Effects of long-term exercise on plasma adipokine levels and inflammation-related gene expression in subcutaneous adipose tissue in sedentary dysglycaemic, overweight men and sedentary normoglycaemic men of healthy weight

Abstract

Aims/hypothesis Obesity and insulin resistance may be associated with altered expression and secretion of adipokines. Physical activity can markedly improve insulin sensitivity, but the association with adipokines remains largely unknown. In this study, we examined the effects of physical activity on the subcutaneous white adipose tissue (scWAT) secretome and its relationship to insulin sensitivity. Methods As reported previously, we enrolled 26 sedentary, middle-aged men (13 dysglycaemic and overweight; 13 normoglycaemic and of healthy weight) into a 12 week, supervised, intensive physical exercise intervention that included two endurance and two resistance sessions each week. Insulin sensitivity was measured as the glucose infusion rate from a euglycaemic-hyperinsulinaemic clamp. In our previous study, we measured maximum oxygen uptake, upper-and lower-body strength and a range of circulating biomarkers, and quantified adipose tissue depots using MRI and magnetic resonance spectroscopy. We have now performed global mRNA sequencing, microarrays and RT-PCR of scWAT and skeletal muscle biopsies, and quantified selected plasma adipokines by ELISA. Results Insulin sensitivity increased similarly in both dysglycaemic (45%) and normoglycaemic (38%) men after 12 weeks of exercise, as reported previously. mRNA sequencing of scWAT revealed 90 transcripts that responded to exercise in dysglycaemic men, whereas only marginal changes were observed in normoglycaemic men. These results were validated using microarrays and RT-PCR. A total of 62 out of 90 transcripts encoded secreted proteins. Overall, 17 transcripts were upregulated and 73 transcripts were downregulated. Downregulated transcripts included several macrophage markers, and were associated with inflammatory and immune-related pathways. Levels of these immune-related transcripts were enhanced in dysglycaemic men vs normoglycaemic men at baseline, but were normalised after the exercise intervention. Principal component and correlation analyses revealed inverse correlations between levels of these immune-related transcripts and insulin sensitivity at baseline, after the intervention, and for the change between baseline and after the intervention. In addition, levels of these transcripts at baseline could predict exercise-induced improvements in insulin sensitivity. Adipokine levels in scWAT (but not in skeletal muscle) were significantly correlated with corresponding plasma adipokine concentrations, as exemplified by leptin, high-molecular-weight adiponectin and secreted frizzledrelated protein 4 (SFRP4). SFRP4 mRNA was the most exercise-responsive transcript in scWAT from dysglycaemic men, and plasma SFRP4 concentrations were reduced in dysglycaemic men, but not in normoglycaemic men, after 12 weeks of exercise.

Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease

“…Several studies have shown that a high level of fitness (defined by a high activity level with maximal oxygen uptake) negatively associates with visceral adiposity (506)(507)(508), even in subjects with obesity and/or T2DM, suggesting that aerobic exercise contributes to a favorable adipose distribution profile that reduces the risk of metabolic syndrome. Hepatic fat is also mobilized and decreased following intense aerobic exercise (509). Studies in mice suggest that not only visceral fat mass is lost with regular exercise, but subcutaneous and brown fat mass are also diminished (510).…”

Adipose Tissue Immunomodulation: A Novel Therapeutic Approach in Cardiovascular and Metabolic Diseases

“…Exercise and lifestyle modifications lower the mortality risk, improve quality of life and have been extensively studied. Physical activity improves insulin sensitivity and alters AT adipokine expression, which affect whole-body metabolic health in human subjects (512,513). Recent studies highlighted the mechanistic pathways, linking those two interventions with decreasing AT inflammation.…”

“…Zielger et al demonstrated that exercise enhances the antiinflammatory phenotype in VATs of old mice (517). Endurance training regardless of weight loss induced an increase in M2 macrophages in scWAT (513,518). The role of physical activity in thermogenesis and WAT browning is debated as some reported scWAT browning with bicycle training programs while another study failed to find a correlation between aerobic exercises and recruitment of beige adipocytes (519,520).…”

Exercise training improves adipose tissue metabolism and vasculature regardless of baseline glucose tolerance and sex

“…Previous animal and human studies have shown that regular exercise training has beneficial effects on adipose tissue. Regular exercise training has been shown, both in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), to reduce adipose tissue mass, 4 5 adipocyte hypertrophy, adipose tissue inflammation 6 and increase mitochondrial function and biogenesis 7 in humans and rodents. A recent study showed that exercise training influences (increase/decrease) global expression of inflammation-related factors especially in abdominal SAT especially in dysglycemic men.…”