Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21

Diabetes. 2009 Jul;58(7):1532-8. doi: 10.2337/db08-1775. Epub 2009 Apr 28.


Objective: Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator-activator receptor (PPAR) alpha-dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARalpha, might modify FGF-21 levels.

Research design and methods: The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARgamma activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks.

Results: Oleate and linoleate increased FGF-21 expression and secretion in a PPARalpha-dependent fashion, as demonstrated by small-interfering RNA-induced PPARalpha knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect.

Conclusions: The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism*
  • Fasting / physiology*
  • Fatty Acids, Nonesterified / metabolism*
  • Female
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Gene Expression Regulation / drug effects
  • Glucose Clamp Technique
  • Glycerol / pharmacology
  • Homeostasis
  • Humans
  • Hyperinsulinism / metabolism
  • Hyperinsulinism / physiopathology
  • Hypoglycemic Agents / therapeutic use
  • Lecithins / pharmacology
  • Male
  • Obesity / complications
  • Obesity / metabolism
  • PPAR alpha / genetics
  • PPAR alpha / physiology
  • PPAR gamma / genetics
  • PPAR gamma / physiology*
  • RNA, Messenger / genetics
  • Reference Values
  • Rosiglitazone
  • Thiazolidinediones / therapeutic use*


  • Fatty Acids, Nonesterified
  • Hypoglycemic Agents
  • Lecithins
  • PPAR alpha
  • PPAR gamma
  • RNA, Messenger
  • Thiazolidinediones
  • fibroblast growth factor 21
  • Rosiglitazone
  • Fibroblast Growth Factors
  • Glycerol