Mitochondrial Substrate Availability and its Role in Lipid-Induced Insulin Resistance and Proinflammatory Signalling in Skeletal Muscle

Christopher Lipina, Katherine Macrae, Tamara Suhm, Cora Weigert, Agnieszka Blachnio-Zabielska, Marcin Baranowksi, Jan Gorski, Karl Burgess, Harinder S. Hundal (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    12 Citations (Scopus)

    Abstract

    The relationship between glucose and lipid metabolism has been of significant interest in understanding the pathogenesis of obesity-induced insulin resistance. To gain insight into this metabolic paradigm, we explored the potential interplay between cellular glucose flux and lipid-induced metabolic dysfunction within skeletal muscle. Here we show that palmitate-induced insulin resistance and pro-inflammation in muscle cells, which is associated with reduced mitochondrial integrity and oxidative capacity, can be attenuated under conditions of glucose-withdrawal or glycolytic inhibition using 2-deoxyglucose (2DG). Importantly, these glucopenic-driven improvements coincide with the preservation of mitochondrial function, and are dependent on palmitate oxidation which becomes markedly enhanced in the absence of glucose. Intriguingly, despite its ability to upregulate mitochondrial palmitate oxidation, glucose withdrawal did not attenuate palmitate-induced increases in total intramyocellular diacylglycerol and ceramide. Furthermore, consistent with our findings in cultured muscle cells, we also report enhanced insulin sensitivity and reduced pro-inflammatory tone in soleus muscle from obese Zucker rats fed a 2DG-supplemented diet. Notably, this improved metabolic status following 2DG dietary intervention is associated with markedly reduced plasma free fatty acids. Collectively, our data highlights the key role that mitochondrial substrate availability plays in lipid-induced metabolic dysregulation both in vitro and in vivo.
    Original languageEnglish
    Pages (from-to)3426-3436
    Number of pages11
    JournalDiabetes
    Volume62
    Issue number10
    DOIs
    Publication statusPublished - Oct 2013

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    Palmitates
    Insulin Resistance
    Skeletal Muscle
    Deoxyglucose
    Lipids
    Glucose
    Muscle Cells
    Zucker Rats
    Ceramides
    Diglycerides
    Lipid Metabolism
    Nonesterified Fatty Acids
    Cultured Cells
    Up-Regulation
    Obesity
    Diet
    Inflammation

    Cite this

    Lipina, Christopher ; Macrae, Katherine ; Suhm, Tamara ; Weigert, Cora ; Blachnio-Zabielska, Agnieszka ; Baranowksi, Marcin ; Gorski, Jan ; Burgess, Karl ; Hundal, Harinder S. / Mitochondrial Substrate Availability and its Role in Lipid-Induced Insulin Resistance and Proinflammatory Signalling in Skeletal Muscle. In: Diabetes. 2013 ; Vol. 62, No. 10. pp. 3426-3436.
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    abstract = "The relationship between glucose and lipid metabolism has been of significant interest in understanding the pathogenesis of obesity-induced insulin resistance. To gain insight into this metabolic paradigm, we explored the potential interplay between cellular glucose flux and lipid-induced metabolic dysfunction within skeletal muscle. Here we show that palmitate-induced insulin resistance and pro-inflammation in muscle cells, which is associated with reduced mitochondrial integrity and oxidative capacity, can be attenuated under conditions of glucose-withdrawal or glycolytic inhibition using 2-deoxyglucose (2DG). Importantly, these glucopenic-driven improvements coincide with the preservation of mitochondrial function, and are dependent on palmitate oxidation which becomes markedly enhanced in the absence of glucose. Intriguingly, despite its ability to upregulate mitochondrial palmitate oxidation, glucose withdrawal did not attenuate palmitate-induced increases in total intramyocellular diacylglycerol and ceramide. Furthermore, consistent with our findings in cultured muscle cells, we also report enhanced insulin sensitivity and reduced pro-inflammatory tone in soleus muscle from obese Zucker rats fed a 2DG-supplemented diet. Notably, this improved metabolic status following 2DG dietary intervention is associated with markedly reduced plasma free fatty acids. Collectively, our data highlights the key role that mitochondrial substrate availability plays in lipid-induced metabolic dysregulation both in vitro and in vivo.",
    author = "Christopher Lipina and Katherine Macrae and Tamara Suhm and Cora Weigert and Agnieszka Blachnio-Zabielska and Marcin Baranowksi and Jan Gorski and Karl Burgess and Hundal, {Harinder S.}",
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    Lipina, C, Macrae, K, Suhm, T, Weigert, C, Blachnio-Zabielska, A, Baranowksi, M, Gorski, J, Burgess, K & Hundal, HS 2013, 'Mitochondrial Substrate Availability and its Role in Lipid-Induced Insulin Resistance and Proinflammatory Signalling in Skeletal Muscle', Diabetes, vol. 62, no. 10, pp. 3426-3436. https://doi.org/10.2337/db13-0264

    Mitochondrial Substrate Availability and its Role in Lipid-Induced Insulin Resistance and Proinflammatory Signalling in Skeletal Muscle. / Lipina, Christopher; Macrae, Katherine; Suhm, Tamara; Weigert, Cora; Blachnio-Zabielska, Agnieszka; Baranowksi, Marcin; Gorski, Jan; Burgess, Karl; Hundal, Harinder S. (Lead / Corresponding author).

    In: Diabetes, Vol. 62, No. 10, 10.2013, p. 3426-3436.

    Research output: Contribution to journalArticle

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    AU - Lipina, Christopher

    AU - Macrae, Katherine

    AU - Suhm, Tamara

    AU - Weigert, Cora

    AU - Blachnio-Zabielska, Agnieszka

    AU - Baranowksi, Marcin

    AU - Gorski, Jan

    AU - Burgess, Karl

    AU - Hundal, Harinder S.

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    N2 - The relationship between glucose and lipid metabolism has been of significant interest in understanding the pathogenesis of obesity-induced insulin resistance. To gain insight into this metabolic paradigm, we explored the potential interplay between cellular glucose flux and lipid-induced metabolic dysfunction within skeletal muscle. Here we show that palmitate-induced insulin resistance and pro-inflammation in muscle cells, which is associated with reduced mitochondrial integrity and oxidative capacity, can be attenuated under conditions of glucose-withdrawal or glycolytic inhibition using 2-deoxyglucose (2DG). Importantly, these glucopenic-driven improvements coincide with the preservation of mitochondrial function, and are dependent on palmitate oxidation which becomes markedly enhanced in the absence of glucose. Intriguingly, despite its ability to upregulate mitochondrial palmitate oxidation, glucose withdrawal did not attenuate palmitate-induced increases in total intramyocellular diacylglycerol and ceramide. Furthermore, consistent with our findings in cultured muscle cells, we also report enhanced insulin sensitivity and reduced pro-inflammatory tone in soleus muscle from obese Zucker rats fed a 2DG-supplemented diet. Notably, this improved metabolic status following 2DG dietary intervention is associated with markedly reduced plasma free fatty acids. Collectively, our data highlights the key role that mitochondrial substrate availability plays in lipid-induced metabolic dysregulation both in vitro and in vivo.

    AB - The relationship between glucose and lipid metabolism has been of significant interest in understanding the pathogenesis of obesity-induced insulin resistance. To gain insight into this metabolic paradigm, we explored the potential interplay between cellular glucose flux and lipid-induced metabolic dysfunction within skeletal muscle. Here we show that palmitate-induced insulin resistance and pro-inflammation in muscle cells, which is associated with reduced mitochondrial integrity and oxidative capacity, can be attenuated under conditions of glucose-withdrawal or glycolytic inhibition using 2-deoxyglucose (2DG). Importantly, these glucopenic-driven improvements coincide with the preservation of mitochondrial function, and are dependent on palmitate oxidation which becomes markedly enhanced in the absence of glucose. Intriguingly, despite its ability to upregulate mitochondrial palmitate oxidation, glucose withdrawal did not attenuate palmitate-induced increases in total intramyocellular diacylglycerol and ceramide. Furthermore, consistent with our findings in cultured muscle cells, we also report enhanced insulin sensitivity and reduced pro-inflammatory tone in soleus muscle from obese Zucker rats fed a 2DG-supplemented diet. Notably, this improved metabolic status following 2DG dietary intervention is associated with markedly reduced plasma free fatty acids. Collectively, our data highlights the key role that mitochondrial substrate availability plays in lipid-induced metabolic dysregulation both in vitro and in vivo.

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