title: Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates.
abstract: Fibroblast-growth factor 21 (FGF21) is thought to be important in metabolic regulation. Recently, low protein diets have been shown to increase circulating FGF21 levels. However, when energy contribution from dietary protein is lowered, other macronutrients, such as carbohydrates, must be increased to meet eucaloric balance. This raises the possibility that intake of a diet rich in carbohydrates may induce an increase in plasma FGF21 levels per se. Here we studied the role of dietary carbohydrates on the levels of circulating FGF21 and concomitant physiologic effects by feeding healthy men a carbohydrate rich diet without reducing protein intake.
  
  
  
  A diet enriched in carbohydrates (80 E% carbohydrate; CHO) and a eucaloric control diet (CON) were provided to nine healthy men for three days. The energy intake during the CHO diet was increased (+75% energy) to ensure similar dietary protein intake in CHO and CON. To control for the effect of caloric surplus, we similarly overfed (+75% energy) the same subjects for three days with a fat-rich diet (78 E% fat; FAT), consisting of primarily unsaturated fatty acids. The three diets were provided in random order.
  
  
  
  After CHO, plasma FGF21 concentration increased 8-fold compared to CON (329 ± 99 vs. 39 ± 9 pg ml-1, p < 0.05). In contrast, after FAT only a non-significant tendency (p = 0.073) to an increase in plasma FGF21 concentration was found. The increase in FGF21 concentration after CHO correlated closely (r = 0.88, p < 0.01) with increased leg glucose uptake (62%, p < 0.05) and increased hepatic glucose production (17%, p < 0.01), indicating increased glucose turnover. Plasma fatty acid (FA) concentration was decreased by 68% (p < 0.01), supported by reduced subcutaneous adipose tissue HSL Ser660phosphorylation (p < 0.01) and perilipin 1 protein content (p < 0.01), pointing to a suppression of adipose tissue lipolysis. Concomitantly, a 146% increase in the plasma marker of hepatic de novo lipogenesis C16:1 n-7 FA (p < 0.01) was observed together with 101% increased plasma TG concentration (p < 0.001) in association with CHO intake and increased plasma FGF21 concentration.
  
  
  
  Excess dietary carbohydrate, but not fat, led to markedly increased FGF21 secretion in humans, notably without protein restriction, and affected glucose and lipid homeostais.
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lundsgaard
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Fritzen
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Sjøberg
authors.affiliation: National Institute of Nutrition and Seafood Research, Bergen, Norway.
authors.forename: Lene S
authors.initials: LS
authors.lastname: Myrmel
authors.affiliation: National Institute of Nutrition and Seafood Research, Bergen, Norway; Laboratory of Genomics and Molecular Biomedicine, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Madsen
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jørgen F P
authors.initials: JFP
authors.lastname: Wojtaszewski
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Richter
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark. Electronic address: bkiens@nexs.ku.dk.
authors.forename: Bente
authors.initials: B
authors.lastname: Kiens
mesh_terms: D000328:Adult; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D004041:Dietary Fats / Q000008:administration & dosage / Q000378:metabolism; D004044:Dietary Proteins / Q000008:administration & dosage / Q000378:metabolism; D002149:Energy Intake; D004734:Energy Metabolism / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000097:blood / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D050155:Lipogenesis / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008297:Male
chemical_list: D004040:Dietary Carbohydrates; D004041:Dietary Fats; D004044:Dietary Proteins; D007328:Insulin; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005947:Glucose
keywords: AMPK, AMP-activated kinase; ATGL, adipose triglyceride lipase; BCA, bicinchoninic acid; BM, body mass; BMI, body mass index; CHO, carbohydrate-rich diet; CON, control diet; Carbohydrates; ChREBP, carbohydrate-responsive element binding protein; Diet; FA, fatty acid; FAT, fat-rich diet; FGF21; FGF21, fibroblast growth factor 21; GLUT4, glucose transporter 4; HSL, hormone sensitive lipase; LM, leg mass; Lipolysis; Liver; PKA, protein kinase A; Ra, rate of appearance; TG, triacylglycerol; VLDL, very low density lipoprotein; VO2peak, maximal oxygen consumption