q, Zhang B (2021) Diosmetin Ameliorates Nonalcoholic Steatohepatitis through modulating lipogenesis and inflammatory response in a STAT1/CXCL10-Dependent manner. J Agric Food Chem 69:655–667

    Article  CAS  PubMed  Google Scholar 

  28. Li HL, Wei YY, Li XH, Zhang SS, Zhang RT, Li JH et al (2022) Diosmetin has therapeutic efficacy in colitis regulating gut microbiota, inflammation, and oxidative stress via the circ-Sirt1/Sirt1 axis. Acta Pharmacol Sin 43:919–932

    Article  CAS  PubMed  Google Scholar 

  29. Mo G, He Y, Zhang X, Lei X, Luo Q (2020) Diosmetin exerts cardioprotective effect on myocardial ischaemia injury in neonatal rats by decreasing oxidative stress and myocardial apoptosis. Clin Exp Pharmacol Physiol 47:1713–1722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Abdelmageed ME, Shehatou GS, Abdelsalam RA, Suddek GM, Salem HA (2019) Cinnamaldehyde ameliorates STZ-induced rat diabetes through modulation of IRS1/PI3K/AKT2 pathway and AGEs/RAGE interaction. Naunyn Schmiedebergs Arch Pharmacol 392:243–258

    Article  CAS  PubMed  Google Scholar 

  31. Gao JF, Tang L, Luo F, Chen L, Zhang YY, Ding H (2023) Myricetin treatment has ameliorative effects in DNFB-induced atopic dermatitis mice under high-fat conditions. Toxicol Sci 191:308–320

    Article  CAS  PubMed  Google Scholar 

  32. Cheng Y, Zeng X, Mai Q, Bai X, Jiang Y, Li J et al (2021) Insulin injections inhibits PTZ-induced mitochondrial dysfunction, oxidative stress and neurological deficits via the SIRT1/PGC-1alpha/SIRT3 pathway. Biochim Biophys Acta Mol Basis Dis 1867:166124

    Article  CAS  PubMed  Google Scholar 

  33. Raymond J, Morin A, Plamondon H (2022) Delivery method matters: omega-3 supplementation by restricted feeding period and oral gavage has a distinct impact on corticosterone secretion and anxious behavior in adolescent rats. Nutr Neurosci 25:169–179

    Article  CAS  PubMed  Google Scholar 

  34. Kraeuter AK, Guest PC, Sarnyai Z (2019) The Open Field Test for measuring locomotor activity and Anxiety-like Behavior. Methods Mol Biol 1916:99–103

    Article  CAS  PubMed  Google Scholar 

  35. Kraeuter AK, Guest PC, Sarnyai Z (2019) The elevated plus maze test for measuring anxiety-like Behavior in rodents. Methods Mol Biol 1916:69–74

    Article  CAS  PubMed  Google Scholar 

  36. Othman MZ, Hassan Z, Che HA (2022) Morris water maze: a versatile and pertinent tool for assessing spatial learning and memory. Exp Anim 71:264–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang S, Wang L, Zeng Y, Wang Y, Pei T, Xie Z et al (2023) Salidroside alleviates cognitive impairment by inhibiting ferroptosis via activation of the Nrf2/GPX4 axis in SAMP8 mice. Phytomedicine 114:154762

    Article  CAS  PubMed  Google Scholar 

  38. Zhuang H, Yao X, Li H, Li Q, Yang C, Wang C et al (2022) Long-term high-fat diet consumption by mice throughout adulthood induces neurobehavioral alterations and hippocampal neuronal remodeling accompanied by augmented microglial lipid accumulation. Brain Behav Immun 100:155–171

    Article  CAS  PubMed  Google Scholar 

  39. Kesby JP, Kim JJ, Scadeng M, Woods G, Kado DM, Olefsky JM et al (2015) Spatial cognition in adult and aged mice exposed to High-Fat Diet. PLoS ONE 10:e0140034

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kwon HS, Koh SH (2020) Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener 9:42

    Article  PubMed  PubMed Central  Google Scholar 

  41. Yao P, Li Y, Yang Y, Yu S, Chen Y (2019) Triptolide improves cognitive dysfunction in rats with vascular dementia by activating the SIRT1/PGC-1alpha signaling pathway. Neurochem Res 44:1977–1985

    Article  CAS  PubMed  Google Scholar 

  42. Zhao Z, Yao M, Wei L, Ge S (2020) Obesity caused by a high-fat diet regulates the Sirt1/PGC-1alpha/FNDC5/BDNF pathway to exacerbate isoflurane-induced postoperative cognitive dysfunction in older mice. Nutr Neurosci 23:971–982

    Article  CAS  PubMed  Google Scholar 

  43. Iqbal Z, Bashir B, Ferdousi M, Kalteniece A, Alam U, Malik RA et al (2021) Lipids and peripheral neuropathy. Curr Opin Lipidol 32:249–257

    Article  CAS  PubMed  Google Scholar 

  44. Ji Y, Lang X, Wang W, Li S, Zhao C, Shen X et al (2021) Lactobacillus paracasei ameliorates cognitive impairment in high-fat induced obese mice via insulin signaling and neuroinflammation pathways. Food Funct 12:8728–8737

    Article  CAS  PubMed  Google Scholar 

  45. Hainmueller T, Bartos M (2020) Dentate gyrus circuits for encoding, retrieval and discrimination of episodic memories. Nat Rev Neurosci 21:153–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sa-Nguanmoo P, Tanajak P, Kerdphoo S, Satjaritanun P, Wang X, Liang G et al (2016) FGF21 improves cognition by restored synaptic plasticity, dendritic spine density, brain mitochondrial function and cell apoptosis in obese-insulin resistant male rats. Horm Behav 85:86–95

    Article  CAS  PubMed  Google Scholar 

  47. Leigh SJ, Morris MJ (2020) Diet, inflammation and the gut microbiome: mechanisms for obesity-associated cognitive impairment. Biochim Biophys Acta Mol Basis Dis 1866:165767

    Article  CAS  PubMed  Google Scholar 

  48. Zhou B, Wang L, Yang S, Liang Y, Zhang Y, Pan X et al (2023) Diosmetin alleviates benzo[a]pyrene-exacerbated H1N1 influenza virus-induced acute lung injury and dysregulation of inflammation through modulation of the PPAR-gamma-NF-kappaB/P38 MAPK signaling axis. Food Funct 14:3357–3378

    Article  CAS  PubMed  Google Scholar 

  49. Aggarwal A, Sharma N, Khera A, Sandhir R, Rishi V (2020) Quercetin alleviates cognitive decline in ovariectomized mice by potentially modulating histone acetylation homeostasis. J Nutr Biochem 84:108439

    Article  CAS  PubMed  Google Scholar 

  50. Maneechote C, Chunchai T, Apaijai N, Chattipakorn N, Chattipakorn SC (2022) Pharmacological targeting of mitochondrial fission and Fusion alleviates cognitive impairment and brain pathologies in pre-diabetic rats. Mol Neurobiol 59:3690–3702

    Article  CAS  PubMed  Google Scholar 

  51. Yapa N, Lisnyak V, Reljic B, Ryan MT (2021) Mitochondrial dynamics in health and disease. Febs Lett 595:1184–1204

    Article  CAS  PubMed  Google Scholar 

  52. Vilela WR, Bellozi P, Picolo VL, Cavadas BN, Marques K, Pereira L et al (2023) Early-life metabolic dysfunction impairs cognition and mitochondrial function in mice. J Nutr Biochem 117:109352

    Article  CAS  PubMed  Google Scholar 

  53. Kang W, Suzuki M, Saito T, Miyado K (2021) Emerging role of TCA cycle-related enzymes in Human diseases. Int J Mol Sci.;22

  54. Guo Z, Fan D, Liu FY, Ma SQ, An P, Yang D et al (2022) NEU1 regulates mitochondrial energy metabolism and oxidative stress post-myocardial infarction in mice via the SIRT1/PGC-1 alpha Axis. Front Cardiovasc Med 9:821317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tian L, Cao W, Yue R, Yuan Y, Guo X, Qin D et al (2019) Pretreatment with Tilianin improves mitochondrial energy metabolism and oxidative stress in rats with myocardial ischemia/reperfusion injury via AMPK/SIRT1/PGC-1 alpha signaling pathway. J Pharmacol Sci 139:352–360

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements and Contributions

The authors’ responsibilities were as followed. Y. Z. and H. D. designed research; Y. Z., C.L., P.H., Y.C., Y.M. and J.G. conducted research; Y. Z. and H. D. analyzed data; Y. Z. wrote the paper; Y. Z. and H. D. had primary responsibility for the final content. All authors read and approved the final version of the paper.

Funding

No.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Science, Wuhan University, 430000, Wuhan, China

    Yiyuan Zhang, Chunyun Luo, Puxin Huang, Yahong Cheng, Yufang Ma, Jiefang Gao & Hong Ding

Authors
  1. Yiyuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chunyun Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Puxin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yahong Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yufang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiefang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hong Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hong Ding.

Ethics declarations

Ethics Approval

Protocols were conducted according to the Regulations of the Chinese Council on Animal Care and approved by the Ethics Committee of Wuhan University Center for Animal Experiment, Wuhan, China (NO. WP20210532).

Consent to Participate

Not applicable.

Consent for Publication

All authors give their consent to publish this manuscript.

Conflict of Interest

Y. Zhang, C. Luo, P. Huang, Y. Cheng, Y. Ma, J. Gao, H. Ding, no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Luo, C., Huang, P. et al. Diosmetin Ameliorates HFD-induced Cognitive Impairments via Inhibiting Metabolic Disorders, Mitochondrial Dysfunction and Neuroinflammation in Male SD Rats. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04083-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12035-024-04083-x

Keywords

Search

Navigation