Oleate protects against palmitate-induced insulin resistance in L6 myotubes

School of Life and Health Sciences, Aston University, Birmingham, UK.
The British journal of nutrition (Impact Factor: 3.45). 08/2009; 102(11):1557-63. DOI: 10.1017/S0007114509990948
Source: PubMed


Oleate has been shown to protect against palmitate-induced insulin resistance. The present study investigates mechanisms involved in the interaction between oleate and palmitate on insulin-stimulated glucose uptake by L6 skeletal muscle cells. L6 myotubes were cultured for 6 h with palmitate or oleate alone, and combinations of palmitate with oleate, with and without phosphatidylinositol 3-kinase (PI3-kinase) inhibition. Insulin-stimulated glucose uptake, measured by uptake of 2-deoxy-d-[3H]glucose, was almost completely prevented by 300 microm-palmitate. Cells incubated with oleate up to 750 micromol/l maintained a significant increase in insulin-stimulated glucose uptake. Co-incubation of 50-300 microm-oleate with 300 microm-palmitate partially prevented the decrease in insulin-stimulated glucose uptake associated with palmitate. Adding the PI3-kinase inhibitors wortmannin (10- 7 mol/l) or LY294002 (25 micromol/l) to 50 microm-oleate plus 300 microm-palmitate significantly reduced the beneficial effect of oleate against palmitate-induced insulin resistance, indicating that activation of PI3-kinase is involved in the protective effect of oleate. Thus, the prevention of palmitate-induced insulin resistance by oleate in L6 muscle cells is associated with the ability of oleate to maintain insulin signalling through PI3-kinase.

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Available from: Helen R Griffiths, Jan 15, 2014
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    • "Palmitate and palmitoleate have distinct direct effects upon insulin-stimulated glucose disposal in L6 myotubes (Dimopoulos et al., 2006), but the effects of palmitoleate were not shown to be mediated through a protective effect on insulin signalling previously . However, others have shown that oleate protects against the effects of palmitate by reducing the impairment in PI3K signalling (Coll et al., 2008; Gao et al., 2009) and through anti-inflammatory effects (Coll et al., 2008), including prevention of MAPK activation (Kadotani et al., 2009). This is likely mediated through reduced synthesis of ceramide and/or diacylglycerol in palmitate-treated myotubes (Chavez and Summers, 2003), rather than accumulation of the more inert triacylglycerol and this mechanism may also result in increased pro-inflammatory cytokine production by macrophages (Schilling et al., 2013). "
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    ABSTRACT: Obesity and saturated fatty acid (SFA) treatment are both associated with skeletal muscle insulin resistance (IR) and increased macrophage infiltration. However, the relative effects of SFA and unsaturated fatty acid (UFA)-activated macrophages on muscle are unknown. Here, macrophages were treated with palmitic acid, palmitoleic acid or both and the effects of the conditioned medium (CM) on C2C12 myotubes investigated. CM from palmitic acid-treated J774s (palm-mac-CM) impaired insulin signalling and insulin-stimulated glycogen synthesis, reduced Inhibitor κBα and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in myotubes. p38 MAPK inhibition or siRNA partially ameliorated these defects, as did addition of tumour necrosis factor-α blocking antibody to the CM. Macrophages incubated with both FAs generated CM that did not induce IR, while palmitoleic acid-mac-CM alone was insulin sensitising. Thus UFAs may improve muscle insulin sensitivity and counteract SFA-mediated IR through an effect on macrophage activation.
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    • "Coincubation of palmitate with BSA alone had a much smaller but still significant effect (Fig. 1B). Other studies have shown a similar effect in myotubes exposed to palmitate with/without BSA [35] and that even BSA alone has some anti-oxidative [42] and anti-apoptotic [43] actions. However, as shown in the results of Figs. "
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    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 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.
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    • "Furthermore, treatment with antioxidants prevented the development of insulin resistance in both cell culture and ex vivo experimental models [15,16,18]. Antioxidants also partially prevented cellular insulin resistance caused by tumor necrosis factor-alpha (TNFα), glucocorticoids, and the saturated fatty acid palmitic acid, suggesting that oxidative stress plays a key role in their action on glucose metabolism [19,20]. Together, these data show that oxidative stress can both directly and indirectly inhibit glucose metabolism. "
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