Obesity is a major risk factor for the development of various pathological conditions including insulin resistance, diabetes, cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD). Central to these conditions is obesity-associated chronic low-grade inflammation in many tissues including adipose, liver, muscle, kidney, pancreas, and brain. There is increasing evidence that saturated fatty acids (SFAs) increase the phosphorylation of MAPKs, enhance the activation of transcription factors such as nuclear factor (NF)-κB, and elevate the expression of inflammatory genes. This paper focuses on the mechanisms by which SFAs induce inflammation. SFAs may induce the expression inflammatory genes via different pathways including toll-like receptor (TLR), protein kinase C (PKC), reactive oxygen species (ROS), NOD-like receptors (NLRs), and endoplasmic reticulum (ER) stress. These findings suggest that SFAs act as an important link between obesity and inflammation.

Obesity and metabolic syndrome are associated with cognitive decline and dementia. Palmitic acid (PA) is increased in the cerebrospinal fluid of obese patients with cognitive impairment. This study was therefore designed to examine fatty acid (FA) lipotoxicity in BV2 microglia cells. We found that PA induced time- and dose-dependent decrease in cell viability and increase in cell death without affecting the cell cycle profile and that PA lipotoxicity did not depend on cell surface free fatty acid receptors but rather on FA uptake. Treatment with sulfosuccinimidyl oleate (SSO), an irreversible inhibitor of fatty acid translocase CD36, significantly inhibited FA uptake in BSA- and PA-treated cells and blocked PA-induced decrease in cell viability. Inhibition of ER stress or treatment with N-acetylcysteine was not able to rescue PA lipotoxicity. Our study also showed that unsaturated fatty acids (UFAs), such as linoleic acid (LA), oleic acid (OA), α-linolenic acid (ALA), and docosahexaenoic acid (DHA), were not lipotoxic but instead protected microglia against PA-induced decrease in cell viability. Co-treatment of PA with LA, OA, and DHA significantly inhibited FA uptake in PA-treated cells. All UFAs tested induced the incorporation of FAs into and the amount of neutral lipids, while PA did not significantly affect the amount of neutral lipids compared with BSA control.

Long-chain free fatty acids (FFA) play many important roles in cell growth and metabolism. Accumulation of excess saturated fatty acids (SFA) leads to deleterious lipotoxic effects in non-adipose tissues while unsaturated fatty acids (UFA) often exert protective effects against SFA lipotoxicity, yet the lipotoxic effects of SFA in neuronal cells have not been well characterized. This study examined the differential effects of SFA and UFA on the viability of Neuro-2a (N2a) cells and the accumulation of neutral lipids in these cells. Our study found that all the UFA tested, namely oleic acid (OA), linoleic acid (LA), α-linolenic acid (ALA), and docosahexaenoic acid (DHA), were able to abolish PAinduced decrease in cell viability regardless of the position of the double bond or degree of unsaturation, and that 200 μM LA, OA, and DHA significantly enhanced the amount of neutral lipid staining than BSA control while PA did not, suggesting that LA, OA, and DHA, but not PA, increased the amount of neutral lipid synthesis and accumulation. The neutral lipid staining also appeared more in particulates in UFA-treated cells than PAtreated cells, suggesting that UFA, but not PA, enhanced LD formation. We also found that the amount of neutral lipid staining in cells co-treated with UFA and PA was comparable to that in cells treated with BSA or PA alone, and that the neutral lipid staining in cells co-treated with UFA and PA appeared more concentrated in particulates than PA-treated cells, suggesting that UFA may not enhance neutral lipid accumulation, but may increase LD formation in PA-treated cells. Our results suggest that UFA and SFA have differential effects on cell viability, neutral lipid accumulation, and LD formation in N2a cells. Further studies will be needed to examine the role of LD formation in UFA protection against PA lipotoxicity.

Elevated level of palmitic acid (PA), a long-chain saturated fatty acid (SFA), is lipotoxic to many different types of cells including Neuro-2a (N2a) neuroblastoma cells. CD36 is a multifunctional membrane glycoprotein that acts as a fatty acid translocase (FAT) facilitating the transport of long-chain free fatty acids (FFAs) into cells, serves a fatty acid (FA) sensing function in areas including taste buds and the proximal gut, and acts as a scavenger receptor that binds to many ligands, including FAs, collagen, oxidized low-density lipoproteins, and anionic phospholipids. However, the involvement of CD36 in FA uptake and PA lipotoxicity in N2a cells remains unclear. In this study, we examined FA uptake in BSA- and PA-treated N2a cells and investigated the involvement of CD36 in FA uptake and PA lipotoxicity in N2a cells. Our data showed that PA treatment promoted FA uptake in N2a cells, and that treatment with sulfo-N-succinimidyl oleate (SSO), a CD36 inhibitor, significantly decreased FA uptake in BSA- and PA-treated N2a cells, and ameliorated PA-induced decrease of cell viability, decrease of diploid cells, and increase of tetraploid cells. We also found that CD36 knockdown significantly decreased FA uptake in both BSA- and PA-treated cells as compared to their corresponding wild-type controls, and dramatically attenuated PA-induced cell cycle defects in N2a cells. Our data suggest that CD36 may play a critical role in FA uptake and PA lipotoxicity in N2a cells. CD36 may therefore represent a regulatory target against pathologies caused by excess FAs.

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