Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Marit Hjorth
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
Gunn-Helen Moen
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia; The Frazer Institute, The University of Queensland, Woolloongabba, Australia; Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
Emily Daubney
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia; Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
Andrea L Hevener
Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States; Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, United States
Departments of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, United States; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, United States
James Hilser
Departments of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, United States; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, United States
Jonas Krag Viken
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Hanne Gulseth
Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway
Frode Norheim
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Background: Physical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking. Methods: We analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using two-sample Mendelian randomization and mice models. Results: Following 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7 and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was positively associated with physical activity and negatively associated with glucose levels in the UK Biobank. In this sample, the association between serum CD300LG and physical activity was significantly stronger in men than in women. Mendelian randomization analysis suggested potential causal relationships between levels of serum CD300LG and fasting glucose, 2 hr glucose after an oral glucose tolerance test, and HbA1c. Additionally, Cd300lg responded to exercise in a mouse model, and we observed signs of impaired glucose tolerance in male, but not female, Cd300lg knockout mice. Conclusions: Our study identified several novel proteins in serum whose levels change in response to prolonged exercise and were significantly associated with body composition, liver fat, and glucose homeostasis. Serum CD300LG increased with physical activity and is a potential causal link to improved glucose levels. CD300LG may be a promising exercise biomarker and a therapeutic target in type 2 diabetes. Funding: South-Eastern Norway Regional Health Authority, Simon Fougners Fund, Diabetesforbundet, Johan Selmer Kvanes’ legat til forskning og bekjempelse av sukkersyke. The UK Biobank resource reference 53641. Australian National Health and Medical Research Council Investigator Grant (APP2017942). Australian Research Council Discovery Early Career Award (DE220101226). Research Council of Norway (Project grant: 325640 and Mobility grant: 287198). The Medical Student Research Program at the University of Oslo. Novo Nordisk Fonden Excellence Emerging Grant in Endocrinology and Metabolism 2023 (NNF23OC0082123). Clinical trial number: clinicaltrials.gov: NCT01803568.
