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


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.
Mai
Knut
K
Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Andres
Janin
J
Biedasek
Katrin
K
Weicht
Jessica
J
Bobbert
Thomas
T
Sabath
Markus
M
Meinus
Sabine
S
Reinecke
Franziska
F
Möhlig
Matthias
M
Weickert
Martin O
MO
Clemenz
Markus
M
Pfeiffer
Andreas F H
AF
Kintscher
Ulrich
U
Spuler
Simone
S
Spranger
Joachim
J
D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D005215:Fasting / Q000502:physiology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D015309:Glucose Clamp Technique; D005990:Glycerol / Q000494:pharmacology; D006706:Homeostasis; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D054709:Lecithins / Q000494:pharmacology; D008297:Male; D009765:Obesity / Q000150:complications / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*
D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D054709:Lecithins; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; C414620:fibroblast growth factor 21; D000077154:Rosiglitazone; D005346:Fibroblast Growth Factors; D005990:Glycerol