Involvement of Hepatic SHIP2 and PI3K/Akt Signalling in the Regulation of Plasma Insulin by Xiaoyaosan in Chronic Immobilization-Stressed Rats

Abstract

Background: Long-term exposure to chronic stress is thought to be a factor closely correlated with the development of metabolic disorders, such as diabetes mellitus and metabolic syndrome. Xiaoyaosan, a Chinese herbal formula, has been described in many previous studies to exert anxiolytic-like or antidepressant effects in chronically stressed rats. However, few studies have observed the effects of Xiaoyaosan on the metabolic disorders induced by chronic stress. Objective: We sought to investigate the effective regulation of Xiaoyaosan on 21-day chronic immobility stress (CIS, which is 3 h of restraint immobilization every day)-induced behavioural performance and metabolic responses and to further explore whether the effects of Xiaoyaosan were related to SHIP2 expression in the liver. Methods: Sixty male Sprague Dawley rats were randomly divided into a control group, a CIS group, a Xiaoyaosan group and a rosiglitazone group. The latter three groups were subjected to 21 days of CIS to generate the stress model. After 21 days of CIS, the effects of Xiaoyaosan on body weight, food intake, and behaviour in the open field test, the sucrose preference test and the forced swimming test were observed following chronic stress. Plasma insulin, cholesterol (CHOL), triglyceride (TG), low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) concentrations and blood glucose were examined, and the protein and mRNA expression levels of SHIP2, p85 and Akt in the liver were measured using RT-qPCR and immunohistochemical staining. Results: Rats exposed to CIS exhibited depression-like behaviours, decreased levels of plasma insulin, CHOL, LDL-C, TG and HDL-C, and increased blood glucose. Increased SHIP2 expression and reduced Akt, p-Akt and p85 expression were also observed in the liver. Xiaoyaosan exerted antidepressant effects and effectively reversed the changes caused by CIS. Conclusions: These results suggest that Xiaoyaosan attenuates depression-like behaviours and ameliorates stress-induced abnormal levels of insulin, blood glucose, CHOL, LDL-C and HDL-C in the plasma of stressed rats, which may be associated with the regulation of SHIP2 expression to enhance PI3K/Akt signalling activity in the liver.

Xiaoyaosan Ameliorates Chronic Immobilization Stress-Induced Depression-Like Behaviors and Anorexia in Rats: The Role of the Nesfatin-1–Oxytocin–Proopiomelanocortin Neural Pathway in the Hypothalamus

“…These observations suggest that Xiaoyaosan may exert its pharmacological effect by regulating NES1 signals from the periphery. Although the mechanism of this pharmacological effect remains unclear, several studies have shown that Xiaoyaosan improves depressive-like behavior through the modulation of peripheral organs, for instance, the liver (39) and the intestine (28,40). Additionally, Xiaoyaosan downregulated the CIS-induced overexpression of OT, POMC, and MC4R in the rat hypothalamus.…”

Effect of Xiaoyaosan on Colon Morphology and Intestinal Permeability in Rats With Chronic Unpredictable Mild Stress

“…The Xiaoyaosan powder, provided by Jiuzhitang Co., Ltd. (Changsha, China), was produced based on the procedure described in the Chinese Pharmacopoeia 2015 Edition (National Pharmacopoeia Commission, 2015), and the ratio of different herbs used in production was Radix Bupleuri: Angelica Sinensis: Rhizoma Atractylodis Macrocephalae: Radix Paeoniae Alba: Poria Cocos: Radix Glycyrrhizae: Rhizoma Zingiberis Recens: Herba Menthae=5:5:5:5:5:4:5:1. A brief production process was previously described (Pan et al, 2019). One gram of the powder was obtained from 2.10 g of the raw herbs.…”

Identifying the active components of Baihe–Zhimu decoction that ameliorate depressive disease by an effective integrated strategy: a systemic pharmacokinetics study combined with classical depression model tests

“…In China, many Chinese medicine formulae, which are also regarded as alternative therapeutic agents in other Asian countries, have been used for the treatment of depression [26, 27]. Baihe–Zhimu decoction (BZD) is a classical prescription used to treat depression.…”