Metformin Attenuates the Metabolic Disturbance and Depression-like Behaviors Induced by Corticosterone and Mediates the Glucose Metabolism Pathway

Abstract

Background Metabolism disturbances are common in patients with depression. The drug metformin has been reported to exhibit antidepressant activity. The purpose of this study was to investigate metabolism disturbances induced by corticosterone (CORT) and determine if metformin can reverse these effects and their accompanying depression-like behaviors. Methods Rats were exposed to corticosterone with or without metformin administration. Depression-like behaviors were tested. Gene expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. In addition, the metabolites were quantified by LC-MS/MS analysis. Results Metformin attenuated the depression-like behaviors induced by CORT. Furthermore, metformin reversed disturbances in body weight, serum glucose, and triglyceride levels, as well as hepatic TG levels induced by CORT. Metformin normalized the alterations in the expression of glucose metabolism-related genes (PGC-1α, G6pc, Pepck, Gck, PYGL, Gys2, PKLR, GLUT4) and insulin resistance-related genes (AdipoR1, AdipoR2) in the muscles and livers of rats induced by CORT. Metabolomic analysis showed that metformin reversed the effects of CORT on 11 metabolites involved in the pathways of the tricarboxylic acid cycle, glycolysis, and gluconeogenesis (3-phospho-D-glycerate, β-D-fructose 6-phosphate, D-glucose 6-phosphate, and pyruvate). Conclusion Our findings suggest that metformin can attenuate metabolism disturbances and depression-like behaviors induced by CORT mediating the glucose metabolism pathway.

Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice

“…Disturbed energy metabolism is widely reported in depression patients and animal models. Mounting evidence demonstrated impaired glucose metabolism in the mPFC of depression patients and animal models [11][12][13]40 . However, the role of glycolysis in the pathogenesis of depression has been largely ignored.…”

Metabolomic Approaches to Investigate the Effect of Metformin: An Overview

“…On the other hand, phosphoenolpyruvate levels significantly decreased in liver tissue. Hao et al [ 97 ] investigated metabolism disturbances induced by corticosterone (CORT) and determined that metformin can reverse these effects. In their metabolomic approach, metformin treatment altered several metabolites involved in the pathway of the TCA cycle (isocitrate, citrate, alpha-ketoglutarate, oxaloacetate, malic acid, succinate, and fumarate) and the pathway of glycolysis and gluconeogenesis (3-phospho-D-glycerate, fructose 6-phosphate, glucose 6-phosphate, and pyruvate) in liver tissue.…”

Disrupting the Mood and Obesity Cycle: The Potential Role of Metformin

“…In addition to metabolic and psychological dysfunction in HFD-induced models, metformin also appears effective in reversing corticosterone-mediated metabolic dysfunction and depression-like behaviors [122,123] as well as lipopolysaccharide-induced depressivelike behaviors associated with aberrant glutamatergic neurotransmission and inflammationrelated pathways [124,125]. Chronic stress is associated with elevated corticosteroid levels and prolonged activation of the sympathetic nervous system, leading to increased visceral fat and metabolic derangements that include insulin resistance and T2DM [72,89].…”