Fibroblast Growth Factor 21 (FGF21) has emerged as a central regulator of energy homeostasis and metabolic adaptation, capturing intense interest from researchers and clinicians alike. Initially identified in 2000 as a member of the fibroblast growth factor (FGF) family, FGF21 quickly distinguished itself through its potent effects on glucose and lipid metabolism. Unlike classical FGFs that function as local paracrine factors, FGF21 behaves as an endocrine hormone, secreted primarily by the liver, adipose tissue, and skeletal muscle, and acts on distant organs to coordinate metabolic responses during fasting, feeding, and stress. Over the past two decades, accumulating evidence has linked circulating FGF21 levels to the pathophysiology of type 2 diabetes (T2D) and obesity, positioning FGF21 both as a biomarker of metabolic dysfunction and as a promising target for therapeutic intervention. This article synthesizes current knowledge on the significance of circulating FGF21 in diabetes and obesity, exploring its molecular mechanisms, clinical correlations, and the evolving landscape of FGF21-based therapies.

Discovery and Biology of FGF21

FGF21 belongs to the endocrine subfamily of FGFs, which includes FGF19 and FGF23. It is encoded by the FGF21 gene on chromosome 19 in humans. The mature protein consists of 181–209 amino acids (species-dependent) and binds to FGF receptors (FGFR1c, FGFR2c, FGFR3c) only in the presence of the co-receptor β-Klotho, a single-pass transmembrane protein that restricts FGF21 action to tissues expressing both FGFR and β-Klotho. This unique requirement confers tissue specificity, limiting the metabolic effects of FGF21 primarily to adipose tissue, liver, pancreas, and the central nervous system.

FGF21 expression is induced by a variety of physiological and pharmacological stimuli. In the liver, fasting, peroxisome proliferator-activated receptor α (PPARα) activation, and amino acid deprivation trigger FGF21 secretion. In adipose tissue, cold exposure and β-adrenergic signaling upregulate FGF21 via PPARγ and cAMP response element-binding protein. These regulatory mechanisms underscore FGF21's role as a stress-responsive hormone that orchestrates fuel switching, ketogenesis, and energy expenditure during periods of metabolic demand.

Circulating FGF21 as a Biomarker in Metabolic Disease

Numerous cross-sectional and prospective studies have demonstrated that circulating FGF21 levels are significantly elevated in individuals with obesity, insulin resistance, and type 2 diabetes compared to healthy controls. For example, a seminal study by Kharitonenkov et al. (2008) in transgenic mice first reported that FGF21 reduces blood glucose and triglycerides, and subsequent human investigations confirmed that plasma FGF21 concentrations are positively correlated with body mass index (BMI), fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). More recently, a meta-analysis of over 30 studies found that serum FGF21 levels are higher in patients with T2D than in euglycemic individuals, and the association persists after adjusting for age and sex.

The paradoxical elevation of FGF21 in metabolic disease suggests the presence of FGF21 resistance, a concept analogous to insulin resistance in T2D. In a resistant state, target tissues fail to respond fully to FGF21 despite elevated circulating levels, leading to compensatory overproduction. The mechanisms underlying FGF21 resistance are not fully understood but may involve downregulation of β-Klotho, impaired FGFR signaling, or post-receptor defects. Interestingly, some studies have reported that FGF21 levels are inversely associated with metabolic health markers in certain populations, indicating context-dependent roles that merit further investigation.

FGF21 and the Progression of Diabetes

In the context of diabetes, FGF21 exerts multiple beneficial effects on glucose metabolism. Animal models have shown that FGF21 treatment lowers blood glucose in ob/ob mice, db/db mice, and high-fat diet–fed rodents without causing hypoglycemia. The hormone promotes glucose uptake in adipocytes via upregulation of glucose transporter type 1 (GLUT1) and enhances insulin sensitivity in liver and muscle. Furthermore, FGF21 stimulates pancreatic β-cell survival and insulin secretion, as demonstrated by studies showing reduced β-cell apoptosis and improved islet function with FGF21 administration. These effects are mediated through signaling pathways involving extracellular signal-regulated kinase (ERK), Akt, and AMP-activated protein kinase (AMPK).

In humans, clinical studies have sought to exploit these benefits. A phase 1 trial of a long-acting FGF21 analog (PF-05231023) revealed dose-dependent improvements in lipid profiles and modest reductions in fasting insulin, although glucose-lowering effects were less pronounced than in rodents. More recent analogs, such as efruxifermin (formerly AMG 876 or FGF21-Fc fusion), have shown promise in reducing liver fat and improving markers of glucose metabolism in patients with nonalcoholic steatohepatitis (NASH), a condition closely linked to T2D. These findings highlight the nuanced role of FGF21 in human diabetes and the need for tailored therapeutic strategies.

FGF21 and Obesity: Mechanisms and Therapeutic Implications

Obesity is characterized by chronic low-grade inflammation, insulin resistance, and altered hormone signaling. Circulating FGF21 levels are consistently elevated in obese individuals, yet the degree of elevation often correlates with the severity of metabolic abnormalities. Interestingly, weight loss—whether through bariatric surgery, calorie restriction, or pharmacotherapy—typically reduces FGF21 levels, supporting the idea that hyper-FGF21emia is an adaptive response to metabolic stress that becomes maladaptive when sustained.

Beyond its role in peripheral tissues, FGF21 acts centrally in the brain to regulate energy expenditure and food intake. In rodent models, central administration of FGF21 increases energy expenditure via sympathetic outflow to brown adipose tissue (BAT), a process known as thermogenesis. FGF21 also induces the browning of white adipose tissue (WAT), converting energy-storing white adipocytes into energy-burning beige cells. This browning effect is mediated through the β-Klotho-FGFR1c complex in the suprachiasmatic nucleus and the hypothalamus, influencing neuropeptide Y and pro-opiomelanocortin pathways. Although translation to humans remains incomplete, PET imaging studies have confirmed that BAT is metabolically active in adults, and FGF21 levels correlate with BAT activity during cold exposure.

In the central nervous system, FGF21 reduces appetite and reward-driven eating behavior. A study by Emanuelli et al. (2016) demonstrated that FGF21 triggers a preference for carbohydrate over fat intake, suggesting a role in macronutrient selection. These central effects position FGF21 as a multifaceted regulator of body weight, acting on both sides of the energy balance equation—intake and expenditure.

FGF21 Resistance: The Puzzle of Elevated Levels with Diminished Response

The concept of FGF21 resistance has been proposed to explain the disconnect between high circulating FGF21 and persistent metabolic disease. Studies in diet-induced obese (DIO) mice have shown reduced FGF21-stimulated phosphorylation of ERK and decreased expression of target genes such as Egr1 and c-Fos in adipose tissue, coupled with lower β-Klotho protein levels. Similarly, in humans, a hyperinsulinemic-euglycemic clamp study found that FGF21 infusion failed to increase insulin sensitivity in obese insulin-resistant subjects, despite raising FGF21 levels several-fold. These observations point to a state of impaired FGF21 signaling that may contribute to the progression of metabolic syndrome.

Potential mechanisms of FGF21 resistance include:

  • Downregulation of β-Klotho in target tissues, reducing receptor activation.
  • Desensitization of FGFR1c due to chronic ligand exposure.
  • Post-receptor defects involving impaired MAPK/ERK and PI3K/Akt pathways.
  • Competitive inhibition from other FGF ligands or altered co-factor binding.
  • Chronic inflammation mediated by TNF-α and IL-6, which may suppress FGF21 signaling.

Understanding FGF21 resistance is critical for designing effective therapies. Analogs that are resistant to proteolytic degradation or that possess higher receptor affinity may overcome some aspects of resistance. Combining FGF21 with agents that restore β-Klotho expression, such as PPARγ agonists or metformin, could also enhance efficacy.

Therapeutic Development: FGF21 Analogs and Receptor Agonists

The therapeutic potential of FGF21 has been pursued through multiple approaches, including recombinant FGF21 variants, fusion proteins with enhanced half-life, and small-molecule agonists of the β-Klotho-FGFR complex. Early development was hampered by the short half-life of native FGF21 (approximately 0.5–2 hours), attributed to proteolytic cleavage by enzymes such as fibroblast activation protein (FAP) and neprilysin. To address this, several long-acting FGF21 analogs have been engineered and entered clinical trials.

Efruxifermin

Efruxifermin (also known as EFX or AMG 876) is an Fc-fusion FGF21 analog with an extended half-life of approximately 5–6 days. In the phase 2b BALANCED trial for NASH, efruxifermin significantly reduced liver fat content, improved fibrosis, and lowered triglycerides and LDL cholesterol. Secondary endpoints included improvements in HOMA-IR and fasting insulin, suggesting favorable effects on glucose metabolism. Adverse events, including mild gastrointestinal symptoms and increased appetite, were reported, but the overall safety profile was acceptable. A phase 3 program is currently underway with a focus on NASH and associated metabolic comorbidities.

Pegozafermin

Pegozafermin (formerly BI 456,906) is a polyethylene glycol (PEG)-ylated FGF21 analog designed to reduce renal clearance and improve pharmacokinetics. In the ENLIVEN phase 2b trial, pegozafermin met its primary endpoint of histological improvement in NASH, with significant reductions in liver fat and fibrosis. Additionally, the drug reduced body weight by approximately 5–7% in treated groups, and improvements in glucose parameters were observed. Ongoing studies are evaluating its long-term effects on diabetes and obesity.

BMS-986036

BMS-986036 (previously known as FGF21-LRS) is another PEGylated FGF21 variant. Phase 2 data showed reductions in liver fat and improvements in serum triglycerides in patients with NASH. However, effects on glycemic control were modest, and the program was later deprioritized in favor of other candidates. Nonetheless, these trials collectively validate FGF21 as a druggable target for metabolic disease.

Non-Peptide Agonists

An alternative strategy involves small-molecule agonists that activate the β-Klotho-FGFR1c heterodimer. While still in preclinical stages, these compounds offer the advantages of oral bioavailability and reduced immunogenicity compared to biologics. Advances in structural biology have enabled the design of selective probes that mimic FGF21 binding. Early reports indicate that such agonists can induce FGF21-like metabolic effects in rodents, raising hope for future oral therapies.

Integrating FGF21 into Clinical Practice

Before FGF21-based therapies become mainstream, several challenges must be addressed. First, the heterogeneity of FGF21 resistance among individuals may necessitate personalized dosing or combination regimens. Second, the potential for on-target side effects, such as bone loss or cardiovascular events, requires careful monitoring. FGF21 is known to inhibit bone formation and stimulate bone resorption in rodents, but human data are limited. A recent study by Chen et al. (2022) found no significant changes in bone mineral density after 24 weeks of FGF21 analog treatment in patients with NASH, though longer-term studies are needed.

Second, the role of FGF21 as a biomarker could be translated into routine clinical testing. While enzyme-linked immunosorbent assays (ELISAs) for FGF21 are commercially available, standardization across laboratories is lacking. Establishing reference ranges and validating FGF21 as a predictor of metabolic outcomes would facilitate its inclusion in risk stratification algorithms. Some researchers have proposed using the FGF21-to-insulin ratio as a marker of FGF21 sensitivity, analogous to the HOMA index.

Third, lifestyle interventions such as exercise and dietary modification can modulate FGF21 levels. Acute exercise, particularly high-intensity interval training, transiently increases FGF21, while chronic training may lower it in parallel with improved metabolic health. Similarly, fasting or very-low-calorie diets elevate FGF21, possibly contributing to the metabolic benefits of intermittent fasting. Understanding how these natural fluctuations intersect with pharmacological FGF21 enhancement could guide future combination strategies.

Conclusion and Future Perspectives

Circulating FGF21 has evolved from a curiosity of metabolic endocrinology to a key player in the pathogenesis of diabetes and obesity. The consistent observation of elevated FGF21 in these conditions, alongside evidence of resistance, has spurred the development of novel therapeutics aimed at restoring FGF21 sensitivity or providing supraphysiological FGF21 activity. The promising results from phase 2 trials of FGF21 analogs in NASH, a disease closely linked to obesity and T2D, suggest that these agents may soon add to the existing armamentarium for metabolic disease management.

Future research directions include elucidation of the molecular basis of FGF21 resistance, identification of biomarkers to predict therapy response, and exploration of combinatorial approaches with GLP-1 receptor agonists, SGLT2 inhibitors, or bariatric surgery. Moreover, the role of FGF21 in circadian rhythm, aging, and non-metabolic tissues (e.g., heart, kidney) is only beginning to be uncovered. As the field moves forward, FGF21 represents a compelling paradigm of how an endocrine stress hormone can be harnessed for therapeutic benefit, offering hope to millions affected by metabolic disorders.

  • FGF21 is an endocrine hormone that regulates glucose and lipid metabolism, energy expenditure, and appetite.
  • Elevated circulating FGF21 in diabetes and obesity suggests a state of FGF21 resistance.
  • Therapeutic strategies include long-acting FGF21 analogs and small-molecule agonists.
  • Phase 2/3 trials demonstrate improvements in liver fat, fibrosis, lipids, and glycemic markers.
  • FGF21 holds potential as both a biomarker and a drug target for metabolic diseases.