Effect of Propionic Acid on Diabetes-Induced Impairment of Unfolded Protein Response Signaling and Astrocyte/Microglia Crosstalk in Rat Ventromedial Nucleus of the Hypothalamus

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.

Regulation of the apoptosis/autophagy switch by propionic acid in ventromedial hypothalamus of rats with type 2 diabetes mellitus

“…In addition, the positive point needed to be emphasized here is that the difference compared with the metformin group was that astrocytic glia demonstrated no signs of swelling. Generally, our previous hypothesis that PA may exert neuroprotective effect by activating anti-apoptotic mechanisms in neurons and stimulating an autophagy [ 13 ] as an important protective way to prevent an accumulation of misfolded proteins was decisively confirmed in this study.…”

“…Target protein levels (LC3, Beclin-1, Bcl-xl, Bax, caspase-3) were measured by western blotting. Protein extracts from frozen hypothalamus samples were prepared using a standard protocol with RIPA buffer as described previously [ 13 ]. Equal amounts of protein (30 μg per track) from each sample were loaded onto 10–15% PAAG (depending on the molecular weight of protein) for electrophoresis.…”

“…ER stress-associated mechanisms may influence the autophagy process through the involvement of PERK (protein kinase R-like ER kinase)-mediated signaling pathways [ 11 , 12 ]. Our previous results showed that the elevated level of PERK, one of the major UPR sensors, in VMH under diabetic condition was essential for an autophagy induction [ 13 ]. Thus, particular attention should be paid in order to explore how the regulation of switch between the processes of apoptosis and autophagy as a tightly coordinated system for maintaining intracellular homeostasis and an important factor in the development of T2DM-associated hypothalamic dysfunction occurs.…”

Why antidiabetic drugs are potentially neuroprotective during the Sars-CoV-2 pandemic: The focus on astroglial UPR and calcium-binding proteins

“…It is not our intention to discuss all the possible mechanisms of these drugs but to seek their associations with the UPR and, consequently, with their potential to attenuate or prevent the development of neurodegenerative diseases, associated with cognitive deficit and dementia. It should be noted that all of these drugs act beneficially on astrocytic functions in different models of injury; however, their specific role in the UPR of these cells is less explored (e.g., Déry and LeBlanc, 2017;Natrus et al, 2022). A summary of the data presented in this section about the effects of metformin, statins, and Ca 2+ channel blockers (CCB) on UPR and neuroprotection is presented in Table 1.…”

Insulin resistance and intestinal microbial metabolites in childhood obesity

“…З іншого боку, С 3 має антиобесогенні властивості, покращуючи глікемію натще, масу тіла та толерантність до інсуліну у тваринних моделях [42], а також має здатність протидіяти спричиненому діабетом ER стресу в гіпоталамусі [43]. Безпосередній вплив SCFA на секрецію інсуліну вважається суперечливим або взагалі відсутнім [44].…”