title: Mitochondrial substrate availability and its role in lipid-induced insulin resistance and proinflammatory signaling in skeletal muscle.
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 (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.
authors.affiliation: Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, U.K.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lipina
authors.forename: Katherine
authors.initials: K
authors.lastname: Macrae
authors.forename: Tamara
authors.initials: T
authors.lastname: Suhm
authors.forename: Cora
authors.initials: C
authors.lastname: Weigert
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Blachnio-Zabielska
authors.forename: Marcin
authors.initials: M
authors.lastname: Baranowski
authors.forename: Jan
authors.initials: J
authors.lastname: Gorski
authors.forename: Karl
authors.initials: K
authors.lastname: Burgess
authors.forename: Harinder S
authors.initials: HS
authors.lastname: Hundal
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D003847:Deoxyglucose / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D015151:Immunoblotting; D007249:Inflammation / Q000209:etiology / Q000378:metabolism*; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010168:Palmitates / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000963:Antimetabolites; D005230:Fatty Acids, Nonesterified; D010168:Palmitates; D003847:Deoxyglucose