title: Diet Polyphenol Curcumin Stimulates Hepatic Fgf21 Production and Restores Its Sensitivity in High-Fat-Diet-Fed Male Mice.
abstract: We found previously that short-term curcumin gavage stimulated mouse hepatic fibroblast growth factor 21 (Fgf21) expression. Here we conducted mechanistic exploration and investigated the potential pathophysiological relevance on this regulation. Fgf21 stimulation was observed at messenger RNA and protein levels in mice with daily curcumin gavage for 4 or 8 days and in primary hepatocytes with curcumin treatment. Using peroxisome proliferator-activated receptor α (PPARα) agonist and antagonist, along with luciferase reporter and chromatin immune-precipitation approaches, we determined that curcumin stimulates Fgf21 transcription in a mechanism involving PPARα activation. High-fat diet (HFD) feeding also increased mouse hepatic and serum Fgf21 levels, whereas dietary curcumin intervention attenuated these increases. We found that HFD feeding reduced hepatic expression levels of genes that encode FGFR1 and βKlotho, PGC1α, and the targets of the PPARα-PGC1α axis, whereas concomitant curcumin intervention restored or partially restored their expression levels. Importantly, hepatocytes from HFD-fed mice showed a loss of response to FGF21 treatment on Erk phosphorylation and the expression of Egr1 and cFos; this response was restored in hepatocytes from HFD-fed mice with curcumin intervention. This investigation expanded our mechanistic understanding of the metabolic beneficial effects of dietary curcumin intervention involving the regulation of Fgf21 production and the attenuation of HFD-induced Fgf21 resistance.
authors.affiliation: 600 Tianhe Rd, Tianhe District, Third Affiliated Hospital of Sun Yet-Sen University, Guangzhou 510630, China.|Toronto General Research Institutes, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kejing
authors.initials: K
authors.lastname: Zeng
authors.affiliation: Toronto General Research Institutes, University of Toronto, Toronto, Ontario, Canada.|Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lili
authors.initials: L
authors.lastname: Tian
authors.affiliation: Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rucha
authors.initials: R
authors.lastname: Patel
authors.affiliation: Toronto General Research Institutes, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Shao
authors.affiliation: Toronto General Research Institutes, University of Toronto, Toronto, Ontario, Canada.|Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Zhuolun
authors.initials: Z
authors.lastname: Song
authors.affiliation: Toronto General Research Institutes, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.affiliation: Transplant Core Laboratory, Multi-organ transplantation, University Health Network, Toronto, Ontario, Canada.
authors.forename: Justin
authors.initials: J
authors.lastname: Manuel
authors.affiliation: Transplant Core Laboratory, Multi-organ transplantation, University Health Network, Toronto, Ontario, Canada.
authors.forename: Xuezhong
authors.initials: X
authors.lastname: Ma
authors.affiliation: Transplant Core Laboratory, Multi-organ transplantation, University Health Network, Toronto, Ontario, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: McGilvray
authors.affiliation: Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.|Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
authors.forename: Jianping
authors.initials: J
authors.lastname: Weng
authors.affiliation: Toronto General Research Institutes, University of Toronto, Toronto, Ontario, Canada.|Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.|Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tianru
authors.initials: T
authors.lastname: Jin
mesh_terms: D000818:Animals; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D059305:Diet, High-Fat / Q000009:adverse effects*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008659:Metabolic Diseases / Q000209:etiology / Q000517:prevention & control; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000517:prevention & control; D047493:PPAR alpha / Q000378:metabolism
chemical_list: D047493:PPAR alpha; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D003474:Curcumin