Exercise Training Induces Mitochondrial Biogenesis and Glucose Uptake in Subcutaneous Adipose Tissue Through eNOS-Dependent Mechanisms

Abstract

Insulin resistance and obesity are associated with a reduction of mitochondrial content in various tissues of mammals. Moreover, a reduced nitric oxide (NO) bioavailability impairs several cellular functions, including mitochondrial biogenesis and insulin-stimulated glucose uptake, two important mechanisms of body adaptation in response to physical exercise. Although these mechanisms have been thoroughly investigated in skeletal muscle and heart, few studies have focused on the effects of exercise on mitochondria and glucose metabolism in adipose tissue. In this study, we compared the in vivo effects of chronic exercise in subcutaneous adipose tissue of wild-type (WT) and endothelial NO synthase (eNOS) knockout (eNOS 2/2 ) mice after a swim training period. We then investigated the in vitro effects of NO on mouse 3T3-L1 and human subcutaneous adipose tissue-derived adipocytes after a chronic treatment with an NO donor: diethylenetriamine-NO (DETA-NO). We observed that swim training increases mitochondrial biogenesis, mitochondrial DNA content, and glucose uptake in subcutaneous adipose tissue of WT but not eNOS 2/2 mice. Furthermore, we observed that DETA-NO promotes mitochondrial biogenesis and elongation, glucose uptake, and GLUT4 translocation in cultured murine and human adipocytes. These results point to the crucial role of the eNOS-derived NO in the metabolic adaptation of subcutaneous adipose tissue to exercise training.Reduced mitochondrial content and/or activity is associated with impaired cell function in several diseases (1,2). In particular, it has been hypothesized that mitochondrial impairment may be involved in the pathogenesis of obesity and insulin resistance and their progression toward type 2 diabetes (3,4), even though the role of mitochondria in health and disease is still under discussion (5,6). At the same time, metabolic disorders are also associated with a reduction of endothelial nitric oxide synthase (eNOS) enzymatic activity (7,8); in fact, mice lacking the eNOS gene are considered a useful murine model for metabolic syndrome because they display typical features, including hypertension, hypertriglyceridemia, endothelial dysfunction, insulin resistance, and visceral obesity (9). It is well known that physical exercise induces profound physiological adaptations in several tissues as a response to increased metabolic requirements. One of the major events induced by physical activity is the upregulation of eNOS gene expression and the consequent

Exercise regulation of adipose tissue

“…[25][26][27] In another study, exercise training by swimming mice for 90 min per day for 30 d resulted in a significant beiging of scWAT as evidenced by increases in Ucp1 and Prdm16. 26 Our work demonstrated that exercise training by voluntary running in a cage containing a wheel for only 11 d resulted in a marked upregulation of numerous beige adipocyte marker genes including Ucp1, Prdm16, Cidea, Elovl3, Pgc1a, Pparg, Cox8b, Dio2, otopetrin, and Tbx1. 21 The wheel cage-trained mice had dramatically increased UCP1 immunofluorescence and the presence of multilocular cells in the scWAT, all of which are consistent with the beiging of scWAT.…”

“…[25][26][27] These beige cells were identified by an increase in multilocular adipocytes and an increase in Ucp1, Prdm16 and other markers of BAT or beiging. [25][26][27] In another study, exercise training by swimming mice for 90 min per day for 30 d resulted in a significant beiging of scWAT as evidenced by increases in Ucp1 and Prdm16. 26 Our work demonstrated that exercise training by voluntary running in a cage containing a wheel for only 11 d resulted in a marked upregulation of numerous beige adipocyte marker genes including Ucp1, Prdm16, Cidea, Elovl3, Pgc1a, Pparg, Cox8b, Dio2, otopetrin, and Tbx1.…”

“…21,23,[25][26][27] In rodent studies, 3-4 weeks of exposure to an enriched environment, which included the presence of a running wheel, resulted in the emergence of beige cells in scWAT. [25][26][27] These beige cells were identified by an increase in multilocular adipocytes and an increase in Ucp1, Prdm16 and other markers of BAT or beiging. [25][26][27] In another study, exercise training by swimming mice for 90 min per day for 30 d resulted in a significant beiging of scWAT as evidenced by increases in Ucp1 and Prdm16.…”

Exercise-induced adaptations to white and brown adipose tissue

“…Exercise-training, defined as regular bouts of physical activity over a span of weeks, months or years, has well-established effects on adipocyte size (Gollisch et al, 2009;Craig et al, 1981), mitochondrial activity (Stanford et al, 2015a,b;Trevellin et al, 2014;Stallknecht et al, 1991), secretion of adipokines (Golbidi and Laher, 2014;Zachwieja et al, 1997;Bradley et al, 2008;Kraemer et al, 1999;Kanaley et al, 2001) and gene expression (Stanford et al, 2015a,b) in both vWAT and scWAT. There are also specific adaptations to each WAT depot, including adaptations to the structural lipidomic profile changes in scWAT (May et al, 2017) and the beiging of scWAT in rodents (Stanford et al, 2015a,b;Sutherland et al, 2009;Trevellin et al, 2014;Boström et al, 2012;Cao et al, 2011;Stanford and Goodyear, 2016) (Fig.…”

“…Beige adipocytes are found intermixed within the WAT and appear morphologically similar to brown adipocytes with multilocular lipid droplets and an abundance of mitochondria (Hirshman et al, 1989;Enerbäck, 2009;Petrovic et al, 2010;Ishibashi and Seale, 2010). In rodents, beige cells can be induced by a variety of stimuli, including β3-selective adrenergic agonists (Ishibashi and Seale, 2010), cold-exposure (Petrovic et al, 2010), exercise (Stanford et al, 2015a,b;Sutherland et al, 2009;Trevellin et al, 2014;Boström et al, 2012;Cao et al, 2011) and an enriched environment (Cao et al, 2011). Upon stimulation, beige adipocytes express very high levels of Ucp1, show increased fuel oxidation and contribute to non-shivering thermogenesis Shabalina et al, 2013).…”