Abstract
Background The aim was to investigate the influence of propionic acid (PA) on the endoplasmic reticulum (ER), unfolded protein response (UPR) state, and astrocyte/microglia markers in rat ventromedial hypothalamus (VMH) after type 2 diabetes mellitus (T2DM). Methods Male Wistar rats were divided: (1) control, (2) T2DM, and groups that received the following (14 days, orally): (3) metformin (60 mg/kg), (4) PA (60 mg/kg), and (5) PA+metformin. Western blotting, RT-PCR, transmission electron microscopy, and immunohistochemical staining were performed. Results We found T2DM-associated enlargement of ER cisterns, while drug administration slightly improved VMH ultrastructural signs of damage. GRP78 level was 2.1-fold lower in T2DM vs. control. Metformin restored GRP78 to control, while PA increased it by 2.56-fold and metformin+PA—by 3.28-fold vs. T2DM. PERK was elevated by 3.61-fold in T2DM, after metformin—by 4.98-fold, PA—5.64-fold, and metformin+PA—3.01-fold vs. control. A 2.45-fold increase in ATF6 was observed in T2DM. Metformin decreased ATF6 content vs. T2DM. Interestingly, PA exerted a more pronounced lowering effect on ATF6, while combined treatment restored ATF6 to control. IRE1 increased in T2DM (2.4-fold), metformin (1.99-fold), and PA (1.45-fold) groups vs. control, while metformin+PA fully normalized its content. The Iba1 level was upregulated in T2DM (5.44-fold) and metformin groups (6.88-fold). Despite PA treatment leading to a further 8.9-fold Iba1 elevation, PA+metformin caused the Iba1 decline vs. metformin and PA treatment. GFAP level did not change in T2DM but rose in metformin and PA groups vs. control. PA+metformin administration diminished GFAP vs. PA. T2DM-induced changes were associated with dramatically decreased ZO-1 levels, while PA treatment increased it almost to control values. Conclusions T2DM-induced UPR imbalance, activation of microglia, and impairments in cell integrity may trigger VMH dysfunction. Drug administration slightly improved ultrastructural changes in VMH, normalized UPR, and caused an astrocyte activation. PA and metformin exerted beneficial effects for counteracting diabetes-induced ER stress in VMH.
Highlights
Obesity, metabolic syndrome (MS), and type 2 diabetes mellitus (T2DM) are among the most serious health problems in the 21st century
We found that after 3.5 months from the start of experiment, body weight of T2DM rats was significantly higher by 1.65-fold (p = 0:0003), and the length and waist were increased compared with control animals (Table 2)
Administration of metformin and propionic acid (PA), as well as their combination, had no significant effects on body weight compared with the T2DM group; the body weight in metformin group, in PA group, and in metformin+PA group was higher compared with control animals
Summary
Metabolic syndrome (MS), and type 2 diabetes mellitus (T2DM) are among the most serious health problems in the 21st century. Significant efforts have been made to discover cellular and molecular pathogenic mechanisms underlying MS. They turned out to be complex, still debated, and remain to be fully elucidated. Metformin restored GRP78 to control, while PA increased it by 2.56-fold and metformin+PA—by 3.28fold vs T2DM. IRE1 increased in T2DM (2.4-fold), metformin (1.99-fold), and PA (1.45-fold) groups vs control, while metformin +PA fully normalized its content. GFAP level did not change in T2DM but rose in metformin and PA groups vs control. T2DM-induced changes were associated with dramatically decreased ZO-1 levels, while PA treatment increased it almost to control values. Drug administration slightly improved ultrastructural changes in VMH, normalized UPR, and caused an astrocyte activation. PA and metformin exerted beneficial effects for counteracting diabetes-induced ER stress in VMH
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