Increased Fibroblast Growth Factor 21 in Obesity and Nonalcoholic Fatty Liver Disease

Gastroenterology
Volume 139, Issue 2 , Pages 456-463, August 2010

Jody Dushay, Patricia C. Chui, Gosala S. Gopalakrishnan, Marta Varela–Rey, Meghan Crawley, Ffolliott M. Fisher, Michael K. Badman, Maria L. Martinez–Chantar, Eleftheria Maratos–Flier

Received 21 January 2010; accepted 29 April 2010. published online 07 May 2010.

Abstract

Background & Aims
Fibroblast growth factor 21 (FGF21) is an hepatic protein that plays a critical role in metabolism, stimulating fatty acid oxidation in liver and glucose uptake in fat. Systemic administration to obese rodents and diabetic monkeys leads to improved glucose homeostasis and weight loss. In rodents, FGF21 increases with fasting and consumption of a ketogenic diet (KD). In humans, FGF21 correlates with body mass index (BMI), but studies evaluating other parameters show inconsistent results. We examined FGF21 serum levels in lean and obese individuals and in response to dietary manipulation. We also evaluated FGF21 serum levels and liver messenger RNA (mRNA) expression in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

Methods
Serum FGF21 was measured after an overnight fast in individuals with BMI ranging from normal to obese. Volunteers fasted for 16 or 72 hours and then ate a standard meal. Another group consumed KD for 12 days. Serum FGF21 and hepatic mRNA expression were measured in obese individuals with NAFLD or NASH.

Results
There was a positive correlation between BMI and FGF21. There was no change in FGF21 in response to a short fast or KD. A nonstatistically significant fall in FGF21 levels was seen after a 72-hour fast. Hepatic FGF21 mRNA expression was significantly elevated in NAFLD, which correlated with a substantial increase in serum FGF21. In NASH, serum FGF21 but not liver mRNA was increased.

Conclusions
FGF21 correlates with BMI and may be a novel biomarker for NAFLD, but is not nutritionally regulated in humans.

Keywords: FGF21, NAFLD, NASH, Obesity

Abbreviations used in this paper: BMI, body mass index, FGF21, fibroblast growth factor 21, GCRC, General Clinical Research Center, KD, ketogenic diet, mRNA, messenger RNA, NAFLD, nonalcoholic fatty liver disease, NASH, nonalcoholic steatohepatitis, PPARα, peroxisome proliferator−activated receptor-α

Conflicts of interest The authors disclose no conflicts.

Funding This study was supported in part by National Institutes of Health (NIH) grant M01-RR01032, Beth Israel Deaconess Medical Center General Clinical Research Center, NIH grant AT-1576, SAF2005-00855, and HEPADIP-EULSHM-CT-205 (to M.L.M.-C.), NIH grants 5R01DK069983-04 and NIH/5P01DK056106-10 (to E.M.F.), and the Boston Obesity and Nutrition Research Center DK46200.

PII: S0016-5085(10)00662-1

doi:10.1053/j.gastro.2010.04.054

© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

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