Mechanism of Intermittent Fasting in Improving Olanzapine-induced Metabolic Disorders in Mice

doi:10.12300/j.issn.1674-5817.2022.089

Abstract

Abstract:

Objective To explore the beneficial role and potential mechanism of intermittent fasting in olanzapine-induced metabolic disorders. Methods C57BL/6J mice were randomly divided into four groups: Saline + ad libitum (Saline+Ad libitum), Saline + intermittent fasting (Saline +IF), olanzapine administration + ad libitum (Olanzapine+ Ad libitum), and olanzapine administration + intermittent fasting (Olanzapine+IF)， with eight mice in each group. The IF group adopted the 5∶2 scheme, that is, fasting on Monday and Thursday every week, and eating freely in the rest of the time. Ad libitum feeding as the control of intermittent fasting, Saline gavage as the control of olanzapine administration. The experiment lasted for 12 weeks. The differences of body mass, liver mass and epididymal adipose tissue mass were compared between the olanzapine-treated group and the control group after IF intervention. The body fat mass, lean body mass, and visceral fat infiltration of mice were analyzed by nuclear magnetic resonance and HE staining, respectively. Furthermore, the levels of fasting blood glucose, insulin, and insulin resistance index (HOMA-IR) in the process of glucose metabolism were also measured by glucose oxidase method and radioimmunoassay, respectively. The effects of IF on H₂O₂ release and the level of cytochrome C mRNA, a marker related to mitochondrial damage, were detected by ELISA and real-time fluorescence quantitative PCR. Results After 12 weeks of treatment, olanzapine induced a significant increase in body mass, body fat, lean body mass and visceral fat infiltration (P<0.05), as well as fasting blood glucose, insulin, and HOMA-IR (P<0.05); however, IF significantly reduced the above indicators (P<0.05). Further studies showed that the release of H₂O₂ and the expression of Cytochrome C mRNA in adipose tissue of mice after intermittent fasting treatment were significantly decreased (P<0.05). Conclusion Intermittent fasting therapy can alleviate olanzapine-induced metabolic disorders in mice. The underlying mechanism may involve the inhibition of oxidative stress level and the maintenance of mitochondrial functions.

Key words: Intermittent fasting therapy, Obesity, Oxidative stress, Mitochondria, C57BL/6J mice

CLC Number:

Q95-33

Han LI, Xiaorui ZHANG, Chengfang ZHANG. Mechanism of Intermittent Fasting in Improving Olanzapine-induced Metabolic Disorders in Mice[J]. Laboratory Animal and Comparative Medicine, 2023, 43(1): 3-10.

Figures/Tables 4

Figure 1 Effects of intermittent fasting on body mass， body fat distribution， visceral fat infiltration in olanzapine-induced miceNote：A， Body mass changes of mice in different treatment groups for 12 consecutive weeks （F=161.20， *P<0.001， two-way ANOVA followed by Turkey's post-test）. B， Effect of intermittent fasting on body mass of mice with olanzapine diet for 12 weeks （*F=62.87，P<0.001， one-way ANOVA followed by Turkey's post-test）. C， The changes of fat mass in mice after olanzapine diet for 12 weeks （*F=0.027，P<0.001， one-way ANOVA followed by Turkey's post-test）. D， The changes of lean mass in mice after olanzapine diet for 12 weeks （n.sF=78.54， P=0.994，one-way ANOVA followed by Turkey's post-test）. E， Liver and epididymal adipose morphology after olanzapine diet for 12 weeks（HE staining，the scale bar is 200 μm）.

Figure 2 Effects of intermittent fasting on fasting blood glucose, insulin, and HOMA-IR, in olanzapine-induced miceNote：After 12 weeks of intermittent fasting， detecting fasting insulin levels （A）（*F=18.08，P<0.001， one-way ANOVA followed by Turkey's post-test）， homeostatic model assessment of insulin resistance （HOMA-IR）（B）（*F=9.707， P=0.000 4， one-way ANOVA followed by Turkey's post-test）， and fasting glucose levels （C）（n.sF=0.860， P=0.477， one-way ANOVA followed by Turkey's post-test）.

Figure 3 Effects of intermittent fasting on oxidative stress， mitochondrial function in olanzapine-induced miceNote：Hydrogen peroxide release was detected by ELISA （A）（*F=4.633， P=0.016）， and the transcriptional level of Cytochrome C mRNA was detected by real-time fluorescence quantitative PCR （B）（*F=3.605， P=0.031） after 12 weeks of intermittent fasting treatment in mice.

Figure 4 Schematic illustration of potential pathways underlying the mechanism of intermittent fasting in ameliorating olanzapine-induced metabolic disorders in mice

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