title: 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.
authors.affiliation: Department of Vascular Biology (J.M.A., E.E.M., A.C.B., B.G.S., D.E.T., S.S.C., C.G.S., M.W.H.) and Imaging Research Laboratories (M.D.), Robarts Research Institute, London, Ontario, Canada N6A 5B7; Children's Health Research Institute and Departments of Paediatrics, Physiology and Pharmacology, and Oncology (C.L.P.); Departments of Biochemistry (J.M.A., E.E.M., A.C.B., S.S.C., M.W.H.), Medical Biophysics (M.D.) and Medicine (D.E.T., C.G.S., M.W.H.), The University of Western Ontario, London, Ontario, Canada N6A 5B7; and Lilly Research Laboratories (A.C.A., A.K.), Division of Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Assini
authors.forename: Erin E
authors.initials: EE
authors.lastname: Mulvihill
authors.forename: Amy C
authors.initials: AC
authors.lastname: Burke
authors.forename: Brian G
authors.initials: BG
authors.lastname: Sutherland
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Telford
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Chhoker
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Sawyez
authors.forename: Maria
authors.initials: M
authors.lastname: Drangova
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Adams
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Pin
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D044950:Flavanones / Q000627:therapeutic use*; D018149:Glucose Intolerance / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D044950:Flavanones; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C005273:naringenin