Stine Ringholm Jørgensen PGC-1alpha in exercise- and exercise training-induced metabolic adaptations

Background: The aim of the present study was to test the hypotheses that 1) a single exercise bout increases UCP1 mRNA in both inguinal (i)WAT and epididymal (e)WAT, 2) UCP1expression and responsiveness to exercise are different in iWAT and eWAT, 3) PGC-1αdetermines the basal levels of UCP1 and PRDM16 in WAT and 4) exercise and exercise trainingregulate UCP1 and PRDM16 expression in WAT in a PGC-1α-dependent manner. Methods: Whole body PGC-1α knockout (KO) and wildtype (WT) littermate mice performed a singletreadmill exercise bout at 14 m/min and 10% slope for 1 hour. Mice were sacrificed and iWAT,eWAT and quadriceps muscle were removed immediately after, 2, 6 and 10 hours after running,and from sedentary mice that served as controls. In addition, PGC-1α KO mice and WTlittermates were exercise trained for 5 weeks with sedentary mice as untrained controls. Thirty-six-37 hours after the last exercise bout iWAT was removed. Results: UCP1 mRNA contentincreased 19-fold in iWAT and 7.5-fold in eWAT peaking at 6h and 0’ of recovery, respectively,in WT but with no changes in PGC-1α KO mice. UCP1 protein was undetectable in eWAT andvery low in iWAT of untrained mice but increased with exercise training to 4.4 (AU) in iWAT from WT mice without significant effects in PGC-1α KO mice. Conclusion: The present observations provide evidence that exercise training increases UCP1 protein in iWAT through PGC-1α, likely as a cumulative effect of transient increases in UCP1 expression after each exercise bout. Moreover, the results suggest that iWAT is more responsive than eWAT inexercise-induced regulation of UCP1. In addition, as PRDM16 mRNA content decreased in recovery from acute exercise, the present findings suggest that acute exercise elicits regulation of several brown adipose tissue genes in mouse WAT. Abbreviations: CD31, cluster of differentiation 31; COX, cytochrome c oxidase; eWAT,epididymal white adipose tissue; GLUT4, glucose transporter 4; iWAT, inguinal white adipose tissue; PGC-1α, peroxisome proliferator-activated receptor γ co-activator 1α; PRDM16, proteincontaining PR (PRD1-BF-1-RIZ1 homologous) domain 16; UCP1, uncoupling protein 1