Abstract
The chain length of saturated fatty acids may dictate their impact on inflammation and mitochondrial dysfunction, two pivotal players in the pathogenesis of insulin resistance. However, these paradigms have only been investigated in animal models and cell lines so far. Thus, the aim of this study was to compare the effect of palmitic (PA) (16:0) and lauric (LA) (12:0) acid on human primary myotubes mitochondrial health and metabolic inflammation. Human primary myotubes were challenged with either PA or LA (500 μM). After 24 h, the expression of interleukin 6 (IL-6) was assessed by quantitative polymerase chain reaction (PCR), whereas Western blot was used to quantify the abundance of the inhibitor of nuclear factor κB (IκBα), electron transport chain complex proteins and mitofusin-2 (MFN-2). Mitochondrial membrane potential and dynamics were evaluated using tetraethylbenzimidazolylcarbocyanine iodide (JC-1) and immunocytochemistry, respectively. PA, contrarily to LA, triggered an inflammatory response marked by the upregulation of IL-6 mRNA (11-fold; P < 0.01) and a decrease in IκBα (32%; P < 0.05). Furthermore, whereas PA and LA did not differently modulate the levels of mitochondrial electron transport chain complex proteins, PA induced mitochondrial fragmentation (37%; P < 0.001), decreased MFN-2 (38%; P < 0.05), and caused a drop in mitochondrial membrane potential (11%; P < 0.01) compared to control, with this effect being absent in LA-treated cells. Thus, LA, as opposed to PA, did not trigger pathogenetic mechanisms proposed to be linked with insulin resistance and therefore represents a healthier saturated fatty acid choice to potentially preserve skeletal muscle metabolic health.
Highlights
There is an exponential increase in the incidence of obesity and type 2 diabetes mellitus (T2DM) in the developed and developing countries, [1]
Metabolic inflammation and the activation of the NFκB signalling pathway was investigated in order to assess the difference between PA and LA in their ability to trigger an inflammatory response
PA-induced decrease in IκBα marks the activation of the NFκB signalling pathway, which was further confirmed by the upregulation of interleukin 6 (IL-6), a NFκB target gene [46], compared to bovine serum albumin (BSA) and LA-treated cells (p < 0.01) (Figure 1C)
Summary
There is an exponential increase in the incidence of obesity and type 2 diabetes mellitus (T2DM) in the developed and developing countries, [1]. Individuals affected by T2DM are at higher risk of developing severe health consequences including cardiovascular disease, nephropathy, and neuropathy [2]. This metabolic disorder is emerging as a risk factor for the development of neurodegenerative diseases including Parkinson and Alzheimer disease [3, 4]. Insulin resistance is the hallmark of T2DM and develops in the skeletal muscle decades before pancreatic β-cells become dysfunctional and overt hyperglycaemia develops [5]. In terms of the mechanisms underpinning the onset of skeletal muscle insulin resistance, mitochondrial dysfunction and metabolic inflammation have been reported to play a pivotal role [6,7,8]. With regard to metabolic inflammation, the activation of proinflammatory nuclear factor κ light-chain enhancer of activated B cells (NFκB) signalling and c-Jun N-terminal kinases (JNKs) have been reported to impede insulin signal transduction pathway, underpinned by the serine phosphorylation of insulin receptor substrate [10, 11]
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