Short-Term Curcumin Gavage Sensitizes Insulin Signaling in Dexamethasone-Treated C57BL/6 Mice.
BACKGROUND
Long-term dietary curcumin (>12 wk) improves metabolic homeostasis in obese mice by sensitizing insulin signaling and reducing hepatic gluconeogenesis. Whether these occur only secondary to its chronic anti-inflammatory and antioxidative functions is unknown.


OBJECTIVE
In this study, we assessed the insulin sensitization effect of short-term curcumin gavage in a rapid dexamethasone-induced insulin resistance mouse model, in which the chronic anti-inflammatory function is eliminated.


METHODS
Six-week-old male C57BL/6 mice received an intraperitoneal injection of dexamethasone (100 mg/kg body weight) or phosphate-buffered saline every day for 5 d, with or without simultaneous curcumin gavage (500 mg/kg body weight). On day 7, insulin tolerance tests were performed. After a booster dexamethasone injection and curcumin gavage on day 8, blood glucose and insulin concentrations were measured. Liver tissues were collected on day 10 for quantitative polymerase chain reaction and Western blotting to assess gluconeogenic gene expression, insulin signaling, and the expression of fibroblast growth factor 21 (FGF21). Primary hepatocytes from separate, untreated C57BL/6 mice were used for testing the in vitro effect of curcumin treatment.


RESULTS
Dexamethasone injection impaired insulin tolerance (P < 0.05) and elevated ambient plasma insulin concentrations by ~2.7-fold (P < 0.01). Concomitant curcumin administration improved insulin sensitivity and reduced hepatic gluconeogenic gene expression. The insulin sensitization effect of curcumin was demonstrated by increased stimulation of S473 phosphorylation of protein kinase B (P < 0.01) in the dexamethasone-treated mouse liver, as well as the repression of glucose production in primary hepatocytes (P < 0.001). Finally, curcumin gavage increased FGF21 expression by 2.1-fold in the mouse liver (P < 0.05) and curcumin treatment increased FGF21 expression in primary hepatocytes.


CONCLUSIONS
These observations suggest that the early beneficial effect of curcumin intervention in dexamethasone-treated mice is the sensitization of insulin signaling, involving the stimulation of FGF21 production, a known insulin sensitizer.
Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Canada; Department of Medicine and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada;
Lili
http://orcid.org/0000-0003-0556-4449
L
Tian
Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Canada; Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China;
Kejing
http://orcid.org/0000-0002-7578-7923
K
Zeng
Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Canada;
Weijuan
W
Shao
Sunnybrook Research Institute, Toronto, Canada; and.
Burton B
BB
Yang
Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Canada; Department of Medicine and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada.
I George
IG
Fantus
Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China;
Jianping
J
Weng
Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada tianru.jin@utoronto.ca.
Tianru
http://orcid.org/0000-0002-0307-7391
T
Jin
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D003474:Curcumin / Q000378:metabolism / Q000627:therapeutic use*; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000633:toxicity; D019587:Dietary Supplements; D005346:Fibroblast Growth Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000633:toxicity; D005943:Gluconeogenesis / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D011236:Prediabetic State / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011897:Random Allocation; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000975:Antioxidants; D001786:Blood Glucose; D005938:Glucocorticoids; D007328:Insulin; D011994:Recombinant Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D003907:Dexamethasone; D003474:Curcumin
FGF21; curcumin; gluconeogenic gene; hepatocytes; insulin signaling