Fibroblast growth factor 21 (FGF-21) treatment is known to lower body weight and to increase insulin sensitivity in rodent models of obesity, probably via increased energy expenditure. Stimulation of non-shivering thermogenesis by FGF-21 was hypothesized to be the crucial antiobesogenic action. Thermogenesis is normally driven by stimulation of β3-adrenergic receptors. FGF-21 has been shown to inhibit lipolysis, while β3-adrenergic agonists are pro-lipolytic. In lean mice, acute β3-adrenergic stimulation results in drop in blood glucose, which is believed to be caused by a rise in non-esterified fatty acid (NEFA) and (subsequently) increase in plasma insulin. Thus, the effects of FGF-21 and β3-adrenergic agonists on thermogenesis could be synergistic, while their effects on NEFA seem opposite. Here we investigate the effect of combination of FGF-21 and the β3-adrenergic agonist CL316.243 on blood glucose level in mice. Dietary obese C57Bl/6 mice were housed at thermoneutral temperature (i.e., at 30 °C) in order to minimize basal adrenergic tone. Animals were treated twice daily with 65 µg FGF-21 or its vehicle for 8 days. This treatment was not sufficient to significantly decrease body weight and non-fasted blood glucose, but it lowered insulin (indicating increase in insulin sensitivity). Subsequently, the mice were injected with 35 µg of the β3-adrenergic agonist CL316.243. CL316.243 increased NEFA and insulin in control mice, but surprisingly (in contrast to earlier observations in lean mice) it acutely increased blood glucose as well. In FGF-21-treated mice, CL316.243 altered neither NEFA nor insulin levels, but it dramatically decreased blood glucose. In contrast to earlier works, our result demonstrates a complex nature of the glucose-lowering effects of β3-adrenergic agonists which does not simply correlate to changes in insulin and NEFA levels. We also show that FGF-21 has a potential to restore the glucose-lowering action of β3-adrenergic stimulation in obese mice.
P. Zouhar: None. B. Spilakova: None. B. Andersen: Employee; Self; Novo Nordisk A/S. J. Nedergaard: None. J. Kopecky: None.
Czech Science Foundation (19-05356Y)