Catoire, Milène2; Alex, Sheril2; Paraskevopulos, Nicolas2; Mattijssen, Frits2; Evers-van Gogh, Inkie3; Schaart, Gert4; Jeppesen, Jacob Fuglsbjerg11; Kneppers, Anita2; Mensink, Marco2; Voshol, Peter J6; Olivecrona, Gunilla7; Tan, Nguan Soon8; Hesselink, Matthijs K C6; Berbée, Jimmy F9; Rensen, Patrick C N9; Kalkhoven, Eric3; Schrauwen, Patrick10; Kersten, Sander2
1 Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, Københavns Universitet2 Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen3 Department of Metabolic Diseases, University Medical Centre Utrecht, Utrecht4 Department of Human Movement Sciences, Maastricht University Medical Centre, Maastricht5 Department of Exercise and Sport Sciences, Faculty of Science, Københavns Universitet6 Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge7 Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå8 School of Biological Sciences, Nanyang Technological University, Singapore9 Department of Endocrinology and Metabolic Diseases and i Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden10 Department of Human Biology, Maastricht University Medical Centre, Maastricht11 Department of Exercise and Sport Sciences, Faculty of Science, Københavns Universitet
Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-δ, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise.
Proceedings of the National Academy of Sciences of the United States of America, 2014, Vol 111, Issue 11