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Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes.

Berti L, Irmler M, Zdichavsky M, Meile T, Böhm A, Stefan N, Fritsche A, Beckers J, Königsrainer A, Häring HU, de Angelis MH, Staiger H - Mol Metab (2015)

Bottom Line: Serum FGF21 concentrations were more than two-fold higher in MUHO as compared to MHO subjects (457 ± 378 vs. 211 ± 123 pg/mL; p < 0.05).FGF21 treatment of human preadipocytes for the entire differentiation period was modestly lipogenic (+15%; p < 0.05), reduced the expression of key adipogenic transcription factors (PPARG and CEBPA, -15% and -40%, respectively; p < 0.01 both), reduced adiponectin expression (-20%; p < 0.05), markedly reduced adiponectin release (-60%; p < 0.01), and substantially increased leptin (+60%; p < 0.01) and interleukin-6 (+50%; p < 0.001) release.The hepatokine FGF21 exerts weak lipogenic and anti-adipogenic actions and marked adiponectin-suppressive and leptin and interleukin-6 release-promoting effects in human differentiating preadipocytes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental Genetics, Helmholtz Centre Munich GmbH, German Research Centre for Environmental Health, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.

ABSTRACT

Objective: Serum concentrations of the hepatokine fibroblast growth factor (FGF) 21 are elevated in obesity, type-2 diabetes, and the metabolic syndrome. We asked whether FGF21 levels differ between subjects with metabolically healthy vs. unhealthy obesity (MHO vs. MUHO), opening the possibility that FGF21 is a cross-talker between liver and adipose tissue in MUHO. Furthermore, we studied the effects of chronic FGF21 treatment on adipocyte differentiation, lipid storage, and adipokine secretion.

Methods: In 20 morbidly obese donors of abdominal subcutaneous fat biopsies discordant for their whole-body insulin sensitivity (hereby classified as MHO or MUHO subjects), serum FGF21 was quantified. The impact of chronic FGF21 treatment on differentiation, lipid accumulation, and adipokine release was assessed in isolated preadipocytes differentiated in vitro.

Results: Serum FGF21 concentrations were more than two-fold higher in MUHO as compared to MHO subjects (457 ± 378 vs. 211 ± 123 pg/mL; p < 0.05). FGF21 treatment of human preadipocytes for the entire differentiation period was modestly lipogenic (+15%; p < 0.05), reduced the expression of key adipogenic transcription factors (PPARG and CEBPA, -15% and -40%, respectively; p < 0.01 both), reduced adiponectin expression (-20%; p < 0.05), markedly reduced adiponectin release (-60%; p < 0.01), and substantially increased leptin (+60%; p < 0.01) and interleukin-6 (+50%; p < 0.001) release.

Conclusions: The hepatokine FGF21 exerts weak lipogenic and anti-adipogenic actions and marked adiponectin-suppressive and leptin and interleukin-6 release-promoting effects in human differentiating preadipocytes. Together with the higher serum concentrations in MUHO subjects, our findings reveal FGF21 as a circulating factor promoting the development of metabolically unhealthy adipocytes.

No MeSH data available.


Related in: MedlinePlus

FGF21 effects on white and brown adipocyte marker gene expression in differentiating hasc preadipocytes The mRNA expression of PPARG encoding PPAR-γ (A), CEBPA encoding C/EBP-α (B), ADIPOQ encoding adiponectin (C), UCP1 encoding UCP-1 (D), PPARGC1A encoding PGC-1α (E), and CIDEA encoding CIDEA (F) was monitored by real-time qPCR (means ± SEM; N = 20). Black bars – rhFGF21-treated cultures; white bars – untreated controls. C/EBP-α – CCAAT/enhancer-binding protein α; CIDEA – cell death-inducing DNA fragmentation factor-like effector a; hasc – human abdominal subcutaneous; PGC-1α – PPAR-γ coactivator 1α; PPAR-γ – peroxisome proliferator-activated receptor γ; qPCR – quantitative polymerase chain reaction; rh – recombinant human; UCP-1 – uncoupling protein 1. *p < 0.05, **p < 0.01, ***p < 0.001.
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fig4: FGF21 effects on white and brown adipocyte marker gene expression in differentiating hasc preadipocytes The mRNA expression of PPARG encoding PPAR-γ (A), CEBPA encoding C/EBP-α (B), ADIPOQ encoding adiponectin (C), UCP1 encoding UCP-1 (D), PPARGC1A encoding PGC-1α (E), and CIDEA encoding CIDEA (F) was monitored by real-time qPCR (means ± SEM; N = 20). Black bars – rhFGF21-treated cultures; white bars – untreated controls. C/EBP-α – CCAAT/enhancer-binding protein α; CIDEA – cell death-inducing DNA fragmentation factor-like effector a; hasc – human abdominal subcutaneous; PGC-1α – PPAR-γ coactivator 1α; PPAR-γ – peroxisome proliferator-activated receptor γ; qPCR – quantitative polymerase chain reaction; rh – recombinant human; UCP-1 – uncoupling protein 1. *p < 0.05, **p < 0.01, ***p < 0.001.

Mentions: Chronic rhFGF21 treatment significantly impaired the expression of the key adipogenic transcription factors peroxisome proliferator-activated receptor-γ (PPAR-γ; -15%, day 18; Figure 4A) and CCAAT/enhancer-binding protein-α (C/EBP-α; up to −40%, days 8–18; Figure 4B). In addition, rhFGF21 reduced the expression of the adipokine adiponectin (up to −20%; days 4 and 18; Figure 4C), whereas leptin expression remained unaffected (p > 0.08). Unexpectedly, the brown adipocyte marker genes encoding uncoupling protein-1 (UCP-1), PPAR-γ coactivator-1α (PGC-1α), and cell death-inducing DNA fragmentation factor-like effector a (CIDEA) were differently regulated with UCP-1 being 2-fold induced by rhFGF21 (days 12 and 18; Figure 4D) and PGC-1α and CIDEA being repressed by up to −40% and −50%, respectively (all time-points; Figure 4E,F). Similar regulations of the brown adipocyte marker genes were seen when rhFGF21 was sub-chronically added for three days to adipocytes (from day 18) that were differentiated in the absence of rhFGF21 (data not shown). It should be noted that the UCP-1 expression levels were very low (mean Cp-value on day 0: 35.9; mean Cp-value on day 18: 31.4). Moreover, we did not obtain higher expression levels using isoproterenol, a well-known and potent inducer of the gene. Therefore, we concluded that hasc preadipocytes represent a cell type with very limited capacity to brown. In accordance with this, we did not detect any convincing signal for UCP-1 protein by immunocytochemistry.


Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes.

Berti L, Irmler M, Zdichavsky M, Meile T, Böhm A, Stefan N, Fritsche A, Beckers J, Königsrainer A, Häring HU, de Angelis MH, Staiger H - Mol Metab (2015)

FGF21 effects on white and brown adipocyte marker gene expression in differentiating hasc preadipocytes The mRNA expression of PPARG encoding PPAR-γ (A), CEBPA encoding C/EBP-α (B), ADIPOQ encoding adiponectin (C), UCP1 encoding UCP-1 (D), PPARGC1A encoding PGC-1α (E), and CIDEA encoding CIDEA (F) was monitored by real-time qPCR (means ± SEM; N = 20). Black bars – rhFGF21-treated cultures; white bars – untreated controls. C/EBP-α – CCAAT/enhancer-binding protein α; CIDEA – cell death-inducing DNA fragmentation factor-like effector a; hasc – human abdominal subcutaneous; PGC-1α – PPAR-γ coactivator 1α; PPAR-γ – peroxisome proliferator-activated receptor γ; qPCR – quantitative polymerase chain reaction; rh – recombinant human; UCP-1 – uncoupling protein 1. *p < 0.05, **p < 0.01, ***p < 0.001.
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fig4: FGF21 effects on white and brown adipocyte marker gene expression in differentiating hasc preadipocytes The mRNA expression of PPARG encoding PPAR-γ (A), CEBPA encoding C/EBP-α (B), ADIPOQ encoding adiponectin (C), UCP1 encoding UCP-1 (D), PPARGC1A encoding PGC-1α (E), and CIDEA encoding CIDEA (F) was monitored by real-time qPCR (means ± SEM; N = 20). Black bars – rhFGF21-treated cultures; white bars – untreated controls. C/EBP-α – CCAAT/enhancer-binding protein α; CIDEA – cell death-inducing DNA fragmentation factor-like effector a; hasc – human abdominal subcutaneous; PGC-1α – PPAR-γ coactivator 1α; PPAR-γ – peroxisome proliferator-activated receptor γ; qPCR – quantitative polymerase chain reaction; rh – recombinant human; UCP-1 – uncoupling protein 1. *p < 0.05, **p < 0.01, ***p < 0.001.
Mentions: Chronic rhFGF21 treatment significantly impaired the expression of the key adipogenic transcription factors peroxisome proliferator-activated receptor-γ (PPAR-γ; -15%, day 18; Figure 4A) and CCAAT/enhancer-binding protein-α (C/EBP-α; up to −40%, days 8–18; Figure 4B). In addition, rhFGF21 reduced the expression of the adipokine adiponectin (up to −20%; days 4 and 18; Figure 4C), whereas leptin expression remained unaffected (p > 0.08). Unexpectedly, the brown adipocyte marker genes encoding uncoupling protein-1 (UCP-1), PPAR-γ coactivator-1α (PGC-1α), and cell death-inducing DNA fragmentation factor-like effector a (CIDEA) were differently regulated with UCP-1 being 2-fold induced by rhFGF21 (days 12 and 18; Figure 4D) and PGC-1α and CIDEA being repressed by up to −40% and −50%, respectively (all time-points; Figure 4E,F). Similar regulations of the brown adipocyte marker genes were seen when rhFGF21 was sub-chronically added for three days to adipocytes (from day 18) that were differentiated in the absence of rhFGF21 (data not shown). It should be noted that the UCP-1 expression levels were very low (mean Cp-value on day 0: 35.9; mean Cp-value on day 18: 31.4). Moreover, we did not obtain higher expression levels using isoproterenol, a well-known and potent inducer of the gene. Therefore, we concluded that hasc preadipocytes represent a cell type with very limited capacity to brown. In accordance with this, we did not detect any convincing signal for UCP-1 protein by immunocytochemistry.

Bottom Line: Serum FGF21 concentrations were more than two-fold higher in MUHO as compared to MHO subjects (457 ± 378 vs. 211 ± 123 pg/mL; p < 0.05).FGF21 treatment of human preadipocytes for the entire differentiation period was modestly lipogenic (+15%; p < 0.05), reduced the expression of key adipogenic transcription factors (PPARG and CEBPA, -15% and -40%, respectively; p < 0.01 both), reduced adiponectin expression (-20%; p < 0.05), markedly reduced adiponectin release (-60%; p < 0.01), and substantially increased leptin (+60%; p < 0.01) and interleukin-6 (+50%; p < 0.001) release.The hepatokine FGF21 exerts weak lipogenic and anti-adipogenic actions and marked adiponectin-suppressive and leptin and interleukin-6 release-promoting effects in human differentiating preadipocytes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental Genetics, Helmholtz Centre Munich GmbH, German Research Centre for Environmental Health, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.

ABSTRACT

Objective: Serum concentrations of the hepatokine fibroblast growth factor (FGF) 21 are elevated in obesity, type-2 diabetes, and the metabolic syndrome. We asked whether FGF21 levels differ between subjects with metabolically healthy vs. unhealthy obesity (MHO vs. MUHO), opening the possibility that FGF21 is a cross-talker between liver and adipose tissue in MUHO. Furthermore, we studied the effects of chronic FGF21 treatment on adipocyte differentiation, lipid storage, and adipokine secretion.

Methods: In 20 morbidly obese donors of abdominal subcutaneous fat biopsies discordant for their whole-body insulin sensitivity (hereby classified as MHO or MUHO subjects), serum FGF21 was quantified. The impact of chronic FGF21 treatment on differentiation, lipid accumulation, and adipokine release was assessed in isolated preadipocytes differentiated in vitro.

Results: Serum FGF21 concentrations were more than two-fold higher in MUHO as compared to MHO subjects (457 ± 378 vs. 211 ± 123 pg/mL; p < 0.05). FGF21 treatment of human preadipocytes for the entire differentiation period was modestly lipogenic (+15%; p < 0.05), reduced the expression of key adipogenic transcription factors (PPARG and CEBPA, -15% and -40%, respectively; p < 0.01 both), reduced adiponectin expression (-20%; p < 0.05), markedly reduced adiponectin release (-60%; p < 0.01), and substantially increased leptin (+60%; p < 0.01) and interleukin-6 (+50%; p < 0.001) release.

Conclusions: The hepatokine FGF21 exerts weak lipogenic and anti-adipogenic actions and marked adiponectin-suppressive and leptin and interleukin-6 release-promoting effects in human differentiating preadipocytes. Together with the higher serum concentrations in MUHO subjects, our findings reveal FGF21 as a circulating factor promoting the development of metabolically unhealthy adipocytes.

No MeSH data available.


Related in: MedlinePlus