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

Abstract The balance between autophagy and apoptosis in hypothalamus may be disrupted upon type 2 diabetes mellitus (T2DM). Since propionic acid (PA) exerts neuroprotective effects, the aim was to investigate its effects on apoptosis/autophagy switch in the ventromedial hypothalamus (VMH) in a T2DM rat model. Therefore male Wistar rats were divided into untreated control rats and rats in which T2DM was induced. The untreated T2DM rats were compared to a group that received metformin, a group that received sodium salt of PA and a group that got PA+metformin. Western blotting, RT-PCR, transmission electron microscopy and immunohistochemical staining were from VMH tissue were performed.T2DM-induced apoptosis and mitoptosis, enlarged ER tubules/cisterns were observed in VMH, and accompanied by imbalance of pro- and anti-apoptotic factors. Elevation of pro-apoptotic Bax and caspase-3, decrease in autophagy marker LC3 and anti-apototic Bcl-xl were observed in VMH of T2DM rats. Metformin and PA partially improved VMH ultrastructural changes by reducing mitochondrial swelling and diminishing the number of apoptotic neurons. Metformin inhibited neuronal apoptosis, however caused reactive astrogliosis and accumulation of lipofuscin. Elevated number of autophagosomes was associated with LC3, Beclin-1 and Bcl-xl increase and decrease in Bax and caspase-3 in VMH of T2DM rats. PA switched cell fate from apoptosis to autophagy by elevating LC3 and Beclin-1 levels and increasing Bcl-xl that altogether may represent adaptive response to T2DM-induced apoptosis. PA+metformin administration lowered relative area of ER membranes/cisterns in VMH compared to untreated T2DM rats and metformin alone, and was balancing the ratio of pro-apoptotic, anti-apoptotic and autophagy markers.In conclusion, T2DM was associated with apoptosis activation leading to impairments in VMH. PA in combination with metformin may be effective against diabetes-induced cell death by switching apoptosis to autophagy in VMH.