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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

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.
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Figure 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.

Mentions: Administration of FGF21 leads to acute reduction in circulating glucose and NEFAs in mice. To see if this response is impaired in obese mice, we examined the effect of a dose of 200 ng/g of FGF21 on these parameters. At this dose, FGF21 lowered circulating glucose levels by 17.4% in the lean mice (Fig. 4A; saline 164.4 ± 6.10 mg/dl; FGF21 135.8 ± 7.81 mg/dl; P = 0.0211). Although there was a slight reduction in the obese mice, this did not reach statistical significance (saline 167.6 ± 10.58 mg/dl; FGF21 153.7 ± 4.98 mg/dl; P = NS). Because the ability of FGF21 to lower circulating glucose levels is thought to be due, in part, to increased expression of GLUT1 in adipose tissue, we assessed GLUT1 mRNA expression in the WAT of these mice (Fig. 4B). Although there was a small induction in GLUT1 expression in the obese mice (1.7-fold, P = 0.0048), the response was far more prominent in the lean mice (2.8-fold, P = 0.0003).


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)

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

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

Figure 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.
Mentions: Administration of FGF21 leads to acute reduction in circulating glucose and NEFAs in mice. To see if this response is impaired in obese mice, we examined the effect of a dose of 200 ng/g of FGF21 on these parameters. At this dose, FGF21 lowered circulating glucose levels by 17.4% in the lean mice (Fig. 4A; saline 164.4 ± 6.10 mg/dl; FGF21 135.8 ± 7.81 mg/dl; P = 0.0211). Although there was a slight reduction in the obese mice, this did not reach statistical significance (saline 167.6 ± 10.58 mg/dl; FGF21 153.7 ± 4.98 mg/dl; P = NS). Because the ability of FGF21 to lower circulating glucose levels is thought to be due, in part, to increased expression of GLUT1 in adipose tissue, we assessed GLUT1 mRNA expression in the WAT of these mice (Fig. 4B). Although there was a small induction in GLUT1 expression in the obese mice (1.7-fold, P = 0.0048), the response was far more prominent in the lean mice (2.8-fold, P = 0.0003).

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