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      Palmitate but Not Oleate Exerts a Negative Effect on Oxygen Utilization in Myoblasts of Patients with the m.3243A>G Mutation: A Pilot Study

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          Abstract

          It is known that exposure to excess saturated fatty acids, especially palmitate, can trigger cellular stress responses interpreted as lipotoxicity. The effect of excessive free fatty acids on oxidative phosphorylation capacity in myoblasts of patients with the m.3243A>G mutation was evaluated with the mitochondrial (Mito) stress test using a Seahorse XF96 analyzer. ß-oxidation, measured with the Seahorse XF96 analyzer, was similar in patients and controls, and reduced in both patients and controls at 40 °C compared to 37 °C. Mito stress test in the absence of fatty acids showed lower values in patients compared to controls. The mitochondrial activity and ATP production rates were significantly reduced in presence of palmitate, but not of oleate in patients, showing a negative effect of excessive palmitate on mitochondrial function in patients. Diabetes mellitus is a frequent symptom in patients with m.3243A>G mutation. It can be speculated that the negative effect of palmitate on mitochondrial function might be related to diacylglycerols (DAG) and ceramides (CER) mediated insulin resistance. This might contribute to the elevated risk for diabetes mellitus in m.3243A>G patients.

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          Dietary fat, insulin sensitivity and the metabolic syndrome.

          G. Riccardi, R. Giacco, A A Rivellese (2004)
          Insulin resistance is the pathogenetic link underlying the different metabolic abnormalities clustering in the metabolic syndrome. It can be induced by different environmental factors, including dietary habits. Consumption of energy-dense/high fat diets is strongly and positively associated with overweight that, in turn, deteriorates insulin sensitivity, particularly when the excess of body fat is located in abdominal region. Nevertheless the link between fat intake and overweight is not limited to the high-energy content of fatty foods; the ability to oxidize dietary fat is impaired in some individuals genetically predisposed to obesity. Insulin sensitivity is also affected by the quality of dietary fat, independently of its effects on body weight. Epidemiological evidence and intervention studies clearly show that in humans saturated fat significantly worsen insulin-resistance, while monounsaturated and polyunsaturated fatty acids improve it through modifications in the composition of cell membranes which reflect at least in part dietary fat composition. A recent multicenter study (KANWU) has shown that shifting from a diet rich in saturated fatty acids to one rich in monounsaturated fat improves insulin sensitivity in healthy people while a moderate alpha-3 fatty acids supplementation does not affect insulin sensitivity. There are also other features of the metabolic syndrome that are influenced by different types of fat, particularly blood pressure and plasma lipid levels. Most studies show that alpha-3 fatty acids reduce blood pressure in hypertensive but not in normotensive subjects while shifting from saturated to monounsaturated fat intake reduces diastolic blood pressure. In relation to lipid abnormalities alpha-3 fatty acids reduce plasma triglyceride levels but in parallel, increase LDL cholesterol. Substitution of unsaturated fat for saturated fat not only reduces LDL cholesterol but contributes also to reduce plasma triglycerides in insulin resistant individuals. In conclusion, there is evidence available in humans indicating that dietary fat quality influences insulin sensitivity and associated metabolic abnormalities. Therefore, prevention of the metabolic syndrome has to be targeted: (1) to correct overweight by reducing the energy density of the habitual diet (i.e., fat intake) and (2) to improve insulin sensitivity and associated metabolic abnormalities through a reduction of dietary saturated fat, partially replaced, when appropriate, by monounsaturated and polyunsaturated fats. Copyright 2004 Elsevier Ltd.
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            The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms

            Jan Korbecki, Karolina Bajdak-Rusinek (2019)
            Palmitic acid is a saturated fatty acid whose blood concentration is elevated in obese patients. This causes inflammatory responses, where toll-like receptors (TLR), TLR2 and TLR4, play an important role. Nevertheless, palmitic acid is not only a TLR agonist. In the cell, this fatty acid is converted into phospholipids, diacylglycerol and ceramides. They trigger the activation of various signaling pathways that are common for LPS-mediated TLR4 activation. In particular, metabolic products of palmitic acid affect the activation of various PKCs, ER stress and cause an increase in ROS generation. Thanks to this, palmitic acid also strengthens the TLR4-induced signaling. In this review, we discuss the mechanisms of inflammatory response induced by palmitic acid. In particular, we focus on describing its effect on ER stress and IRE1α, and the mechanisms of NF-κB activation. We also present the mechanisms of inflammasome NLRP3 activation and the effect of palmitic acid on enhanced inflammatory response by increasing the expression of FABP4/aP2. Finally, we focus on the consequences of inflammatory responses, in particular, the effect of TNF-α, IL-1β and IL-6 on insulin resistance. Due to the high importance of macrophages and the production of proinflammatory cytokines by them, this work mainly focuses on these cells.
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              Lipid-induced insulin resistance: unravelling the mechanism.

              Varman Samuel, Kitt Falk Petersen, Gerald I. Shulman (2010)
              Insulin resistance has long been associated with obesity. More than 40 years ago, Randle and colleagues postulated that lipids impaired insulin-stimulated glucose use by muscles through inhibition of glycolysis at key points. However, work over the past two decades has shown that lipid-induced insulin resistance in skeletal muscle stems from defects in insulin-stimulated glucose transport activity. The steatotic liver is also resistant to insulin in terms of inhibition of hepatic glucose production and stimulation of glycogen synthesis. In muscle and liver, the intracellular accumulation of lipids-namely, diacylglycerol-triggers activation of novel protein kinases C with subsequent impairments in insulin signalling. This unifying hypothesis accounts for the mechanism of insulin resistance in obesity, type 2 diabetes, lipodystrophy, and ageing; and the insulin-sensitising effects of thiazolidinediones. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Life (Basel)
                Journal ID (iso-abbrev): Life (Basel)
                Journal ID (publisher-id): life
                Title: Life
                Publisher: MDPI
                ISSN (Electronic): 2075-1729
                Publication date (Electronic): 16 September 2020
                Publication date Collection: September 2020
                Volume: 10
                Issue: 9
                Electronic Location Identifier: 204
                Affiliations
                [1 ]Department of Neurology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany; helena@ 123456schieffers.de (H.S.); annemarie.thaele@ 123456uk-halle.de (A.T.); stephan.zierz@ 123456medizin.uni-halle.de (S.Z.)
                [2 ]Center for Basic Medical Research, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany; samiya.al-robaiy@ 123456uk-halle.de
                [3 ]Department of Neurology, Ulm University, 89070 Ulm, Germany; diana.lehmann@ 123456rku.de
                Author notes
                [* ]Correspondence: Leila.scholle@ 123456medizin.uni-halle.de ; Tel.: +49-345-557-3628; Fax: +49-345-557-3505
                Article
                Publisher ID: life-10-00204
                DOI: 10.3390/life10090204
                PMC ID: 7555433
                PubMed ID: 32947855
                SO-VID: 0d81fba7-2d78-4ea0-adca-f646d9668ea4
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 05 August 2020
                Date accepted : 15 September 2020
                Categories
                Subject: Article

                Keywords: fatty acid oxidation,palmitate,oleate,m.3243a>g mutation
                Data availability:
                Keywords: fatty acid oxidation, palmitate, oleate, m.3243a>g mutation

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