Mitochondrial Substrate Availability and Its Role in Lipid-Induced Insulin Resistance and Proinflammatory Signaling in Skeletal Muscle
Open accessAbstract
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 (PA)-induced insulin resistance and proinflammation 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 PA oxidation, which becomes markedly enhanced in the absence of glucose. Intriguingly, despite its ability to upregulate mitochondrial PA oxidation, glucose withdrawal did not attenuate PA-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 proinflammatory tone in soleus muscle from obese Zucker rats fed a 2DG-supplemented diet. Notably, this improved metabolic status after 2DG dietary intervention is associated with markedly reduced plasma free fatty acids. Collectively, our data highlight the key role that mitochondrial substrate availability plays in lipid-induced metabolic dysregulation both in vitro and in vivo.
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Obesity in rodents and chronic oversupply of metabolic fuel to skeletal muscle cells in vitro is associated with an increase in proinflammatory NFkB signalling and insulin resistance.
“We, and others, have also previously demonstrated that obesity in rodents and chronic oversupply of metabolic fuel to skeletal muscle cells in vitro is associated with an increase in proinflammatory NFkB signalling and insulin resistance [17, 25, 26].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [17]
Heightened NFkB signalling associated with sustained nutrient oversupply, as occurs during obesity, plays an important role in lipid-induced insulin resistance and metabolic dysfunction in skeletal muscle both in vitro and in vivo.
“We have previously shown that heightened NFkB signalling associated with sustained nutrient oversupply, as occurs during obesity, plays an important role in lipid-induced insulin resistance and metabolic dysfunction in skeletal muscle both in vitro and in vivo [17].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [17]
Cox4.1 cellular abundance declines dramatically when the presence of PA in GLC-containing media is raised above 0.4 mM.
“we have shown previously that its cellular abundance declines dramatically when the presence of PA in GLC-containing media is raised above 0.4 mM [17, 31].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [17]
Suppressing NFkB activation in fuel-overloaded myotubes with BI605906 or 2DG antagonises loss of UCP3 and ANT-1, increases mitochondrial proton leak, and improves insulin sensitivity in L6 myotubes and in muscle of obese Zucker rats.
“The fact that suppressing NFkB activation in fuel-overloaded myotubes with BI605906 or 2DG antagonises loss of UCP3 and ANT-1 and that, under these circumstances, we not only see a measurable increase in mitochondrial proton leak, but observe improved insulin sensitivity in L6 myotubes (Fig. 9) and in muscle of obese Zucker rats [17] is fully congruent with this view.”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [17]
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Self-citationMitochondrial involvement in skeletal muscle insulin resistance: A case of imbalanced bioenergetics
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- Authors
- Lipina, C., Macrae, K., Suhm, T., Weigert, C., Blachnio-Zabielska, A., Baranowski, M., Gorski, J., Burgess, K., & Hundal, H. S.
- Affiliations
- University of Dundee (GB)
- University of Tübingen (DE)
- 4Department of Physiology, Medical University of Bialystok, Bialystok, Poland
- Medical University of Białystok (PL)
- University of Glasgow (GB)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2013-09-17
- Volume
- 62
- Issue
- 10
- Pages
- 3426-3436
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3781443
- OpenAlex
- W2139528536
- Cited by
- 26
- References
- 50
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 6 · 2014: 2
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Site cant be reached (submittedVersion)
- Funders
- Diabetes UK (10/0004045)
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- palmitate, lipid-induced insulin resistance, skeletal muscle, glucose deprivation, 2-deoxyglucose, mitochondrial fatty acid oxidation, mitochondrial integrity, oxidative capacity, diacylglycerol, ceramide, pro-inflammatory signaling, soleus muscle, Zucker rats, plasma free fatty acids, obesity
- MeSH terms
- Animals, Antimetabolites, Deoxyglucose, Fatty Acids, Nonesterified, Glycolysis, Inflammation, Insulin Resistance, Male, Mitochondria, Obesity, Oxidation-Reduction, Palmitates, Rats, Zucker, Immunoblotting, Signal Transduction, Up-Regulation, Oxidative Stress, Muscle, Skeletal, Lipid Metabolism, Rats
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