Defining the role of DAG, mitochondrial function, and lipid deposition in palmitate-induced proinflammatory signaling and its counter-modulation by palmitoleate

Macrae, Katherine; Stretton, Clare; Lipina, Christopher; Błachnio-Zabielska, Agnieszka; Baranowski, Marcin; Górski, Jan; Marley, Anna; Hundal, Harinder S.

doi:10.1194/jlr.m036996

Cited by 39 publications

(49 citation statements)

References 62 publications

(74 reference statements)

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“…In contrast, considerable evidence supports the view that insulin sensitivity is positively correlated with supply of MUFAs and PUFAs and that, in many instances, their provision not only promotes beneficial metabolic changes but negate some of the adverse effects associated with SFA oversupply [18], [35], [36]. Indeed, previous work from our group has demonstrated that, unlike PA, provision of MUFAs (e.g.…”

Section: Discussionmentioning

confidence: 79%

“…However, it is apparent, from comparing the net changes, that the ability with which both OA and LOA enhance insulin-dependent Akt phosphorylation is somewhat compromised when cells are also incubated with PA (Fig 6A). We recently demonstrated that PA uptake into myotubes is not affected by co-provision of MUFAs and that under these circumstances there is no reduction in PA-derived ceramide synthesis [18]. Consequently, sustained ceramide generation will activate atypical PKCs that physically associate with and negatively regulate Akt activation [7], [8].…”

Section: Discussionmentioning

confidence: 99%

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Enhanced Insulin Sensitivity Associated with Provision of Mono and Polyunsaturated Fatty Acids in Skeletal Muscle Cells Involves Counter Modulation of PP2A

et al. 2014

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Aims/HypothesisReduced skeletal muscle insulin sensitivity is a feature associated with sustained exposure to excess saturated fatty acids (SFA), whereas mono and polyunsaturated fatty acids (MUFA and PUFA) not only improve insulin sensitivity but blunt SFA-induced insulin resistance. The mechanisms by which MUFAs and PUFAs institute these favourable changes remain unclear, but may involve stimulating insulin signalling by counter-modulation/repression of protein phosphatase 2A (PP2A). This study investigated the effects of oleic acid (OA; a MUFA), linoleic acid (LOA; a PUFA) and palmitate (PA; a SFA) in cultured myotubes and determined whether changes in insulin signalling can be attributed to PP2A regulation.Principal FindingsWe treated cultured skeletal myotubes with unsaturated and saturated fatty acids and evaluated insulin signalling, phosphorylation and methylation status of the catalytic subunit of PP2A. Unlike PA, sustained incubation of rat or human myotubes with OA or LOA significantly enhanced Akt- and ERK1/2-directed insulin signalling. This was not due to heightened upstream IRS1 or PI3K signalling nor to changes in expression of proteins involved in proximal insulin signalling, but was associated with reduced dephosphorylation/inactivation of Akt and ERK1/2. Consistent with this, PA reduced PP2Ac demethylation and tyrosine307phosphorylation - events associated with PP2A activation. In contrast, OA and LOA strongly opposed these PA-induced changes in PP2Ac thus exerting a repressive effect on PP2A.Conclusions/InterpretationBeneficial gains in insulin sensitivity and the ability of unsaturated fatty acids to oppose palmitate-induced insulin resistance in muscle cells may partly be accounted for by counter-modulation of PP2A.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Enhanced Insulin Sensitivity Associated with Provision of Mono and Polyunsaturated Fatty Acids in Skeletal Muscle Cells Involves Counter Modulation of PP2A

et al. 2014

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“…It is conceivable that this action of palmitoleate may arise from its antagonizing action on IB␣ degradation activity because this is an upstream signal for inflammatory cytokine production (43,44). Palmitoleate can similarly antagonize the palmitate-induced NFB activation in myotubes (55).…”

Section: Discussionmentioning

confidence: 97%

Palmitoleate Reverses High Fat-induced Proinflammatory Macrophage Polarization via AMP-activated Protein Kinase (AMPK)

Chan

Pillon

Sivaloganathan

et al. 2015

Journal of Biological Chemistry

159

171

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Background: Elevated saturated fats during obesity activate proinflammatory pathways in macrophages, contributing to insulin resistance. Results: The monounsaturated fatty acid cis-palmitoleate antagonizes saturated fat-induced proinflammatory macrophage polarization through an AMPK-dependent mechanism. Conclusion: Palmitoleate is a lipid mediator that confers an anti-inflammatory macrophage phenotype. Significance: Understanding lipid-mediated macrophage polarization is critical to develop nutritional or cell-based strategies to combat insulin resistance.

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“…Because lipid species of different fatty acid compositions may be important regulators of cellular proliferation (12), inflammation (27), and ER stress-induced apoptosis (4), it is important to delineate the specific lipid signature of NAFLD, as it could provide insights into the signaling pathways relevant in the progression of the condition. In a comparison of murine with human liver tissue samples, mice maintained on a HFD provide a reproducible model of human NAFLD in regard to the specificity of diacylglycerol (DAG) and other lipid species in the liver (14).…”

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confidence: 99%

Analysis of the liver lipidome reveals insights into the protective effect of exercise on high-fat diet-induced hepatosteatosis in mice

Jordy

Kraakman

Gardner

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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The accumulation of lipid at ectopic sites, including the skeletal muscle and liver, is a common consequence of obesity and is associated with tissue-specific and whole body insulin resistance. Exercise is well known to improve insulin resistance by mechanisms not completely understood. We performed lipidomic profiling via mass spectrometry in liver and skeletal muscle samples from exercise-trained mice to decipher the lipid changes associated with exercise-induced improvements in whole body glucose metabolism. Obesity and insulin resistance were induced in C57BL/6J mice by high-fat feeding for 4 wk. Mice then underwent an exercise training program (treadmill running) 5 days/wk (Ex) for 4 wk or remained sedentary (Sed). Compared with Sed, Ex displayed improved ( P < 0.01) whole body metabolism as measured via an oral glucose tolerance test. Deleterious lipid species such as diacylglycerol ( P < 0.05) and cholesterol esters ( P < 0.01) that accumulate with high-fat feeding were decreased in the liver of trained mice. Furthermore, the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) (the PC/PE ratio), which is associated with membrane integrity and linked to hepatic disease progression, was increased by training ( P < 0.05). These findings occurred without corresponding changes in the skeletal muscle lipidome. A concomitant decrease ( P < 0.05) was observed for the fatty acid transporters CD36 and FATP4 in the liver, suggesting that exercise stimulates a coordinated reduction in fatty acid entry into hepatocytes. Given the important role of the liver in the regulation of whole body glucose homeostasis, hepatic lipid regression may be a key component by which exercise can improve metabolism.

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Defining the role of DAG, mitochondrial function, and lipid deposition in palmitate-induced proinflammatory signaling and its counter-modulation by palmitoleate

Cited by 39 publications

References 62 publications

Enhanced Insulin Sensitivity Associated with Provision of Mono and Polyunsaturated Fatty Acids in Skeletal Muscle Cells Involves Counter Modulation of PP2A

Enhanced Insulin Sensitivity Associated with Provision of Mono and Polyunsaturated Fatty Acids in Skeletal Muscle Cells Involves Counter Modulation of PP2A

Palmitoleate Reverses High Fat-induced Proinflammatory Macrophage Polarization via AMP-activated Protein Kinase (AMPK)

Analysis of the liver lipidome reveals insights into the protective effect of exercise on high-fat diet-induced hepatosteatosis in mice

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