The molecular mechanisms and metabolic pathways whereby the citrus
flavonoid,
naringenin, reduces
dyslipidemia and improves
glucose tolerance were investigated in C57BL6/J wild-type mice and
fibroblast growth factor 21 (
FGF21) null (
Fgf21(-/-)) mice.
FGF21 regulates energy homeostasis and the metabolic adaptation to fasting. One avenue of this regulation is through induction of
peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc1a), a regulator of hepatic
fatty acid oxidation and ketogenesis. Because
naringenin is a potent activator of hepatic FA oxidation, we hypothesized that induction of
FGF21 might be an integral part of
naringenin's mechanism of action. Furthermore, we predicted that
FGF21 deficiency would potentiate high-fat diet (HFD)-induced metabolic dysregulation and compromise metabolic protection by
naringenin. The absence of
FGF21 exacerbated the response to a HFD. Interestingly,
naringenin supplementation to the HFD robustly prevented
obesity in both genotypes. Gene expression analysis suggested that
naringenin was not primarily targeting
fatty acid metabolism in white adipose tissue.
Naringenin corrected hepatic
triglyceride concentrations and normalized hepatic expression of Pgc1a, Cpt1a, and Srebf1c in both wild-type and
Fgf21(-/-) mice. HFD-fed
Fgf21(-/-) mice displayed greater muscle
triglyceride deposition,
hyperinsulinemia, and
impaired glucose tolerance as compared with wild-type mice, confirming the role of
FGF21 in
insulin sensitivity; however,
naringenin supplementation improved these metabolic parameters in both genotypes. We conclude that
FGF21 deficiency exacerbates HFD-induced
obesity, hepatic steatosis, and
insulin resistance. Furthermore,
FGF21 is not required for
naringenin to protect mice from HFD-induced metabolic dysregulation. Collectively these studies support the concept that
naringenin has potent
lipid-lowering effects and may act as an
insulin sensitizer in vivo.