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Cited by 830Fibroblast Growth Factor ResearchAdipokines, Inflammation, and Metabolic DiseasesPeroxisome Proliferator-Activated Receptors

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Obesity Is a Fibroblast Growth Factor 21 (FGF21)-Resistant State

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Fisher, ffolliott M., Chui, Patricia C., Antonellis, Patrick J., Bina, Holly A., Kharitonenkov, Alexei, Flier, Jeffrey S., Maratos-Flier, Eleftheria·2010·Diabetes
DOI 10.2337/db10-0193PMC PMC2963536
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Abstract

OBJECTIVE: Fibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 improve glucose tolerance, lower serum free fatty acids, and lead to weight loss in obese mice. Surprisingly, however, FGF21 levels are elevated in obese ob/ob and db/db mice and correlate positively with BMI in humans. However, the expected beneficial effects of endogenous FGF21 to increase glucose tolerance and reduce circulating triglycerides are absent in obesity. RESEARCH DESIGN AND METHODS: To test the hypothesis that obesity is a state of FGF21 resistance, we evaluated the response of obese mice to exogenous FGF21 administration. In doing this, we assessed the impact of diet-induced obesity on FGF21 signaling and resultant transcriptional events in the liver and white adipose tissue. We also analyzed the physiologic impact of FGF21 resistance by assessing serum parameters that are acutely regulated by FGF21. RESULTS: When obese mice are treated with FGF21, they display both a significantly attenuated signaling response as assessed by extracellular mitogen-activated protein kinase 1 and 2 (ERK1/2) phosphorylation as well as an impaired induction of FGF21 target genes, including cFos and EGR1. These effects were seen in both liver and fat. Similarly, changes in serum parameters such as the decline in glucose and free fatty acids are attenuated in FGF21-treated DIO mice. CONCLUSIONS: These data demonstrate that DIO mice have increased endogenous levels of FGF21 and respond poorly to exogenous FGF21. We therefore propose that obesity is an FGF21-resistant state.

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FIG. 1. Circulating levels of FGF21 are increased in mice with diet-induced obesity. Analysis of FGF21 mRNA expression in diet-induced obese mice is shown. mRNA expression was quantified using a standard quantitative PCR technique. Data are shown from the liver (A) and WAT (B). C: Circulating FGF21 levels were determined with the use of an ELISA in serum from a terminal bleed. Data are displayed as the mean ± SE. ***P < 0.001.
FIG. 1. Circulating levels of FGF21 are increased in mice with diet-induced obesity. Analysis of FGF21 mRNA expression in diet-induced obese mice is shown. mRNA expression was quantified using a standard quantitative PCR technique. Data are shown from the liver (A) and WAT (B). C: Circulating FGF21 levels were determined with the use of an ELISA in serum from a terminal bleed. Data are displayed as the mean ± SE. ***P < 0.001.CC BY-NC-ND · PubMed Central
FIG. 2. FGF21 signaling is attenuated in liver and WAT of obese mice. To test whether FGF21 signaling is impaired in obese mice, we assessed FGF21-mediated ERK1/2 phosphorylation in the liver (A) and WAT (B). Results from every Western blot are shown in each case displaying both the phosphorylated form and total ERK1/2 expression. Above each blot, the densitometry is shown for all experimental regimes and is calculated as pERK/total ERK. Data are displayed as the mean ± SE.
FIG. 2. FGF21 signaling is attenuated in liver and WAT of obese mice. To test whether FGF21 signaling is impaired in obese mice, we assessed FGF21-mediated ERK1/2 phosphorylation in the liver (A) and WAT (B). Results from every Western blot are shown in each case displaying both the phosphorylated form and total ERK1/2 expression. Above each blot, the densitometry is shown for all experimental regimes and is calculated as pERK/total ERK. Data are displayed as the mean ± SE.CC BY-NC-ND · PubMed Central
FIG. 3. Induction of immediate early gene expression downstream of FGF21 signaling is impaired in obese mice. To confirm whether FGF21 signaling is impaired in obese mice, we assessed immediate early gene expression downstream of ERK in obese and lean mice. Both mRNA and protein levels were analyzed in the liver (A) and WAT (B). For each tissue, mRNA fold increase is displayed as a bar graph and a Western blot showing Egr1 protein expression presented below. cFos mRNA is also shown in the liver (C) and WAT (D). Data are means ± SE.
FIG. 3. Induction of immediate early gene expression downstream of FGF21 signaling is impaired in obese mice. To confirm whether FGF21 signaling is impaired in obese mice, we assessed immediate early gene expression downstream of ERK in obese and lean mice. Both mRNA and protein levels were analyzed in the liver (A) and WAT (B). For each tissue, mRNA fold increase is displayed as a bar graph and a Western blot showing Egr1 protein expression presented below. cFos mRNA is also shown in the liver (C) and WAT (D). Data are means ± SE.CC BY-NC-ND · PubMed Central
FIG. 4. FGF21 has an impaired capacity to reduce serum glucose and NEFAs in obese mice. To analyze the impact of obesity-associated FGF21 resistance on the physiologic improvements we associate with FGF21 action, we looked at serum parameters that are acutely regulated by FGF21. The effect of FGF21 treatment on circulating glucose (A) and NEFAs (C) are shown in lean and obese mice. mRNA expression for genes regulating these parameters is also shown from epididymal WAT: GLUT1 (B), HSL (D), and perilipin (E). Data are displayed as the mean ± SE. *P < 0.05; **P < 0.01; ***P < 0.001. ■, Lean; □, obese.
FIG. 4. FGF21 has an impaired capacity to reduce serum glucose and NEFAs in obese mice. To analyze the impact of obesity-associated FGF21 resistance on the physiologic improvements we associate with FGF21 action, we looked at serum parameters that are acutely regulated by FGF21. The effect of FGF21 treatment on circulating glucose (A) and NEFAs (C) are shown in lean and obese mice. mRNA expression for genes regulating these parameters is also shown from epididymal WAT: GLUT1 (B), HSL (D), and perilipin (E). Data are displayed as the mean ± SE. *P < 0.05; **P < 0.01; ***P < 0.001. ■, Lean; □, obese.CC BY-NC-ND · PubMed Central
FIG. 5. FGF receptor and βKlotho expression is reduced in WAT of obese mice. FGF21 binds to and activates multiple subtypes of the FGF receptor family in the presence of the co-receptor βKlotho. To see whether FGF receptor and βKlotho expression is reduced in obese mice, we assessed mRNA levels in the liver (A) and WAT (B) of lean and obese mice. Data for each gene are calculated using 36B4 as a reference gene, and data are transformed using the formula 2−ΔΔCt. Data are means ± SE. ***P < 0.001.
FIG. 5. FGF receptor and βKlotho expression is reduced in WAT of obese mice. FGF21 binds to and activates multiple subtypes of the FGF receptor family in the presence of the co-receptor βKlotho. To see whether FGF receptor and βKlotho expression is reduced in obese mice, we assessed mRNA levels in the liver (A) and WAT (B) of lean and obese mice. Data for each gene are calculated using 36B4 as a reference gene, and data are transformed using the formula 2−ΔΔCt. Data are means ± SE. ***P < 0.001.CC BY-NC-ND · PubMed Central
FIG. 6. Obese FGF21 KO mice are phenotypically similar to wild-type littermates. Lean FGF21 KO mice develop mild obesity and glucose intolerance and have elevated circulating NEFAs. However, when fed a high-fat diet, the phenotypes appear to converge with no significant differences between the two groups. Weights (A), glucose tolerance tests (B) (*significance by repeated-measure ANOVA), and circulating NEFAs in each group (C) are shown. Data are displayed as the mean ± SE. *P < 0.05.
FIG. 6. Obese FGF21 KO mice are phenotypically similar to wild-type littermates. Lean FGF21 KO mice develop mild obesity and glucose intolerance and have elevated circulating NEFAs. However, when fed a high-fat diet, the phenotypes appear to converge with no significant differences between the two groups. Weights (A), glucose tolerance tests (B) (*significance by repeated-measure ANOVA), and circulating NEFAs in each group (C) are shown. Data are displayed as the mean ± SE. *P < 0.05.CC BY-NC-ND · PubMed Central
FIG. 7. FGF21 resistance manifests early during weight gain. To test whether FGF21 resistance precedes the onset of obesity, mice were fed a high-fat diet for 4 weeks. At this time, mice were analyzed for FGF21 resistance via acute intraperitoneal injection of 150 ng/g of FGF21. Weights (A), hepatic FGF21-induced EGR1 expression (B), WAT EGR1 (C), and GLUT1 expression (D) are shown. Data are displayed as the mean ± SE. *P < 0.05.
FIG. 7. FGF21 resistance manifests early during weight gain. To test whether FGF21 resistance precedes the onset of obesity, mice were fed a high-fat diet for 4 weeks. At this time, mice were analyzed for FGF21 resistance via acute intraperitoneal injection of 150 ng/g of FGF21. Weights (A), hepatic FGF21-induced EGR1 expression (B), WAT EGR1 (C), and GLUT1 expression (D) are shown. Data are displayed as the mean ± SE. *P < 0.05.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Fisher, F. M., Chui, P. C., Antonellis, P. J., Bina, H. A., Kharitonenkov, A., Flier, J. S., & Maratos-Flier, E.
Affiliations
  • Beth Israel Deaconess Medical Center (US)
  • Eli Lilly (United States) (US)
  • Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts;
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2010-08-03
Volume
59
Issue
11
Pages
2781-2789
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db10-0193
PMC
PMC2963536
OpenAlex
W2134944069
Cited by
830
References
30
Citations by year
2026: 31 · 2025: 61 · 2024: 62 · 2023: 54 · 2022: 66 · 2021: 59 · 2020: 50 · 2019: 56 · 2018: 58 · 2017: 74 · 2016: 60 · 2015: 51 · 2014: 45 · 2013: 29 · 2012: 47
FWCI
13.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R37DK028082)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
FGF21, FGF21 resistance, obesity, diet-induced obesity, ERK1/2 phosphorylation, c-fos, EGR1, liver, white adipose tissue, glucose tolerance, free fatty acids, lipid metabolism, ob/ob mice, db/db mice
MeSH terms
Adipose Tissue, Animals, Drug Resistance, Fibroblast Growth Factors, Humans, Injections, Intravenous, Liver, Mice, Inbred C57BL, Mice, Obese, Obesity, Recombinant Proteins, RNA, Messenger, Signal Transduction, Reverse Transcriptase Polymerase Chain Reaction, Mitogen-Activated Protein Kinase 3, Mice

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