Sex Modulates Lactobacillus johnsonii N6.2 and Phytophenol Effectiveness in Reducing High Fat Diet Induced mTOR Activation in Sprague-Dawley Rats

Abstract

Metabolic syndrome (MetS) is the underlying cause of some devastating diseases, including type 2 diabetes and cardiovascular disease. These diseases have been associated with over-activation of the mechanistic Target of Rapamycin (mTOR) pathway. This study utilizes a high fat diet (HFD) to induce MetS and to dissect the effects of a beneficial bacterium, L. johnsonii N6.2, and natural phenolics on mTOR complex 1 (mTORC1) expression compared to a reduced energy density diet (REDD). HFD significantly elevated MetS markers in males, as noted through an increase in weight, glucose levels, and triglyceride levels. Treatments were effective in reducing mTORC1-activating phosphorylation of pAKT-T308 and pAKT-S473 (p = 0.0012 and 0.0049, respectively) in HFD-fed females, with the combined treatments of L. johnsonii and phytophenols reducing phosphorylation below REDD-fed control levels, and significantly below HFD-fed control levels. Meanwhile, diet was the significant factor influencing male mTORC1-activating phosphorylation (p < 0.0001), as treatments were only effective in reducing phosphorylation in REDD-fed animals. Downstream analysis of mTORC1 activated genes phosphogluconate dehydrogenase (pgd) and phosphofructose kinase (pfk) followed this similar trend, enforcing the significant effect sex has on a treatments’ ability to modulate diet induced abnormalities. Analyzing mTORC1 stimulators such as insulin, inflammatory cytokines, and tryptophan, revealed no significant differences among groups. These results indicate that the effects observed on mTORC1 are a direct consequence of the treatments, and not exerted indirectly via the modulation of stimuli. This study highlights the potential use of commensal microorganisms and natural compounds in reducing the onset of metabolic diseases through mTORC1.

Lactobacillus johnsonii N6.2 and Blueberry Phytophenols Affect Lipidome and Gut Microbiota Composition of Rats Under High-Fat Diet

“…Lower activation of the mTOR pathway was previously observed in the GI tract of animals treated with L. johnsonii N6.2 and phytophenols (30). mTORC1 phosphorylation signaling is critical in the activation of SREBP1 activity in the liver and adipose tissue.…”

Canagliflozin attenuates lipotoxicity in cardiomyocytes and protects diabetic mouse hearts by inhibiting the mTOR/HIF-1α pathway

“…mTOR serves as a central regulator of lipid storage and metabolism ( Chakrabarti and Kandror, 2015 ). High-fat uptake promoted mTOR phosphorylation ( Kling et al, 2018 ). Following mTOR activation, the accumulation of triglycerides is facilitated by the increase in adipogenesis and lipogenesis ( Caron et al., 2015 ), which also contributed to lipotoxicity.…”

Canagliflozin Attenuates Lipotoxicity in Cardiomyocytes and Protects Diabetic Mouse Hearts by Targeting the mTOR/HIF-1α Pathway

“…mTOR serves as a central regulator of lipid storage and metabolism (46). High-fat uptake promoted mTOR phosphorylation (47). Following mTOR activation, the accumulation of triglycerides is facilitated by the increase in adipogenesis and lipogenesis (48), which also contributed to lipotoxicity.…”