Nutrient regulation of energy metabolism in relation to obesity and type 2 diabetes
Appears in the following Collection
AbstractOver the past decades many western countries have witnessed an epidemic rise in obesity, insulin resistance and type 2 diabetes. There clearly is a link between increased fat storage and decreased insulin sensitivity leading to type 2 diabetes, but the mechanistic explanations have been difficult to pinpoint biochemically and genetically.
In this thesis we have observed that there likely are differences in the way skeletal muscle myotubes, derived from type 2 diabetic or healthy controls metabolize fatty acids and respond towards various lipids. We have observed that T2D myotubes on average have a reduced capacity for mitochondrial fatty acids oxidation as compared to myotubes derived from healthy donors. During periods of high fatty acid load, this difference in oxidative capacity may either result in ectopic storage of intramyocellular triacylglycerols imTAG or an increased level of fatty acid metabolic intermediates that may further interfere with insulin signaling. Preincubation of myotubes with eicosapentaenoic acid (EPA) resulted in enhanced fatty acid uptake and storage of imTAG, but also reduced levels of total intracellular acyl-CoA with improved glucose oxidation and unchanged insulin mediated glucose uptake. Preincubetion with the sulfur modified fatty acid analogue tetradecylthioacetic acid (TTA) improved mitochondrial fatty acid oxidation in both T2D and control myotubes, and may thus help alleviate this metabolic difference in T2D. TTA given as a supplement to rodents fed a high fat diet for 7 weeks resulted in 40% reduced weight gain and similar marked reductions in white adipose tissue mass. TTA has previously been shown to activate all peroxisomal proliferator activated receptors (PPARs), and the reduced weight gain possibly resulted because of hepatic PPARα activation, increasing energy expenditure through some unknown mechanism likely involving ectopic uncoupling protein 3 (ucp3) expression.
List of publications
Paper I Kase ET, Wensaas AJ, Aas V, Højlund K, Levin K, Thoresen GH, Beck-Nielsen H, Rustan AC, Gaster M. Skeletal muscle lipid accumulation in type 2 diabetes may involve the liver X receptor pathway. Diabetes. 2005; 54:1108-15. DOI: 10.2337/diabetes.54.4.1108
Paper II Wensaas AJ, Rustan AC, Just M, Berge RK, Drevon CA, Gaster M. Fatty acid incubation of myotubes from humans with type 2 diabetes leads to enhanced release of beta-oxidation products because of impaired fatty acid oxidation: effects of tetradecylthioacetic acid and eicosapentaenoic acid. Diabetes. 2009; 58:527-35. DOI: 10.2337/db08-1043
Paper III Wensaas AJ, Rustan AC, Lövstedt K, Kull B, Wikström S, Drevon CA, Hallén S. Cell-based multiwell assays for the detection of substrate accumulation and oxidation. J Lipid Res. 2007; 48:961-7. DOI: 10.1194/jlr.D600047-JLR200
Paper IV Wensaas AJ, Rustan AC, Rokling-Andersen MH, Caesar R, Jensen J, Kaalhus O, Graff BA, Gudbrandsen OA., Berge RK., Drevon CA. Dietary supplementation of tetradecylthioacetic acid increases feed intake but reduces body weight gain and adipose depot sizes in rats fed high-fat diets. Diabetes Obes Metab. Accepted for publication 2009 May 9. DOI: 10.1111/j.1463-1326.2009.01092.x