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Endocrinology. 2016 Dec 14:jc20161596. [Epub ahead of print]

Diet polyphenol curcumin stimulates hepatic Fgf21 production and restores its sensitivity in high fat diet fed male mice.

Author information

  • 11 Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-Sen University; Guangdong Provincial Key Laboratory of Diabetology, 600# Tianhe Road, Guangzhou, 510630, P. R. China.
  • 22 Toronto General Research Institutes, University Health Network, Toronto, Canada.
  • 33 Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.
  • 44 Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • 55 Transplant Core Laboratory, Multi-organ transplantation, University Health Network.
  • 66 Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada.
  • 77 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.

Abstract

We found previously that short-term curcumin gavage stimulated mouse hepatic Fgf21 expression. Here we conducted mechanistic exploration and investigated the potential pathophysiological relevance on this regulation. Fgf21 stimulation was observed at mRNA and protein levels in mice with daily-curcumin gavage for 4 or 8 days; and in primary hepatocytes with curcumin treatment. Using 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 while dietary curcumin intervention attenuated the increases. We found that HFD feeding reduced hepatic expression levels of genes that encode FGFR1 and βKlotho, PGC1α, as well as the targets of the PPARα-PGC1α axis; while concomitant curcumin intervention restored or partially restored their expression levels. Importantly, hepatocytes from HFD-fed mouse showed the loss of response to FGF21 treatment on Erk phosphorylation and the expression of Egr1 and cFos, while the response were restored in hepatocytes from HFD-fed mouse with curcumin intervention. Together, 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.

PMID:
27967217
DOI:
10.1210/en.2016-1596
[PubMed - as supplied by publisher]
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