Fibroblast Growth Factor 1: A Pleiotropic Regulator of Metabolism, Tissue Repair, and Neuroprotection with Implications for Therapeutic Development

Abstract

Fibroblast Growth Factor 1 (FGF1), an archetypal member of the FGF family, is distinguished by its broad receptor specificity and potent, multifaceted biological activities. While initially recognized for its role in angiogenesis and wound healing, recent research has unveiled a far more expansive repertoire of functions encompassing metabolic regulation, tissue regeneration, and neuroprotection. This review aims to provide a comprehensive overview of FGF1, exploring its intricate signaling pathways, diverse physiological functions, and emerging therapeutic potential. We will delve into the molecular mechanisms underlying its actions, including its interaction with various FGF receptors (FGFRs) and co-receptors, its impact on glucose homeostasis and lipid metabolism, its involvement in tissue repair processes, and its promising neuroprotective effects. Furthermore, we will critically evaluate the challenges and opportunities associated with developing FGF1-based therapies for a range of disorders, from metabolic diseases like type 2 diabetes and non-alcoholic steatohepatitis (NASH) to neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases. We will also explore the potential for combining FGF1 with other therapeutic modalities to enhance efficacy and address the complexity of these multifaceted diseases.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

The fibroblast growth factor (FGF) family comprises 22 members in mammals, acting as signaling molecules that regulate a wide spectrum of biological processes. These processes range from embryonic development and angiogenesis to wound healing, metabolic homeostasis, and neurotrophic support [1]. Among these, FGF1 holds a unique position due to its unusually broad receptor specificity and potent biological activity [2]. Unlike many other FGFs that exhibit restricted receptor binding profiles, FGF1 can bind and activate all seven tyrosine kinase FGF receptors (FGFR1-4 with various splice variants) in the presence of appropriate co-receptors, typically heparan sulfate proteoglycans (HSPGs) [3]. This broad receptor specificity allows FGF1 to elicit diverse cellular responses depending on the cellular context and the availability of specific FGFR isoforms and co-receptors.

FGF1, also known as acidic FGF (aFGF), was initially characterized as a potent mitogen for fibroblasts and endothelial cells, playing a critical role in angiogenesis and wound healing [4]. However, recent studies have revealed a much broader range of functions, highlighting its importance in metabolic regulation, tissue regeneration, and neuroprotection [5]. The discovery of FGF1’s potent glucose-lowering and insulin-sensitizing effects in preclinical models has sparked significant interest in its potential as a novel therapeutic target for type 2 diabetes (T2D) [6]. Moreover, FGF1 has demonstrated remarkable neuroprotective properties in various in vitro and in vivo models of neurodegenerative diseases, suggesting its potential as a therapeutic agent for conditions such as Alzheimer’s disease and Parkinson’s disease [7].

This review aims to provide a comprehensive overview of FGF1, exploring its intricate signaling pathways, diverse physiological functions, and emerging therapeutic potential. We will delve into the molecular mechanisms underlying its actions, including its interaction with various FGF receptors (FGFRs) and co-receptors, its impact on glucose homeostasis and lipid metabolism, its involvement in tissue repair processes, and its promising neuroprotective effects. Furthermore, we will critically evaluate the challenges and opportunities associated with developing FGF1-based therapies for a range of disorders, from metabolic diseases to neurodegenerative conditions. We will also explore the potential for combining FGF1 with other therapeutic modalities to enhance efficacy and address the complexity of these multifaceted diseases.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. FGF1 Signaling Pathways: Receptor Specificity and Downstream Effects

The signaling mechanisms of FGF1 are complex and context-dependent, primarily relying on the activation of FGFRs. These receptors are receptor tyrosine kinases (RTKs) that, upon FGF1 binding, undergo dimerization and autophosphorylation, initiating a cascade of intracellular signaling events [8]. The specificity of FGF1 signaling is not solely determined by the FGFR isoform expressed by a given cell type but also by the availability of appropriate co-receptors, particularly HSPGs, and the intracellular signaling milieu.

2.1. FGFR Activation and Co-receptor Involvement

FGF1 binds to FGFRs with varying affinities, and the specific FGFR isoform activated dictates the downstream signaling pathways engaged [9]. HSPGs play a crucial role in FGF1 signaling by facilitating FGF1-FGFR interaction and stabilizing the receptor complex. The sulfation pattern of the heparan sulfate chains within HSPGs is critical for their interaction with FGF1 and FGFRs [10]. Variations in HSPG expression and sulfation patterns across different tissues and cell types contribute to the tissue-specific effects of FGF1. Moreover, Klotho proteins, particularly β-Klotho, can also act as co-receptors for specific FGFRs, modulating FGF1 signaling in certain tissues, such as the liver [11].

2.2. Downstream Signaling Pathways

Activation of FGFRs by FGF1 triggers several major downstream signaling pathways, including:

• MAPK/ERK Pathway: The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is a central signaling cascade activated by FGF1-FGFR interaction. This pathway regulates cell proliferation, differentiation, and survival [12]. The MAPK/ERK pathway is particularly important for FGF1-mediated angiogenesis and wound healing.
• PI3K/Akt Pathway: The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is another critical signaling cascade activated by FGF1. This pathway promotes cell survival, growth, and metabolism [13]. The PI3K/Akt pathway is crucial for FGF1’s metabolic effects, including glucose uptake and insulin sensitization.
• PLCγ Pathway: The phospholipase C gamma (PLCγ) pathway is involved in calcium signaling and the regulation of various cellular processes, including cell adhesion and migration [14].
• STAT Pathway: The signal transducer and activator of transcription (STAT) pathway is involved in gene regulation and immune responses [15].

The relative activation of these pathways depends on the specific FGFR isoform engaged, the cellular context, and the presence of other signaling molecules. Crosstalk between these pathways adds further complexity to FGF1 signaling, allowing for fine-tuned regulation of cellular responses.

2.3. Intracellular Regulation of FGF1 Activity

FGF1 activity is also regulated by intracellular mechanisms. For example, Sprouty proteins, such as Sprouty2 and Sprouty4, can inhibit FGF1 signaling by binding to FGFRs and preventing their activation of downstream signaling pathways [16]. Furthermore, ubiquitination and degradation of FGFRs can attenuate FGF1 signaling [17]. These intracellular regulatory mechanisms provide feedback loops that control the duration and intensity of FGF1 signaling.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Metabolic Regulation by FGF1: Glucose Homeostasis and Lipid Metabolism

One of the most exciting recent discoveries regarding FGF1 is its role in metabolic regulation, particularly its ability to improve glucose homeostasis and modulate lipid metabolism. Preclinical studies have demonstrated that FGF1 administration can lower blood glucose levels, improve insulin sensitivity, and reduce hepatic steatosis in animal models of T2D and obesity [18]. These effects are mediated by multiple mechanisms, including increased glucose uptake in peripheral tissues, reduced hepatic glucose production, and improved lipid metabolism.

3.1. Glucose Homeostasis

FGF1 promotes glucose uptake in skeletal muscle and adipose tissue by increasing the translocation of glucose transporter 4 (GLUT4) to the cell membrane [19]. This effect is mediated by the activation of the PI3K/Akt pathway, which is essential for GLUT4 trafficking. Furthermore, FGF1 can suppress hepatic glucose production by inhibiting the expression of key gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) [20]. The precise mechanisms underlying this effect are still under investigation, but it is likely mediated by the activation of FGFRs in the liver and the subsequent modulation of transcription factors involved in gluconeogenesis. Intriguingly, studies also suggest a role for FGF1 in promoting insulin secretion from pancreatic β-cells, although the mechanisms remain to be fully elucidated [21].

3.2. Lipid Metabolism

FGF1 also plays a significant role in lipid metabolism. It has been shown to reduce hepatic steatosis, or fatty liver, in animal models of non-alcoholic steatohepatitis (NASH) [22]. FGF1 promotes fatty acid oxidation and reduces lipogenesis in the liver, leading to a decrease in triglyceride accumulation. This effect is mediated by the activation of FGFRs in the liver and the subsequent modulation of transcription factors involved in lipid metabolism, such as peroxisome proliferator-activated receptor alpha (PPARα) and sterol regulatory element-binding protein-1c (SREBP-1c) [23]. Furthermore, FGF1 can increase energy expenditure and promote weight loss in obese mice [24].

3.3. Advantages over Existing Diabetes Drugs

FGF1 offers several potential advantages over existing diabetes drugs. Unlike insulin and sulfonylureas, FGF1 does not cause hypoglycemia, as it does not directly stimulate insulin secretion in a glucose-independent manner [25]. Instead, FGF1 appears to enhance insulin sensitivity and improve glucose homeostasis without increasing the risk of dangerously low blood sugar levels. Furthermore, FGF1 has been shown to improve lipid metabolism and reduce hepatic steatosis, which are common complications of T2D and obesity. These effects are not typically observed with many existing diabetes drugs. However, more research is required to fully characterise its safety and efficacy profile in humans.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Tissue Repair and Regeneration

FGF1 was initially recognized for its role in angiogenesis and wound healing. It is a potent mitogen for fibroblasts and endothelial cells, promoting their proliferation and migration [26]. FGF1 stimulates the formation of new blood vessels (angiogenesis), which is essential for tissue repair and regeneration. It also promotes the deposition of extracellular matrix components, such as collagen, which provides structural support for newly formed tissues [27].

4.1. Wound Healing

FGF1 has been shown to accelerate wound healing in various animal models [28]. It promotes the formation of granulation tissue, which is essential for wound closure. FGF1 also stimulates the migration of keratinocytes, which are the main cells that form the epidermis, the outer layer of the skin. Furthermore, FGF1 can reduce scar formation by promoting the organized deposition of collagen [29].

4.2. Bone Regeneration

FGF1 also plays a role in bone regeneration. It stimulates the proliferation and differentiation of osteoblasts, which are the cells that form new bone [30]. FGF1 promotes the formation of new bone tissue and improves bone density. It has been shown to accelerate bone healing in animal models of bone fractures [31].

4.3. Cardiac Repair

Emerging evidence suggests that FGF1 may also have potential in cardiac repair following myocardial infarction (heart attack). FGF1 can promote angiogenesis in the infarcted heart, improving blood flow to the damaged tissue [32]. It can also reduce the size of the infarct and improve cardiac function. However, further research is needed to fully understand the mechanisms underlying FGF1’s effects on cardiac repair and to evaluate its potential as a therapeutic agent for heart disease.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Neuroprotection and Cognitive Enhancement

Recent studies have revealed that FGF1 exhibits remarkable neuroprotective properties and may even enhance cognitive function. It has been shown to protect neurons from damage in various in vitro and in vivo models of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease [33]. FGF1 promotes neuronal survival, reduces inflammation, and enhances synaptic plasticity, which is the ability of synapses to strengthen or weaken over time.

5.1. Alzheimer’s Disease

In Alzheimer’s disease models, FGF1 has been shown to reduce the accumulation of amyloid-beta plaques, which are a hallmark of the disease [34]. FGF1 promotes the clearance of amyloid-beta from the brain and reduces its production. It also protects neurons from the toxic effects of amyloid-beta. Furthermore, FGF1 can improve cognitive function in Alzheimer’s disease models, enhancing memory and learning [35].

5.2. Parkinson’s Disease

In Parkinson’s disease models, FGF1 has been shown to protect dopaminergic neurons, which are the neurons that are affected in the disease [36]. FGF1 promotes the survival of dopaminergic neurons and reduces their degeneration. It also improves motor function in Parkinson’s disease models. The neuroprotective effects of FGF1 in Parkinson’s disease may be mediated by its ability to reduce oxidative stress and inflammation in the brain [37].

5.3. Mechanisms of Neuroprotection

The mechanisms underlying FGF1’s neuroprotective effects are complex and multifactorial. FGF1 activates FGFRs on neurons, leading to the activation of downstream signaling pathways, such as the MAPK/ERK and PI3K/Akt pathways, which promote neuronal survival and reduce apoptosis [38]. FGF1 also stimulates the production of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which further supports neuronal survival and function [39]. Furthermore, FGF1 can reduce inflammation in the brain by suppressing the activation of microglia, which are the immune cells of the brain [40].

5.4. Cognitive Enhancement

Intriguingly, some studies suggest that FGF1 may also enhance cognitive function in healthy individuals. FGF1 has been shown to improve memory and learning in animal models [41]. It promotes synaptic plasticity and increases the number of synapses in the brain. These effects may be mediated by FGF1’s ability to stimulate the production of BDNF, which is known to play a critical role in cognitive function. However, further research is needed to determine whether FGF1 can enhance cognitive function in humans.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Challenges and Opportunities in Developing FGF1-Based Therapies

While FGF1 holds significant promise as a therapeutic agent for a range of disorders, several challenges need to be addressed to translate its potential into clinical reality.

6.1. Delivery and Stability

One of the major challenges is the delivery of FGF1 to the target tissue. FGF1 is a protein that is susceptible to degradation in the body. Therefore, it is important to develop delivery strategies that protect FGF1 from degradation and ensure that it reaches the target tissue in sufficient amounts [42]. Various delivery methods are being explored, including gene therapy, protein engineering, and nanoparticle-based delivery systems [43]. Furthermore, chemical modifications to FGF1 may improve its stability and resistance to proteolytic degradation. The development of orally bioavailable FGF1 mimetics or small molecule FGFR agonists also represents an attractive alternative strategy.

6.2. Specificity and Off-Target Effects

Another challenge is to ensure that FGF1 acts specifically on the target tissue and does not cause unwanted side effects. FGF1’s broad receptor specificity can lead to off-target effects, such as angiogenesis in non-target tissues. Therefore, it is important to develop strategies to target FGF1 signaling to specific tissues or cell types [44]. This can be achieved by using tissue-specific promoters in gene therapy vectors or by developing FGF1 variants that selectively bind to specific FGFR isoforms. It might be prudent to focus on FGFR selectivity, or downstream pathway selectivity, to overcome issues of broad receptor affinity. This could be achieved by developing small molecules that specifically target a single FGFR isoform or downstream effector.

6.3. Immunogenicity

FGF1, being a protein, may elicit an immune response in some individuals. This immune response can neutralize FGF1 and reduce its therapeutic efficacy. Therefore, it is important to develop strategies to minimize the immunogenicity of FGF1 [45]. This can be achieved by using humanized FGF1 variants or by co-administering immunosuppressive agents. However, systemic immunosuppression is not desirable and should be avoided if possible.

6.4. Clinical Trials and Regulatory Approval

Despite these challenges, there are also significant opportunities in developing FGF1-based therapies. Several clinical trials are underway to evaluate the safety and efficacy of FGF1 in various diseases, including T2D and wound healing [46]. The results of these trials will provide valuable information about the potential of FGF1 as a therapeutic agent. Furthermore, regulatory agencies are becoming increasingly receptive to novel therapeutic approaches, which may facilitate the approval of FGF1-based therapies. The relatively well understood signalling pathways, and the decades of research into FGF1, should facilitate rapid regulatory approval, provided it is proven safe and effective.

6.5. Combination Therapies

FGF1 may be particularly effective when combined with other therapeutic agents. For example, combining FGF1 with existing diabetes drugs may lead to synergistic effects on glucose homeostasis and lipid metabolism [47]. Similarly, combining FGF1 with other neuroprotective agents may enhance its neuroprotective effects. Combination therapies offer the potential to address the complexity of multifaceted diseases and improve treatment outcomes. However, careful attention to potential drug-drug interactions and additive toxicities is warranted.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Long-Term Effects on Metabolic Health and Overall Well-being

While short-term studies have demonstrated the beneficial effects of FGF1 on glucose homeostasis, lipid metabolism, and tissue repair, the long-term effects of FGF1 on metabolic health and overall well-being remain to be fully elucidated. It is important to evaluate the long-term safety and efficacy of FGF1-based therapies to ensure that they provide sustained benefits without causing adverse effects. Long-term studies should assess the impact of FGF1 on various aspects of metabolic health, including insulin sensitivity, glucose tolerance, lipid profile, and liver function. Furthermore, it is important to evaluate the long-term effects of FGF1 on cardiovascular health, bone density, and cognitive function. Given the pleiotropic nature of FGF1, assessing its broader impact on overall well-being, including mood, sleep quality, and physical function, is also crucial. However, given the number of different receptors and co-receptors, it is extremely unlikely that the pleiotropic effects can be isolated. Careful design of clinical trials will be required to tease apart the different effects of FGF1.

7.1. Potential for Disease Modification

One of the most exciting possibilities is that FGF1 may have the potential to modify the course of chronic diseases, such as T2D and Alzheimer’s disease. By improving insulin sensitivity, reducing hepatic steatosis, and protecting neurons from damage, FGF1 may be able to slow down the progression of these diseases and prevent long-term complications [48]. However, more research is needed to determine whether FGF1 can truly modify the course of these diseases. This will require long-term clinical trials that assess the impact of FGF1 on disease progression and patient outcomes. The expense of such studies should not be underestimated.

7.2. Personalized Medicine

The response to FGF1 may vary among individuals, depending on their genetic background, lifestyle, and disease stage. Therefore, personalized medicine approaches may be particularly relevant for FGF1-based therapies. By identifying individuals who are most likely to respond to FGF1, we can improve treatment outcomes and minimize the risk of adverse effects. This may involve using biomarkers to predict response to FGF1 or tailoring the dose and delivery method to individual needs. However, the costs associated with personalised medicine may be prohibitive.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Conclusion

FGF1 is a pleiotropic regulator of metabolism, tissue repair, and neuroprotection with significant therapeutic potential. Its ability to improve glucose homeostasis, modulate lipid metabolism, promote tissue regeneration, and protect neurons from damage makes it an attractive target for the development of novel therapies for a range of disorders, including T2D, NASH, Alzheimer’s disease, and Parkinson’s disease. While several challenges remain, ongoing research efforts are focused on addressing these challenges and translating the potential of FGF1 into clinical reality. The development of improved delivery methods, strategies to enhance specificity, and long-term clinical trials will be crucial for realizing the full therapeutic potential of FGF1. Further research into the long-term effects of FGF1 on metabolic health and overall well-being is also essential. Ultimately, FGF1 holds great promise as a novel therapeutic agent that can improve the lives of millions of people affected by metabolic diseases, tissue injuries, and neurodegenerative conditions. However, it is important to maintain a balanced perspective, and avoid overly optimistic predictions, while carefully considering the potential risks and benefits of FGF1-based therapies. With further research, we may unlock the full potential of this remarkable growth factor and develop effective treatments for these devastating diseases.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

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