Regulation of energy metabolism in human skeletal muscle cells : Effects of fatty acids, in vitro exercise and extreme obesity with and without type 2 diabetes

Abstract

Obesity and type 2 diabetes (T2D) are associated with reduced metabolic flexibility and the development of these conditions are positively associated with dietary saturated fatty acids (e.g. palmitic acid) and negatively associated with poly- and monounsaturated fatty acids (e.g. ω-3 eicosapentaenoic acid and oleic acid). Furthermore, obesity is strongly associated with insulin resistance and T2D, however some extremely obese individuals may possess certain characteristics that protect them against developing T2D. Moreover, physical activity plays a central role in both prevention and improvement of these conditions and we wanted to establish an in vitro model for exercise (electrical pulse stimulation) to study these effects. This thesis aimed to explore some aspects of energy metabolism, especially lipid storage and turnover and metabolic flexibility in human skeletal muscle cells. Eicosapentaenoic acid increased metabolic flexibility and lipid accumulation and upregulated interleukin-6 (IL-6) mRNA expression in myotubes from lean individuals. Palmitic acid had a lower lipid accumulation and upregulated adipose triacylglycerol lipase protein expression compared to oleic acid in myotubes. Eicosapentaenoic acid coincubation with palmitic and oleic acid eliminated the differences by increasing palmitic acid accumulation. Furthermore, myotubes showed a higher palmitic acid oxidation than oleic acid oxidation, and palmitic acid upregulated the β-oxidation pathway. Furthermore, a reduced insulin response was observed in myotubes isolated from T2D subjects. Mitochondrial content and lipid accumulation was higher, while lipolysis was lower in extremely obese non-diabetic myotubes compared to cells from extremely obese diabetics. Besides, the metabolic flexibility parameters adaptability was higher and substrateregulated flexibility tended to be higher in non-diabetics. However, myotubes from extremely obese subjects had a higher fatty acid oxidation, but a lower suppression of glucose on fatty acid oxidation than the myotubes from lean subjects. After electrical pulse stimulation of the myotubes derived from lean, healthy donors, number of lipid droplets and IL-6 mRNA expression tended to be higher, while oxidation, mitochondrial content, muscle fiber type I marker expression and insulin sensitivity was higher than in unstimulated myotubes. The results presented in this thesis, from extremely obese diabetic cells and electrical pulse stimulated/fatty acid-treated cells, suggest a favorable role of a higher capacity for intramyocellular lipid accumulation and increased metabolic flexibility with regards to improved insulin sensitivity and glucose metabolism in human skeletal muscle.