Oleate prevents palmitate-induced mitochondrial dysfunction, insulin resistance and inflammatory signaling in neuronal cells

Abstract

Elevated circulating levels of saturated free fatty acids (sFFAs; e.g. palmitate) are known to provoke inflammatory responses and cause insulin resistance in peripheral tissue. By contrast, mono- or poly-unsaturated FFAs are protective against sFFAs. An excess of sFFAs in the brain circulation may also trigger neuroinflammation and insulin resistance, however the underlying signaling changes have not been clarified in neuronal cells. In the present study, we examined the effects of palmitate on mitochondrial function and viability as well as on intracellular insulin and nuclear factor-κB (NF-κB) signaling pathways in Neuro-2a and primary rat cortical neurons. We next tested whether oleate preconditioning has a protective effect against palmitate-induced toxicity. Palmitate induced both mitochondrial dysfunction and insulin resistance while promoting the phosphorylation of mitogen-activated protein kinases and nuclear translocation of NF-κB p65. Oleate pre-exposure and then removal was sufficient to completely block subsequent palmitate-induced intracellular signaling and metabolic derangements. Oleate also prevented ceramide-induced insulin resistance. Moreover, oleate stimulated ATP while decreasing mitochondrial superoxide productions. The latter were associated with increased levels of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Inhibition of protein kinase A (PKA) attenuated the protective effect of oleate against palmitate, implicating PKA in the mechanism of oleate action. Oleate increased triglyceride and blocked palmitate-induced diacylglycerol accumulations. Oleate preconditioning was superior to docosahexaenoic acid (DHA) or linoleate in the protection of neuronal cells against palmitate- or ceramide-induced cytotoxicity. We conclude that oleate has beneficial properties against sFFA and ceramide models of insulin resistance-associated damage to neuronal cells.

Oleate protects beta-cells from the toxic effect of palmitate by activating pro-survival pathways of the ER stress response

“…oleate. This finding and the fact that oleate prevents the negative effects of palmitate even in cell types that lack GPR40 [14,36] suggest that FFAR1 is unlikely to play a role in the protective action of oleate.…”

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

“…Proposed mechanisms for these observations include attenuating palmitate‐induced ER stress (Colvin et al ., 2017), preventing activation of the unfolded protein response (Sommerweiss et al ., 2013), activating prosurvival pathways of ER stress (Sargsyan et al ., 2016), restoring insulin stimulated protein kinase B (Akt) signaling (Capel et al ., 2016), and activating AMP‐activated protein kinase and mechanistic target of rapamycin signaling (Kwon and Querfurth, 2015). Oleate treatment in a range of cells also modulates palmitate metabolism including stimulating TAG synthesis, preventing diacylglycerol accumulation (Capel et al ., 2016; Kwon et al ., 2014), and preventing mitochondrial reactive oxygen species production and dysfunction (Kwon et al ., 2014). These observations were predominantly made by cotreatment with oleate and palmitate.…”

Synergistic effects of β-amyloid and ceramide-induced insulin resistance on mitochondrial metabolism in neuronal cells

“…Ceramide is a proven inducer of intracellular insulin resistance in non-neuronal cells [40], primary neurons [56] and in the present study, SY5Y cells. In previous work we found that Aβ expression also decreased insulin-stimulated Akt phosphorylation in skeletal muscle cells [31].…”

“…We recently reported that ceramide (50 μM) induced insulin resistance in N2a and primary rat cortical neurons [56]. The time course of insulin response was checked by Akt phosphorylation in SY5Y cells (Supplemental Fig.…”