Increased growth of brown adipose tissue but its reduced thermogenic activity in creatine-depleted rats fed β-guanidinopropionic acid

To study the responses of thermogenic activity in brown adipose tissue (BAT) to creatine depletion, male Wistar rats were fed creatine analogue β-guanidinopropionic acid (β-GPA) for about 10 weeks. Compared to control rats, a marked decrease in the levels of high-energy phosphates, such as phosphocreatine and ATP, was noted in BAT of β-GPA rats. Conversely, upward trends in other chemical components (DNA, glycogen, and total protein) in BAT as well as an increase in BAT mass were observed in β-GPA rats, suggesting a tendency to hyperplasia of the BAT. The thermogenic activity (which was assessed by guanosine 5′-diphosphate binding to BAT mitochondria) in the mitochondria recovered from BAT of β-GPA rats, however, was not increased in response to such changes but rather decreased. Moreover, uncoupling protein (UCP) content in the mitochondrial fraction of β-GPA rats was significantly lower than that in control rats (the relative amounts were 77 ± 6 and 100 ± 4%, respectively). Nevertheless, surprisingly, the level of UCP mRNA was remarkably greater in β-GPA rats than in control rats. These observations indicate that there is a discordance between BAT growth and activity in β-GPA rats, thereby suggesting that a failure on and after UCP translation may be involved in the impairment of BAT thermogenic activity with creatine depletion. The impairment of BAT thermogenic activity, that is, UCP activity may indicate that uncoupling or heat production was inhibited in order to increase the ATP synthesis in BAT of β-GPA rats in compensation for a reduction in the levels of high-energy phosphates (including ATP), with resultant hypothermia.