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Obesity is a fibroblast growth factor 21 (FGF21)-resistant state.

Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, Maratos-Flier E - Diabetes (2010)

Bottom Line: Fibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism.However, the expected beneficial effects of endogenous FGF21 to increase glucose tolerance and reduce circulating triglycerides are absent in obesity.These effects were seen in both liver and fat.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

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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Related in: MedlinePlus

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.
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Figure 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.

Mentions: Because we have previously reported that chow-fed FGF21 KO mice are heavier than chow-fed WT mice, we investigated the effect of diet-induced obesity on FGF21 KO mice. Although WT mice have substantially increased levels of circulating FGF21, there is little phenotypic difference between WT animals compared with obese FGF21 KO mice. The significant difference in adiposity between chow-fed WT mice and FGF21 KO mice (Fig. 6A; P = 0.033) disappears once they are placed on an obesogenic diet (Fig. 6A; P = 0.11). In addition, chow-fed FGF21 KO mice were more glucose intolerant than wild-type animals with reduced glucose excursion during a glucose tolerance test (Fig. 6B; P = 0.013). This difference was not observed in the mice ingesting a high-fat diet (Fig. 6B; P = 0.85). Circulating NEFAs were also significantly elevated in the chow-fed FGF21 KO mice (Fig. 6C; P = 0.03), which was not observed between the mice on a high-fat diet.


Obesity is a fibroblast growth factor 21 (FGF21)-resistant state.

Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, Maratos-Flier E - Diabetes (2010)

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.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2963536&req=5

Figure 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.
Mentions: Because we have previously reported that chow-fed FGF21 KO mice are heavier than chow-fed WT mice, we investigated the effect of diet-induced obesity on FGF21 KO mice. Although WT mice have substantially increased levels of circulating FGF21, there is little phenotypic difference between WT animals compared with obese FGF21 KO mice. The significant difference in adiposity between chow-fed WT mice and FGF21 KO mice (Fig. 6A; P = 0.033) disappears once they are placed on an obesogenic diet (Fig. 6A; P = 0.11). In addition, chow-fed FGF21 KO mice were more glucose intolerant than wild-type animals with reduced glucose excursion during a glucose tolerance test (Fig. 6B; P = 0.013). This difference was not observed in the mice ingesting a high-fat diet (Fig. 6B; P = 0.85). Circulating NEFAs were also significantly elevated in the chow-fed FGF21 KO mice (Fig. 6C; P = 0.03), which was not observed between the mice on a high-fat diet.

Bottom Line: Fibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism.However, the expected beneficial effects of endogenous FGF21 to increase glucose tolerance and reduce circulating triglycerides are absent in obesity.These effects were seen in both liver and fat.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

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.

Show MeSH
Related in: MedlinePlus