A combined administration of GABA agonist and L-histidine synergistically alleviates obesity-induced neuro-lipotoxicity and distorted metabolic transcriptome

Abstract

Obesity stands as a pervasive and significant global health issue, with a lack of definitive and curative therapeutic solutions currently available. Here we studied the synergetic ameliorating effect of coupled administration of GABA agonist; baclofen with histidine against the high fat (HFD) induced lipotoxicity in experimentally obese rats. Animals were divided into six groups. The control group (group 1) was fed a basal diet. Obesity was induced in groups 2 to 6 by HFD for 60 days and concomitantly treated with distilled water or Fluoxetine or Baclofen or L-Histidine or a half-dose combination of Bac plus His, respectively. HFD leads to aberrations in neuronal function, affecting neurotransmitters such as monoamines, turnover rates, and levels of excitatory and inhibitory amino acids when compared to control (P < 0.05). Additionally, it induces notable cellular oxidative stress and energy homeostasis distortion. Simultaneous dysregulation of genes associated with glucose sensing and availability was observed, characterized by a notable decrease in the expression of the glycogen phosphorylase gene and a marked increase in the expression of glucokinase and proglucagon genes (P < 0.05). Both Bac and His single dosing rectified the HDF-induced alterations in 5HT, DA and NE neurotransmitters with their metabolites 5HIAA, DOPAC and HVA, together with Nrf1 and NF-KB1 inflammatory markers and partially quenched the HDF-induced increase in the level of MDA and 8OHdG oxidative stress byproducts, and restored the activity of GSH and SOD antioxidant enzymes. Remarkably, the combined administration of Bac and His at half-dose exhibited significant behavioral improvement, fully normalizing neurochemical and cellular energy homeostasis, and restoring cellular redox and inflammatory parameters to control values following HFD-induced cellular insult. In conclusion, the combined half-dosing of Bac plus His treatment exhibited substantial improvements in behavior and fully normalized neurochemical and cellular parameters, offering a promising approach for addressing obesity-related complexities.

Keywords

• L-histidine
• Fluoxetine
• GABA agonist
• Gene expression
• Obesity
• Rats