The pharmacological effect of growth differentiation factor 15 (GDF15) on suppressed appetite has undergone scientific scrutiny. However, this effect may be driven by nausea in rodents through the GDNF family receptor a-like (GFRAL), located in the hindbrain. In contract, less is known about the endogenous effect of plasma GDF15 levels on appetite suppression. In Study 1, the aim was to investigate the relationship between exercise-induced endogenous plasma GDF15 levels and appetite suppression. We found that plasma GDF15 levels increased after one bout of exercise in four independent exercise studies and reached “pathological levels” when the exercise bout lasted beyond 2 hours. In mice subjected to forced treadmill running, we observed comparable increase in plasma GDF15 levels as in humans immediately following exercise. However, we did not observe any suppression of appetite in wild type (WT) nor GFRAL knockout (KO) mice in the hours following exercise, suggesting that endogenous GDF15 levels may not be sufficient to suppress appetite.

Metformin, a blood-glucose-lowering medication, has been reported to increase endogenous plasma GDF15 levels and to decrease body weight by reducing appetite in pre-diabetic and type 2 diabetic individuals. In Study 2, we aimed to investigate whether there is a relationship between elevated metformin-induced endogenous plasma GDF15 levels and body weight loss and appetite reduction. We found that metformin treatment increased plasma GDF15 levels in both human and mice. When we administrated metformin to diet-induced obese (DIO) WT, DIO GFRAL KO and DIO GDF15 KO mice, we observed a reduction in body weight and appetite. This effect was independent of the GDF15-GFRAL pathway, in contrast to previous findings. Our data suggest that the lowering effect of metformin on body weight is independent of GDF15, however, further research is needed to elucidate the underlaying mechanisms of the effect of metformin on energy balance.

Fibroblast growth factor 21 (FGF21) has been extensively studied in rodents for its pharmacological effect on energy expenditure. Moreover, endogenous plasma FGF21 levels have been shown to increase in mice fed a protein-restricted diet, which was accompanied by increased energy expenditure. In Study 3, we aimed to investigate whether humans exhibit a similar phenotype when subjected to a prolonged eucaloric protein-restricted diet. We found that a protein-restricted diet high in carbohydrate or fat increased fasting plasma FGF21 levels in healthy young men. Moreover, we found that a protein-restricted diet necessitated an increase in energy intake to maintain body weight. These findings suggest that a protein-restricted diet has the potential to prevent weight gain and the development of obesity by increasing energy utilization in humans, perhaps via increased FGF21 secretion. Further research is required to fully understand the underlaying mechanisms responsible for the need to increase energy intake to maintain body weight when ingesting a protein restricted diet.