Recombinant Human Fibroblast growth factor 19 (FGF19), partial (Active)

What is FGF19 and what are its primary physiological functions?

FGF19 is an endocrine hormone belonging to the heparin-binding growth factors family. It functions primarily as a metabolic regulator with several key roles: suppression of bile acid biosynthesis through down-regulation of CYP7A1 expression, stimulation of glucose uptake in adipocytes, and regulation of inflammatory responses. FGF19 activity requires the presence of KLB (β-Klotho) and FGFR4 (Fibroblast Growth Factor Receptor 4) to exert its biological effects . Research has demonstrated that FGF19 operates through positive regulation of the JNK and ERK1/2 signaling cascades to achieve many of its downstream effects . The protein is expressed as a 21.5 kDa molecule in its active form and has a sequence ranging from amino acids 25-216 in its recombinant form .

How can FGF19 be used in muscle wasting and atrophy research models?

FGF19 has shown promising results in counteracting muscle wasting, particularly in chronic kidney disease (CKD) models. When administered to 5/6 nephrectomized mice (a CKD model), recombinant human FGF19 demonstrated significant effects on muscle preservation. Specifically, FGF19 treatment partially reversed the decrease in muscle fiber surface area induced by CKD, with tibialis anterior myofibers showing an increase from 1083 ± 33.58 μm² in untreated CKD mice to 1206 ± 57.91 μm² in FGF19-treated mice .

The experimental protocol typically involves subcutaneous injections of human recombinant FGF19 for approximately 18 days. Researchers should analyze both glycolytic (tibialis anterior) and oxidative (soleus) muscles to comprehensively evaluate FGF19's effects, as the hypertrophic impact has been observed in both muscle types . For comprehensive analysis, combine histological examination (myofiber cross-sectional measurements) with molecular analysis of myosin gene expression (Myh1, Myh4) to assess both structural and molecular changes.

What is the potential of FGF19 in treating inflammatory conditions and oxidative stress?

FGF19 has demonstrated significant anti-inflammatory and antioxidant properties. In lipopolysaccharide (LPS)-induced inflammatory models, FGF19 pretreatment effectively reduces oxidative stress markers and modulates inflammatory pathways. Experimental evidence shows that FGF19 pretreatment decreases serum malondialdehyde (MDA) levels while increasing catalase (CAT) levels in LPS-challenged mice .

For researchers investigating inflammatory conditions, the recommended protocol involves intravenous injection of recombinant human FGF19 daily for 7 days prior to LPS administration (5 mg/kg, E. coli 0111:B4) . This regimen has been shown to significantly alter linoleic acid metabolism and gamma-linolenic acid pathways, which are involved in regulating oxidative stress and mitochondrial function.

At the molecular level, FGF19 pretreatment increases hepatic expression of antioxidant genes such as glutathione peroxidase 1 (Gpx1) and catalase (Cat), while decreasing inducible nitric oxide synthase (iNOS) expression at both mRNA and protein levels. Additionally, FGF19 promotes the expression of NRF2 and HO-1 in the liver, enhancing cellular antioxidant defense mechanisms .

How does FGF19 influence glucose metabolism and insulin sensitivity?

FGF19 exerts significant effects on glucose homeostasis and insulin sensitivity through multiple mechanisms. In CKD mouse models, FGF19 treatment improves glucose tolerance, as evidenced by improved glucose clearance in glucose tolerance tests . The mechanisms underlying this effect involve:

• Increased hepatic expression of the regulatory subunit p85 of the Pi3k gene

• Enhanced expression of glycogen synthase 2 (Gys2)

• Reduced expression of glucose-6-phosphatase (G6pc1)

Together, these changes promote glucose utilization and storage while reducing gluconeogenesis, contributing to improved glucose tolerance. Additionally, FGF19 has been shown to stimulate glucose uptake in adipocytes, further contributing to glucose homeostasis .

For researchers studying metabolic disorders, it's important to note that FGF19's effects on glucose metabolism are interconnected with its impact on lipid metabolism. FGF19 treatment reduces ectopic lipid accumulation in skeletal muscle, which correlates with improved insulin sensitivity parameters . When designing experiments to study FGF19's metabolic effects, researchers should consider comprehensive metabolic profiling including glucose tolerance tests, insulin sensitivity assessments, and analysis of lipid distribution in metabolically active tissues.

What is the relationship between FGF19 and lipid metabolism?

FGF19 plays a crucial role in regulating lipid metabolism through multiple pathways. Metabolomic analysis reveals that FGF19 pretreatment reverses the increase of LPS-induced fatty acids . Pathway enrichment analysis demonstrates that α-linolenic acid (α-LA) and linoleic acid (LA) metabolism are significantly affected by FGF19 treatment. Specifically, FGF19 decreases serum levels of linoleic acid (LA), gamma-linolenic acid (GLA), dihomo-gamma linolenic acid (DGLA), and docosahexaenoic acid (DHA) .

In CKD models, FGF19 reduces ectopic lipid accumulation in skeletal muscle, as demonstrated by Oil Red O staining. The reduced lipid droplet infiltration in muscle tissue correlates with improved insulin resistance parameters, suggesting a direct link between FGF19's effect on lipid distribution and insulin sensitivity .

For comprehensive investigation of FGF19's impact on lipid metabolism, researchers should consider:

• Metabolomic analysis focusing on fatty acid profiles

• Histological assessment of lipid accumulation in metabolically active tissues

• Correlation analysis between lipid parameters and metabolic outcomes such as insulin sensitivity

What are the optimal administration protocols for FGF19 in different experimental models?

Administration protocols for FGF19 vary depending on the experimental model and research objectives. Based on current literature, the following approaches have been validated:

• For CKD and muscle wasting studies:

  • Subcutaneous injections of recombinant human FGF19 for 18 days

  • Effective in 5/6 nephrectomized mice as a CKD model

  • Evaluation should include analysis of muscle fiber size in both glycolytic and oxidative muscles

• For inflammatory and sepsis-like models:

  • Intravenous injection of recombinant human FGF19 daily for 7 days

  • Followed by LPS administration (5 mg/kg, E. coli 0111:B4) to induce endotoxemia

  • Assessment after 24 hours of LPS stimulation

When designing FGF19 administration protocols, researchers should consider:

• The biological half-life of recombinant FGF19

• The specific tissue distribution and receptor expression in the target organs

• Potential dose-dependent effects, as response may vary with concentration

• The timing of administration relative to disease induction or challenge

How should researchers evaluate the efficacy of FGF19 treatment in inflammatory conditions?

To comprehensively assess FGF19 efficacy in inflammatory conditions, researchers should implement a multi-parameter approach examining:

• Oxidative stress markers:

  • Serum MDA levels (decreased with FGF19 treatment)

  • Serum catalase levels (increased with FGF19 treatment)

  • Expression of antioxidant genes (Gpx1, Cat) in target tissues

• Inflammatory gene expression:

  • Analysis of inflammatory markers including Il-1β, Il-6, Tnfα

  • Assessment of Mcp1 (monocyte chemoattractant protein-1)

  • Expression of Foxo1 and Myd88

• Metabolomic analysis:

  • Focus on unsaturated fatty acid metabolism

  • Assessment of LA, GLA, DGLA, and DHA levels

  • Pathway enrichment analysis to identify affected metabolic networks

• Protein expression analysis:

  • Western blotting for NRF2 and HO-1 expression

  • Protein levels of iNOS and inflammatory cytokines

This comprehensive approach allows researchers to evaluate the multi-faceted effects of FGF19 on inflammatory conditions and provides mechanistic insights into its mode of action.

How does FGF19 interact with other signaling pathways in metabolic regulation?

FGF19 functions through a complex network of signaling interactions. Research indicates that FGF19 activity requires the presence of KLB and FGFR4 to exert its biological effects . The downstream signaling involves positive regulation of the JNK and ERK1/2 cascades, which subsequently affect multiple metabolic processes.

In the liver, FGF19 influences inflammatory signaling pathways by reducing the expression of Foxo1, a master regulator of inflammation, and Myd88, a central adaptor of innate immunity . Additionally, FGF19 interacts with pathways regulating oxidative stress, promoting NRF2 and HO-1 expression while reducing iNOS levels .

Future research should focus on:

• Receptor-specific signaling mechanisms

• Crosstalk between FGF19 signaling and other metabolic regulatory pathways

• Tissue-specific responses to FGF19 administration

• Potential compensatory mechanisms that may develop with chronic FGF19 treatment

What are the implications of FGF19 research for chronic inflammatory conditions beyond CKD?

The anti-inflammatory and metabolic regulatory properties of FGF19 suggest potential applications in various chronic inflammatory conditions. The research demonstrating FGF19's ability to reduce liver inflammatory markers in CKD mice and improve LPS-induced lipid disorders indicates broader therapeutic potential.

Researchers investigating chronic inflammatory conditions should consider:

• The relationship between FGF19's metabolic effects and inflammation reduction

• Potential application in inflammatory bowel diseases, given FGF19's intestinal origins

• Effects on adipose tissue inflammation in metabolic syndrome

• Role in preventing inflammatory damage in cardiovascular diseases

The mechanisms by which FGF19 modulates inflammatory pathways—particularly through reduction of cytokines like Il-1β, Il-6, and Tnfα—warrant investigation in diverse inflammatory conditions. Additionally, FGF19's impact on oxidative stress and mitochondrial function suggests potential applications in age-related inflammatory disorders.

How should researchers interpret changes in skeletal muscle fiber size and type following FGF19 treatment?

When evaluating the effects of FGF19 on skeletal muscle, researchers should consider both quantitative and qualitative changes. In CKD models, FGF19 treatment produces a rightward shift in myofiber size distribution, indicating an increase in larger muscle fibers . Specifically:

• In tibialis anterior muscle, FGF19 treatment increases average cross-sectional area from 1083 ± 33.58 μm² in CKD mice to 1206 ± 57.91 μm² (p = 0.07)

• In soleus muscle, FGF19 reduces the number of small myofibers and increases myofibers within the range of 1200–2200 μm²

When interpreting these results, researchers should consider:

• The differential response in various muscle types (glycolytic vs. oxidative)

• The relationship between fiber size changes and functional improvements

• The modest changes in fiber type versus more pronounced changes in fiber size

• The correlation between muscle changes and systemic metabolic improvements

What constitutes a significant metabolic response to FGF19 in experimental models?

A significant metabolic response to FGF19 in experimental models encompasses multiple parameters:

• Glucose metabolism improvements:

  • Enhanced glucose tolerance in glucose tolerance tests

  • Increased expression of genes involved in glucose utilization (Pi3k, Gys2)

  • Decreased expression of gluconeogenic genes (G6pc1)

• Lipid metabolism changes:

  • Reduced ectopic lipid accumulation in skeletal muscle

  • Altered serum levels of unsaturated fatty acids

  • Changes in α-linolenic acid and linoleic acid metabolism pathways

• Inflammatory marker reductions:

  • Decreased expression of inflammatory cytokines (Il-1β, Il-6, Tnfα)

  • Reduced expression of Mcp1, Foxo1, and Myd88

• Oxidative stress improvements:

  • Reduced serum MDA levels

  • Increased serum catalase levels

  • Enhanced expression of antioxidant genes (Gpx1, Cat)

  • Increased NRF2 and HO-1 expression

Researchers should interpret FGF19 responses in the context of the specific experimental model and disease state being studied. Statistical significance alone may not always indicate biological relevance; therefore, correlating multiple parameters and assessing functional outcomes provides the most comprehensive evaluation of FGF19 efficacy.