Cardiometabolic Effects Of Aerobic Physical Exercise In Diabetes Is Not Associated With Brown Adipose Tissue-Derived FGF21

Aerobic physical exercise (AET) is an effective nonpharmacological therapy for diabetes. Brown adipose tissue (BAT) has been investigated as a therapeutic target due to its ability to oxidize energy substrates, to produce heat through nonshivering thermogenesis, and to secrete proteins with metabolic actions, such as fibroblast growth factor 21 (FGF21). FGF21 has a broad action and may be one of the batokines involved in diabetic cardiometabolic protection. This study investigated whether the cardiometabolic effect of AET in diabetes is mediated by BAT via FGF21. Adult male C57BL6/J mice were assigned into groups: non-diabetic sedentary (NDS, n=18), non-diabetic trained (NDT, n=12), diabetic sedentary (DS, n=17), diabetic trained (DT, n=21), and diabetic trained with interscapular BAT (iBAT) surgically removed (DTR, n=8). Diabetes was induced by high-fat and -fructose diet and intraperitoneal injection of streptozotocin (120 mg/g). AET consisted of 8-wk running session of 60 min at 60% of maximal speed, 5 days/wk. Procedures were approved by Ethics Committees from School of Arts, Science and Humanities of University of São Paulo (#001/2020). Initial body weight (BW) did not differ among groups, however NDT, DS, DT and DTR groups had lower final BW compared with NDS. BW gain in the DS, DT and DTR was lower than NDS group. The weight of retroperitoneal white adipose tissue (WAT) was lower in NDT, DT and DTR groups compared with NDS, and the DS and DT groups had lower iBAT weight compared with NDS and NDT groups. No differences were observed in the weight of periepididymal and subcutaneous WAT, gastrocnemius and soleus muscles, and cardiac chambers. Food consumption (g/animal/day) was lower in DS, DT and DTR groups compared with NDS. The DS, DT and DTR groups showed hyperglycemia, glucose intolerance and insulin resistance compared with NDS and NDT groups, however only the DS group increased fasting glucose levels post-AET compared with pre-AET values. Echocardiographic evaluation revealed that the DS group presented remodeling of ventricular diameter and volume during diastole, and impairment in ventricular relaxation, which were prevented by AET in the DT and DTR groups. No differences were observed in markers of cardiac oxidative metabolism such as citrate synthase enzyme activity and protein expression of total AMPK, p-AMPK and PGC1-α. Serum FGF21 concentration was lower in the DS, DT and DTR groups, however protein expression of FGF21, FGFR1 receptor and β-klotho co-receptor in the heart did not differ among groups. In conclusion, cardiac and metabolic adaptations induced by AET in diabetic animals were not associated with circulating FGF21 secreted by BAT nor with cardiac expression of FGF21/FGFR1/β-klotho. Sao Paulo Research Foundation (FAPESP processes 2020/15748-4 and 2020/12005-0). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.