Quality over Quantity – Influence of Fatty Acid Saturation on Neuronal Insulin Resistance

Background: The prevalence of type 2 diabetes (T2D) continues to rise, with almost one in ten people in Germany now affected ([1]). A known cause for T2D is unhealthy nutrition, more precisely an excessive amount of consumed macronutrients, e. g. fat. While saturated long chain fatty acids are known to have adverse effects on metabolic health and insulin sensitivity, unsaturated fatty acids, such as oleic acid and α-linolenic acid have been shown to improve various health issues and are important for brain function ([2] [3] [4]). Therefore the aim was to investigate the effects and differences of saturated versus unsaturated fatty acids on insulin sensitivity of neuronal cells.

Methods: CLU468 cells, an insulin and leptin sensitive, hypothalamic cell line, were treated with three different fatty acids: stearic acid (SA), oleic acid (OA) and α-linolenic acid (ALA), differently saturated C:18 fatty acids. The viability of the cells after treatment with the different fatty acids was assessed with MTT assays. The insulin sensitivity and activation of negative modulators of insulin signalling was assessed by determining the phosphorylation of the proteins. To investigate possible mechanisms of the SA induced alterations in insulin sensitivity, the expression of different genes and activation of insulin signalling modulators were assessed.

Results: The viability of CLU468 cells was reduced by approximately 25% after treatment with 100 µM SA for 16 hours but remained unchanged after treating the cells with 100 µM OA or ALA for 16 hours. When treated with 100 µM SA and 100 µM OA or ALA simultaneously, the cell viability was not changed. Already 1h of treatment with 100 µM SA, but not OA or ALA caused a decrease in insulin sensitivity in vitro. This was characterized by a reduced phosphorylation of the downstream target Akt by approximately 40% upon acute insulin stimulation. While SA causes a decrease in insulin sensitivity of CLU468 cells, no molecular signs of ER stress, mitochondrial dysfunction or aberrant activation of TLR4 signalling were observed, evidenced by unaltered gene expression of Socs3, Atf4 and Atf6 and phosphorylation of JNK, IKK and IκBα. When the cells were treated with SA and OA or ALA simultaneously the decrease in Akt phosphorylation was no longer observed. The long chain saturated fatty acid SA causes decreased insulin sensitivity while the unsaturated fatty acids OA and ALA do not and can even prevent the negative effect of stearic acid on insulin sensitivity.

Summary: SA causes a decrease of CLU468 cell viability and insulin resistance at the level of Akt phosphorylation. The unsaturated fatty acids OA and ALA prevent SA induced insulin resistance and decreased cell viability.

 

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• Literatur

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Publication History

Article published online:
28 May 2025