Beneficial effect of farnesoid X receptor activation on metabolism in a diabetic rat model

Mol Med Rep. 2016 Mar;13(3):2135-42. doi: 10.3892/mmr.2016.4761. Epub 2016 Jan 12.

Abstract

Farnesoid X receptor (FXR) is an important regulator of glucose and lipid homeostasis. However, the exact role of FXR in diabetes remains to be fully elucidated. The present study examined the effects of chenodeoxycholic acid (CDCA), an agonist of FXR, on metabolism profile in a rat model of type 2 diabetes mellitus (T2DM). Male Wistar rats (8‑week‑old; n=40) were randomized into the following four groups (n=10): Untreated control, CDCA‑treated, T2DM, and CDCA‑treated T2DM. To establish the T2DM model, the rats were fed a high‑fat diet (HFD) for 4 weeks and received a single low‑dose intraperitoneal injection of streptozotocin (30 mg/kg), followed by an additional 4 weeks of HFD feeding. CDCA was administrated (10 mg/kg/d) intraperitoneally for 10 days. Reverse transcription‑quantitative polymerase chain reaction and western blotting assays were performed to determine the RNA and protein expression of FXR, phosphoenolpyruvate carboxykinase, G6Pase, proliferator‑activated receptor‑γ coactivator‑1 and short heterodimer partner in rat liver tissue. The results revealed that FXR activation by CDCA did not reduce body weight, but it lowered the plasma levels of fasting glucose, insulin and triglycerides in the T2DM rats. CDCA administration reversed the downregulation of the mRNA and protein expression of FXR in the T2DM rat liver tissue samples. Furthermore, treatment with CDCA reduced the mRNA and protein expression levels of phosphoenolpyruvate carboxykinase, glucose 6‑phosphatase and peroxisome proliferator‑activated receptor‑γ coactivator‑1 in the liver tissue samples of the T2DM rats. By contrast, CDCA treatment increased the mRNA and protein expression levels of short heterodimer partner in the liver tissue samples of the T2DM rats. In conclusion, FXR agonist treatment induces beneficial effects on metabolism in the rat T2DM model. In conclusion, the present study indicated that the FXR agonist may be useful for the treatment of T2DM and hypertriglyceridemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Chenodeoxycholic Acid / pharmacology
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Gluconeogenesis / drug effects
  • Gluconeogenesis / genetics
  • Glucose-6-Phosphatase / metabolism
  • Liver / drug effects
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats, Wistar
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Transcription Factors / metabolism

Substances

  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • farnesoid X-activated receptor
  • Chenodeoxycholic Acid
  • Glucose-6-Phosphatase
  • Phosphoenolpyruvate Carboxykinase (ATP)