We investigate the effects of aerobic exercise training (AET) on the thermogenic response, substrate metabolism and renin angiotensin system (RAS) in the subcutaneous white adipose tissue (SC-WAT) of mice fed cafeteria diet (CAF). Male C57BL/6J mice were assigned into groups CHOW-SED (chow diet, sedentary; n = 10), CHOW-TR (chow diet, trained; n = 10), CAF-SED (CAF, sedentary; n = 10) and CAF-TR (CAF, trained; n = 10). AET consisted in running sessions of 60 min at 60% of maximal speed, five days per week for eight weeks. The CAF-SED group showed higher body weight and adiposity, glucose intolerance and insulin resistance (IR), while AET prevented such damages in CAF-TR group. AET reduced the p-AKT/t-AKT ratio and increased ATGL expression in CHOW-TR and CAF-TR groups and increased t-HSL and p-HSL/t-HSL ratio in CAF-TR. AET prevented adipocyte hypertrophy in CAF-TR group and increased UCP-1 protein expression only in CHOW-TR. Serum ACE2 increased in CHOW-TR and CAF-TR groups, and Ang (1–7) increased in the CHOW-TR group. In the SC-WAT, CAF-TR group increased the expression of AT1, AT2 and Mas receptors, whereas CHOW-TR increased Ang (1–7) and Ang (1–7)/Ang II ratio in SC-WAT. No changes were observed in ACE and Ang II. Positive correlations were observed between UCP-1 and kITT (r = 0.6), between UCP-1 and Ang (1–7) concentration (r = 0.6), and between UCP-1 and Ang (1–7)/Ang II ratio (r = 0.7). In conclusion, the AET prevented obesity and IR, reduced insulin signaling proteins and increased lipolysis signaling proteins in the SC-WAT. In addition, the CAF diet precludes the AET-induced thermogenic response and the partial modulation of the RAS suggests that the protective effect of AET against obesity and IR could not be associated with SC-WAT RAS.

Background We investigate the effect of aerobic physical training (APT) on muscle morphofunctional markers and Angiotensin Converting Enzyme 2/Angiotensin 1-7/Mas receptor (ACE2/Ang 1-7/Mas) axis in an obesity-linked insulin resistance (IR) animal model induced by cafeteria diet (CAF). Methods Male C57BL/6J mice were assigned into groups CHOW-SED (chow diet, sedentary; n = 10), CHOW-TR (chow diet, trained; n = 10), CAF-SED (n = 10) and CAF-TR (n = 10). APT consisted in running sessions of 60 min at 60% of maximal speed, 5 days per week for 8 weeks. Results Trained groups had lower body weight and adiposity compared with sedentary groups. CAF-TR improved the glucose and insulin tolerance tests compared with CAF-SED group (AUC = 28.896 ± 1589 vs. 35.200 ± 1076 mg dL−1 120 min−1; kITT = 4.1 ± 0.27 vs. 2.5 ± 0.28% min−1, respectively). CHOW-TR and CAF-TR groups increased exercise tolerance, running intensity at which VO2 max was reached, the expression of p-AMPK, p-ACC and PGC1-α proteins compared with CHOW-SED and CAF-SED. Mithocondrial protein expression of Mfn1, Mfn2 and Drp1 did not change. Lipid deposition reduced in CAF-TR compared with CAF-SED group (3.71 vs. 5.53%/area), but fiber typing, glycogen content, ACE2 activity, Ang 1-7 concentration and Mas receptor expression did not change. Conclusions The APT prevents obesity-linked IR by modifying the skeletal muscle phenotype to one more oxidative independent of changes in the muscle ACE2/Ang 1-7/Mas axis.

Fibroblast growth factor 21 (FGF-21) is a protein that is involved in the regulation of glucose, lipids, and energy metabolism. To act on target tissues, endocrine FGF-21 binds preferably to FGF receptor 1 (FGFR1) in the presence of the coreceptor named β-klotho (KLB). Some of the effects of FGF-21 include increased fatty acid oxidation, glucose uptake, insulin sensitivity, and thermogenesis, which can regulate body weight and glycemia control. By exerting such metabolic effects, the therapeutic potential of FGF-21 for the treatment of obesity and diabetes has been investigated. Physical exercise has been widely used for the prevention and treatment of obesity. Several mechanisms mediate the effects of physical exercise, including the FGF-21 pathway. Studies have shown that physical exercise increases the concentration of circulating and tissue FGF-21 in animals, while contradictory results are still observed in humans. Considering the metabolic role of FGF-21 and the chance of physical exercise to induce FGF-21 secretion, in this review we explore the potential of physical exercise-induced FGF-21 modulation as a strategy for prevention and treatment of obesity.

Obesity is associated with increased risk of several chronic diseases and the loss of disease-free years, which has increased the focus of much research for the discovery of therapy to combat it. Under healthy conditions, women tend to store more fat in subcutaneous deposits. However, this sexual dimorphism tends to be lost in the presence of comorbidities, such as type 2 diabetes mellitus (T2DM). Aerobic physical exercise (APE) has been applied in the management of obesity, however, is still necessary to better understand the effects of APE in obese female. Thus, we investigated the effect of APE on body weight, adiposity, exercise tolerance and glucose metabolism in female ob/ob mice. Eight-weeks-old female wild-type C57BL/6J and leptin-deficient ob/ob mice (Lepob) were distributed into three groups: wild-type sedentary group (Wt; n = 6), leptin-deficient sedentary group (LepobS; n = 5) and leptin-deficient trained group (LepobT; n = 8). The LepobT mice were subjected to 8 weeks of aerobic physical exercise (APE) at 60% of the maximum velocity achieved in the running capacity test. The APE had no effect in attenuating body weight gain, and did not reduce subcutaneous and retroperitoneal white adipose tissue (SC-WAT and RP-WAT, respectively) and interscapular brown adipose tissue (iBAT) weights. The APE neither improved glucose intolerance nor insulin resistance in the LepobT group. Also, the APE did not reduce the diameter or the area of RP-WAT adipocytes, but the APE reduced the diameter and the area of SC-WAT adipocytes, which was associated with lower fasting glycemia and islet/pancreas area ratio in the LepobT group. In addition, the APE increased exercise tolerance and this response was also associated with lower fasting glycemia in the LepobT group. In conclusion, starting APE at a later age with a more severe degree of obesity did not attenuate the excessive body weight gain, however the APE promoted benefits that can improve the female health, and for this reason it should be recommended as a non-pharmacological therapy for obesity.

Since the incidence of gestational diabetes is higher in obese women and those treated with progestogens during pregnancy, the aim of this study was to investigate the effect of progesterone (PG) on body composition, glucose metabolism and metabolic parameters in obese female mice. Post‐weaned female C57Bl/J6 were distributed into four groups: normocaloric control (NO‐CO, n=11), high fat and fructose control (HFF‐CO, n=10), normocaloric PG (NO‐PG, n=8) and high fat and fructose PG (HFF‐PG, n=9). The NO‐CO and NO‐PG mice fed a AING93 standard diet and the HFF‐CO and HFF‐PG fed a AIN93G diet added of lard (31%) and fructose (24%) during 10 weeks. In the 7th week, NO‐PG and HFF‐PG received an osmotic pump implant for constant infusion (0,25 mg/kg/d) of PG. All procedures were approved by the Ethics Committee of the School of Arts, Sciences and Humanities of University of Sao Paulo (003/2018). The daily food intake in grams was similar in all groups, but in terms of calories, the intake of the HFF‐CO and HFF‐PG (13.24+0.9 and 13.06+0.72 kcal/animal) groups was higher than NO‐CO and NO‐PG (9.22+0.2 and 9.53+0.53 kcal/animal) groups. The body weight gain was greater the HFF‐CO and HFF‐PG (11.52+0.94 and 9.61+0.85 g) groups compared to NO‐CO and NO‐PG (5.85+0.51 and 5.69+0.5 g) groups. Considering the final body weight of these animals (NO‐CO, 22.14+0.34 g; NO‐PG, 21.89+0.33 g; HFF‐CO, 28.76+0.59 g; HFF‐PG, 26.27+0.67 g) we observed not only the predicted increase in the weight of groups that received the HFF‐CO diet but also a lower increase in HFF‐PG group compared to HFF‐CO group. White adipose tissue fat pads (subcutaneous, SC‐WAT and retroperitoneal, RP‐WAT) increased significantly in the HFF‐CO group compared to NO‐CO and PG groups. In HFF‐PG, both WAT fat pads were greater compared to NO‐PG group, but only the WAT‐RP was greater compared to NO‐CO group. No differences were observed in interscapular brown adipose tissue and pancreas weight. On the other hand, the weight of liver was lower in HFF and HFF‐PG compared to NO‐CO and PG groups. No difference was found in the fasting glycaemia in the animals. From the results of the GTT and area under the curve (AUC) we observed that the HFF (23907+1304 mg/dL/120min) presented significantly higher AUC than NO‐CO and NO‐PG (17327+1042 and 18096+989 mg/dL/120min) groups. In addition, kITT of HFF‐CO (2.86+0.26 %/min) was significantly smaller compared to NO‐CO (4.23+0.56 %/min), NO‐PG (4.07+0.64 %/min) and HFF‐PG (3.89+0.4 %/min). Metabolic parameters measured in the indirect calorimetry during resting such as resting oxygen consumption, energy expenditure, respiratory exchange ratio, and the rates of carbohydrate and lipids oxidation did not differ among groups. In conclusion, the treatment with PG in a concentration that mimics those found in pregnancy attenuated body weight gain, adiposity and glycaemic metabolism damage observed in obese female mice.

Physical inactivity reduces aerobic capacity and is directly associated with an increase in cardiometabolic risk factors. Here we investigated whether there is an association between increased aerobic capacity and the prevention of obesity and insulin resistance through aerobic exercise training (AET). Adult male C57BL6/J mice were assigned into chow‐fed controls (C, n=10), cafeteria diet (CAF, n=8), chow‐fed trained (T, n=9), and cafeteria diet plus trained (CAFT, n=8) groups. AET was performed simultaneously with diet and consisted of 8‐wk running session of 60 min at 60% of maximal speed, 5 days/wk. Experimental procedures were approved by Ethics Committee from School of Arts, Science and Humanities, University of Sao Paulo, Brazil (#001/2016). Both trained groups showed lower body weight at the end of protocol compared to C and CAF groups. However, only CAFT group had reduced body weight gain compared to the CAF group. Cafeteria diet induced glucose intolerance and insulin resistance in the CAF group, which was counteracted by AET in CAFT group. Indirect calorimetry measurement at rest revealed no difference in the variables oxygen uptake (VO2), carbon dioxide expiration (VCO2), respiratory exchange ratio (RER), energy expenditure (EE), carbohydrate and fat oxidation among groups. During maximal exercise tests, T and CAFT groups showed an increase in VO2máx (13% and 9.2%, p=0.07) and VO2peak (11.3% and 8.6%, p=0.07) compared to C and CAF, respectively. However no differences among groups were found for RER and rate of substrate oxidation. AET increased the time to exhaustion and maximal velocity in the T compared to C and CAF groups, and in the CAFT compared to CAF. The exercise intensity corresponding to the VO2máx (iVO2) was higher in the T group (2.30 ± 0.42 km⁄h) compared to C (1.86 ± 0.41 km/h) and CAF (1.73 ± 0.17 km/h) groups, and in the CAFT (2.23 ± 0.11 km/h) compared to CAF. Both trained groups showed late anaerobic threshold, improved the relative cost of running, and higher activity of citrate synthase and β‐HAD enzymes in the soleus muscle compared to C and CAF groups. In conclusion, these results revealed that the prevention of obesity and insulin resistance is associated with the improvement in aerobic capacity induced by AET.Support or Funding InformationFinancial Support: FAPESP # 2015/04948‐4; 2016/20659‐5.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

VECCHIATTO, Bruno. The role of ACE2/Ang 1-7/Mas axis on skeletal muscle on the prevention of metabolic diseases by aerobic exercise training. 2019. 89 p.

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