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Fibroblast growth factor 19 entry into brain.

Hsuchou H, Pan W, Kastin AJ - Fluids Barriers CNS (2013)

Bottom Line: This led to the question whether blood-borne FGF19 crosses the blood-brain barrier (BBB) to exert its metabolic effects.This coincided with a slower decline of 125I-FGF19 in blood which suggested there was decreased clearance or peripheral tissue uptake.In support of an altered pattern of peripheral processing of 125I-FGF19 by excess unlabeled FGF19, the high influx to liver was significantly attenuated, whereas the minimal renal uptake was linearly accelerated.

View Article: PubMed Central - HTML - PubMed

Affiliation: Blood-Brain Barrier Group, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA. weihong.pan@pbrc.edu.

ABSTRACT

Background: Fibroblast growth factor (FGF)-19, an endocrine FGF protein mainly produced by the ileum, stimulates metabolic activity and alleviates obesity. FGF19 modulates metabolism after either intravenous or intracerebroventricular injection, and its receptor FGFR4 is present in the hypothalamus. This led to the question whether blood-borne FGF19 crosses the blood-brain barrier (BBB) to exert its metabolic effects.

Methods: We determined the pharmacokinetics of FGF19 permeation from blood to brain in comparison with its distribution in peripheral organs. Multiple-time regression analysis after intravenous bolus injection, in-situ brain perfusion, and HPLC assays were performed.

Results: FGF19 was relatively stable in blood and in the brain compartment. Significant influx was seen in the presence of excess unlabeled FGF19 in blood. This coincided with a slower decline of 125I-FGF19 in blood which suggested there was decreased clearance or peripheral tissue uptake. In support of an altered pattern of peripheral processing of 125I-FGF19 by excess unlabeled FGF19, the high influx to liver was significantly attenuated, whereas the minimal renal uptake was linearly accelerated. In the present setting, we did not detect a saturable transport of FGF19 across the BBB, as the entry rate of 125I-FGF19 was not altered by excess unlabeled FGF19 or its mouse homologue FGF15 during in-situ brain perfusion.

Conclusion: FGF19 remained stable in the blood and brain compartments for up to 10 min. Its influx to the brain was non-linear, non-saturable, and affected by its blood concentration and distribution in peripheral organs. Liver showed a robust and specific uptake of FGF19 that could be inhibited by the presence of excess unlabeled FGF19, whereas kidney clearance was dose-dependent.

No MeSH data available.


Related in: MedlinePlus

In the in-situ brain perfusion study, there was significant influx of 125I-FGF19 (values already normalized by subtraction of 131I-albumin in the same mouse). Each data point represents one mouse. The presence of 50-fold excess FGF19 or FGF15 did not change the influx of 125I-FGF19.
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Figure 4: In the in-situ brain perfusion study, there was significant influx of 125I-FGF19 (values already normalized by subtraction of 131I-albumin in the same mouse). Each data point represents one mouse. The presence of 50-fold excess FGF19 or FGF15 did not change the influx of 125I-FGF19.

Mentions: The results from multiple-time regression analysis after iv bolus injection of FGF19 may be affected by serum binding proteins. Therefore, we further performed in-situ brain perfusion with blood-free physiological buffer. There was a significant influx of 125I-FGF19 from perfusate to brain (Ki = 0.27 ± 0.06 μl/g-min, F1,8 = 22.06, p = 0.002). However, the presence of 50-fold excess of either FGF19 or FGF15 did not change the influx rate of 125I-FGF19. The Ki for 125I-FGF19 was 0.23 ± 0.04 μl/g-min in the presence of excess unlabeled FGF19, and 0.33 ± 0.03 μl/g-min in the presence of excess unlabeled FGF15. The slopes of these three regression lines were not significantly different from each other (F2,21 = 1.10, p = 0.35). Similarly, the excess of FGF19 or FGF15 did not change the volume of distribution of 125I-FGF19 (F2,23 = 0.24, p = 0.79) (Figure 4), the values already being normalized by subtraction of albumin space at each time point. The results suggest that FGF19 had a low level of permeation across the BBB in a process that is probably non-saturable, as the amount of excess FGF19 or FGF15 used in this study was not able to modulate the influx.


Fibroblast growth factor 19 entry into brain.

Hsuchou H, Pan W, Kastin AJ - Fluids Barriers CNS (2013)

In the in-situ brain perfusion study, there was significant influx of 125I-FGF19 (values already normalized by subtraction of 131I-albumin in the same mouse). Each data point represents one mouse. The presence of 50-fold excess FGF19 or FGF15 did not change the influx of 125I-FGF19.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3818657&req=5

Figure 4: In the in-situ brain perfusion study, there was significant influx of 125I-FGF19 (values already normalized by subtraction of 131I-albumin in the same mouse). Each data point represents one mouse. The presence of 50-fold excess FGF19 or FGF15 did not change the influx of 125I-FGF19.
Mentions: The results from multiple-time regression analysis after iv bolus injection of FGF19 may be affected by serum binding proteins. Therefore, we further performed in-situ brain perfusion with blood-free physiological buffer. There was a significant influx of 125I-FGF19 from perfusate to brain (Ki = 0.27 ± 0.06 μl/g-min, F1,8 = 22.06, p = 0.002). However, the presence of 50-fold excess of either FGF19 or FGF15 did not change the influx rate of 125I-FGF19. The Ki for 125I-FGF19 was 0.23 ± 0.04 μl/g-min in the presence of excess unlabeled FGF19, and 0.33 ± 0.03 μl/g-min in the presence of excess unlabeled FGF15. The slopes of these three regression lines were not significantly different from each other (F2,21 = 1.10, p = 0.35). Similarly, the excess of FGF19 or FGF15 did not change the volume of distribution of 125I-FGF19 (F2,23 = 0.24, p = 0.79) (Figure 4), the values already being normalized by subtraction of albumin space at each time point. The results suggest that FGF19 had a low level of permeation across the BBB in a process that is probably non-saturable, as the amount of excess FGF19 or FGF15 used in this study was not able to modulate the influx.

Bottom Line: This led to the question whether blood-borne FGF19 crosses the blood-brain barrier (BBB) to exert its metabolic effects.This coincided with a slower decline of 125I-FGF19 in blood which suggested there was decreased clearance or peripheral tissue uptake.In support of an altered pattern of peripheral processing of 125I-FGF19 by excess unlabeled FGF19, the high influx to liver was significantly attenuated, whereas the minimal renal uptake was linearly accelerated.

View Article: PubMed Central - HTML - PubMed

Affiliation: Blood-Brain Barrier Group, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA. weihong.pan@pbrc.edu.

ABSTRACT

Background: Fibroblast growth factor (FGF)-19, an endocrine FGF protein mainly produced by the ileum, stimulates metabolic activity and alleviates obesity. FGF19 modulates metabolism after either intravenous or intracerebroventricular injection, and its receptor FGFR4 is present in the hypothalamus. This led to the question whether blood-borne FGF19 crosses the blood-brain barrier (BBB) to exert its metabolic effects.

Methods: We determined the pharmacokinetics of FGF19 permeation from blood to brain in comparison with its distribution in peripheral organs. Multiple-time regression analysis after intravenous bolus injection, in-situ brain perfusion, and HPLC assays were performed.

Results: FGF19 was relatively stable in blood and in the brain compartment. Significant influx was seen in the presence of excess unlabeled FGF19 in blood. This coincided with a slower decline of 125I-FGF19 in blood which suggested there was decreased clearance or peripheral tissue uptake. In support of an altered pattern of peripheral processing of 125I-FGF19 by excess unlabeled FGF19, the high influx to liver was significantly attenuated, whereas the minimal renal uptake was linearly accelerated. In the present setting, we did not detect a saturable transport of FGF19 across the BBB, as the entry rate of 125I-FGF19 was not altered by excess unlabeled FGF19 or its mouse homologue FGF15 during in-situ brain perfusion.

Conclusion: FGF19 remained stable in the blood and brain compartments for up to 10 min. Its influx to the brain was non-linear, non-saturable, and affected by its blood concentration and distribution in peripheral organs. Liver showed a robust and specific uptake of FGF19 that could be inhibited by the presence of excess unlabeled FGF19, whereas kidney clearance was dose-dependent.

No MeSH data available.


Related in: MedlinePlus