Xiaoyaosan Ameliorates Depressive-like Behavior and Susceptibility to Glucose Intolerance in Rat: Involvement of LepR-STAT3/PI3K Pathway in Hypothalamic Arcuate Nucleus

Overview

Journal BMC Complement Med Ther

Publisher Biomed Central

Specialty Rehabilitation Medicine

Date 2023 Apr 12

PMID 37046230

Authors

Wenqi Qiu

Qian Wu

Kaiwen Zhang

Xiaoli Da

Kairui Tang

Naijun Yuan

Lijuan Deng

Mansi Wu

Ying Zhang

Jiangyan Quan

Qingyu Ma

Xiaojuan Li

Jiaxu Chen

Affiliations

Soon will be listed here.

Abstract

Background: Accumulating evidence has demonstrated that arcuate nucleus (ARC) of the hypothalamus is likely responsible for the close association between chronic stress, depression, and diabetes. Xiaoyaosan (XYS), a Chinese herbal formula, remarkably improves depressive-like behavior and glucose intolerance, but the mechanism remains unclear. Leptin receptor (LepR) regulates energy expenditure and depression by mediating the action of leptin on the ARC. Therefore, we hypothesized that XYS may regulate depressive-like behavior and glucose intolerance via the leptin and its cascade LepR-STAT3/PI3K pathway in the ARC.

Methods: A rat model of depressive-like behavior and susceptibility to glucose intolerance was induced by exposure to chronic unpredictable mild stress (CUMS) for six weeks. XYS (2.224 g/kg) was orally gavaged for six weeks, and fluoxetine (2.0 mg/kg) was administrated to the positive control group. Depressive-like behaviors were assessed using the open field test (OFT), sucrose preference test (SPT) and forced swim test (FST). Fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were performed to evaluate the effects of XYS on blood glucose. Peripheral leptin and blood lipids were detected using enzyme-linked immunosorbent assay and an automatic biochemical analyzer, respectively. The effects of XYS on the LepR-STAT3/PI3K pathway were detected by quantitative real-time PCR and western blotting.

Results: XYS ameliorated CUMS-induced depressive-like behaviors and elevated blood glucose. XYS improved the food intake but have no significant effects on the body weight. Peripheral leptin and its central receptor were also suppressed by XYS, accompanied by the downregulation of JAK2/STAT3 and PI3K/AKT pathway in the ARC. Additionally, XYS increased AGRP and NPY expression but inhibited POMC in the ARC.

Conclusions: XYS improves depressive-like behaviors and susceptibility to glucose intolerance induced by CUMS, which may be achieved by the downregulation of the LepR-STAT3/PI3K signaling pathway in the ARC.

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References

Huang H, Chen X, Han Q, Wang J, Pilot A, Yu R . The protective effects of Ghrelin/GHSR on hippocampal neurogenesis in CUMS mice. Neuropharmacology. 2019; 155:31-43. DOI: 10.1016/j.neuropharm.2019.05.013. View

Leshan R, Greenwald-Yarnell M, Patterson C, Gonzalez I, Myers Jr M . Leptin action through hypothalamic nitric oxide synthase-1-expressing neurons controls energy balance. Nat Med. 2012; 18(5):820-3. PMC: 3531967. DOI: 10.1038/nm.2724. View

Li X, Qiu W, Li N, Da X, Ma Q, Hou Y . Susceptibility to Hyperglycemia in Rats With Stress-Induced Depressive-Like Behavior: Involvement of IL-6 Mediated Glucose Homeostasis Signaling. Front Psychiatry. 2020; 11:557. PMC: 7324635. DOI: 10.3389/fpsyt.2020.00557. View

van der Kooij M, Jene T, Treccani G, Miederer I, Hasch A, Voelxen N . Chronic social stress-induced hyperglycemia in mice couples individual stress susceptibility to impaired spatial memory. Proc Natl Acad Sci U S A. 2018; 115(43):E10187-E10196. PMC: 6205456. DOI: 10.1073/pnas.1804412115. View

Gogos A, McCarthy M, Walker A, Udawela M, Gibbons A, Dean B . Differential effects of chronic 17β-oestradiol treatment on rat behaviours relevant to depression. J Neuroendocrinol. 2018; 30(11):e12652. DOI: 10.1111/jne.12652. View

Guo X, Qiu W, Liu Y, Zhang Y, Zhao H, Chen J . Effects of Refined Xiaoyaosan on Depressive-Like Behaviors in Rats with Chronic Unpredictable Mild Stress through Neurosteroids, Their Synthesis and Metabolic Enzymes. Molecules. 2017; 22(8). PMC: 6152155. DOI: 10.3390/molecules22081386. View

Li X, Ma Q, Jiang Y, Bai X, Yan Z, Liu Q . Xiaoyaosan exerts anxiolytic-like effects by down-regulating the TNF-α/JAK2-STAT3 pathway in the rat hippocampus. Sci Rep. 2017; 7(1):353. PMC: 5428435. DOI: 10.1038/s41598-017-00496-y. View

Pan Y, Hong Y, Zhang Q, Kong L . Impaired hypothalamic insulin signaling in CUMS rats: restored by icariin and fluoxetine through inhibiting CRF system. Psychoneuroendocrinology. 2012; 38(1):122-34. DOI: 10.1016/j.psyneuen.2012.05.007. View

Yuan N, Gong L, Tang K, He L, Hao W, Li X . An Integrated Pharmacology-Based Analysis for Antidepressant Mechanism of Chinese Herbal Formula Xiao-Yao-San. Front Pharmacol. 2020; 11:284. PMC: 7094752. DOI: 10.3389/fphar.2020.00284. View

10.

Wang S, Chen J, Yue G, Bai M, Kou M, Jin Z . Xiaoyaosan decoction regulates changes in neuropeptide y and leptin receptor in the rat arcuate nucleus after chronic immobilization stress. Evid Based Complement Alternat Med. 2012; 2012:381278. PMC: 3518256. DOI: 10.1155/2012/381278. View

11.

Zhou X, Liu C, Liu Y, Ma Q, Zhao X, Jiang Y . Xiaoyaosan Alleviates Hippocampal Glutamate-Induced Toxicity in the CUMS Rats via NR2B and PI3K/Akt Signaling Pathway. Front Pharmacol. 2021; 12:586788. PMC: 8075411. DOI: 10.3389/fphar.2021.586788. View

12.

Li X, Qiu W, Da X, Hou Y, Ma Q, Wang T . A combination of depression and liver Qi stagnation and spleen deficiency syndrome using a rat model. Anat Rec (Hoboken). 2020; 303(8):2154-2167. DOI: 10.1002/ar.24388. View

13.

Patel S, Mehta V, Changotra H, Udayabanu M . Depression mediates impaired glucose tolerance and cognitive dysfunction: A neuromodulatory role of rosiglitazone. Horm Behav. 2015; 78:200-10. DOI: 10.1016/j.yhbeh.2015.11.010. View

14.

Wang X, Fang C, Wu J, Wang S, Zhao R, Ma J . Xiaoyaosan decoction regulates food intake and body weight via the leptin-leptin receptor-proopiomelanocortin pathway in rats with chronic immobilization stress. J Tradit Chin Med. 2020; 39(1):34-44. View

15.

Ulrich-Lai Y, Herman J . Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009; 10(6):397-409. PMC: 4240627. DOI: 10.1038/nrn2647. View

16.

Ernst J, Hock A, Henning A, Seifritz E, Boeker H, Grimm S . Increased pregenual anterior cingulate glucose and lactate concentrations in major depressive disorder. Mol Psychiatry. 2016; 22(1):113-119. DOI: 10.1038/mp.2016.73. View

17.

Smith K . Mental health: a world of depression. Nature. 2014; 515(7526):181. DOI: 10.1038/515180a. View

18.

Yang F, Zhu X, Kong M, Zou X, Ma Q, Li X . Xiaoyaosan Exerts Antidepressant-Like Effect by Regulating Autophagy Involves the Expression of GLUT4 in the Mice Hypothalamic Neurons. Front Pharmacol. 2022; 13:873646. PMC: 9243304. DOI: 10.3389/fphar.2022.873646. View

19.

Ye Z, Chen L, Yang Z, Li Q, Huang Y, He M . Metabolic effects of fluoxetine in adults with type 2 diabetes mellitus: a meta-analysis of randomized placebo-controlled trials. PLoS One. 2011; 6(7):e21551. PMC: 3145630. DOI: 10.1371/journal.pone.0021551. View

20.

Coppari R, Ichinose M, Lee C, Pullen A, Kenny C, McGovern R . The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity. Cell Metab. 2005; 1(1):63-72. DOI: 10.1016/j.cmet.2004.12.004. View