Naringenin Prevents Obesity, Hepatic Steatosis, and Glucose Intolerance in Male Mice Independent of Fibroblast Growth Factor 21

Abstract

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.

Fibroblast growth factor 21 night watch: advances and uncertainties in the field

“…Moreover, elevated hepatic glucose production was also observed in the same strain of FGF21 null mice in which hypoglycaemia was initially detected , and this result was corroborated by impaired glucose clearance in animals with liver‐specific FGF21 ablation . Of interest, fasting hypoglycaemia was not reported in other independently generated strains of FGF21 knockout mice . Furthermore, the in vitro activity also argues against FGF21 as a direct stimulator of gluconeogenesis; in hepatocytes, the main liver cell type targeted by FGF21 , this protein suppresses glucose output in a manner comparable to that of insulin .…”

“…FGF21 transgenic mice were shown to be leaner than their wild‐type littermates and protected against diet‐induced obesity , but also had a proportionally higher fat mass . FGF21 knockout animals were partially lipodystrophic in one study , but obese in several others . FGF21 is a potent antihyperglycaemic agent in mice , with an FGF21 antagonist elevating glucose in vivo , yet FGF21 was reported to either induce gluconeogenesis or have no physiological relation to glucose homeostasis in animals .…”

Investigation of the effect of naringenin on oxidative stress-related alterations in testis of hydrogen peroxide-administered rats

“…Naringenin is a metabolite of naringin and this molecule reduces the plasma lipid levels in an experimental hyperlipidemia and obesity model . Moreover, Assini et al . reported that naringenin supplementation prevented high fat diet‐induced obesity in wild‐type and transgenic mice.…”

Non-alcoholic Fatty Liver Disease: Beneficial Effects of Flavonoids

“…In ovarectomized mice with metabolic disturbances, also, naringenin attenuated hepatic lipid accumulation, visceral and subcutaneous adiposity, insulin resistance, fasting glucose, and plasma total cholesterol (Ke et al, ). Lower adiposity occurred as a result of reduced caloric intake (Ke et al, ), whereas inhibition of hepatic triglyceride accumulation was exerted by decreasing expression of lipogenesis gene, Srebf1c , as well as by induction of hepatic genes involved in fatty acid oxidation, including peroxisome proliferator‐activated receptor gamma coactivator‐1 and Cpt1a (Assini et al, ).…”