Fibroblast Growth Factor 21 (FGF21) is a metabolic hormone with potent effects on energy balance, glucose homeostasis, and lipid metabolism. Discovered in the early 2000s, FGF21 is primarily secreted by the liver, though it is also expressed in adipose tissue, pancreas, and skeletal muscle. Unlike many fibroblast growth factors that act locally as paracrine signals, FGF21 functions as an endocrine factor, traveling through the bloodstream to regulate metabolic responses in distant tissues. Its unique ability to mimic aspects of fasting physiology—such as increased fatty acid oxidation and improved insulin sensitivity—has made it a compelling target for treating obesity and type 2 diabetes. Over the past two decades, a growing body of evidence from preclinical models and early human trials has established FGF21 as a key player in metabolic regulation and a promising therapeutic candidate for the prevention and treatment of metabolic disease.

Understanding FGF21: Structure, Receptors, and Production

FGF21 is a 181‑amino acid protein belonging to the fibroblast growth factor (FGF) family, which includes 22 members in humans. What sets FGF21 apart is its lack of a heparin‑binding domain, allowing it to escape sequestration in the extracellular matrix and act systemically. FGF21 signals through a receptor complex that includes a conventional FGF receptor (FGFR1c, FGFR2c, or FGFR3c) and the co‑receptor β‑klotho (KLB). The expression of β‑klotho is largely restricted to metabolic tissues such as liver, adipose tissue, pancreas, and the central nervous system, conferring tissue specificity to FGF21 signaling.

Hepatic production of FGF21 is dramatically upregulated during periods of fasting, starvation, or in response to dietary challenges such as a high‑fat diet. This upregulation is driven by the transcription factor peroxisome proliferator‑activated receptor α (PPARα), which binds to the FGF21 gene promoter. Additionally, other nuclear receptors, including PPARγ and the retinoid X receptor, can modulate FGF21 expression in adipose tissue. Under normal conditions, circulating FGF21 levels fluctuate with nutritional state: they are low in the fed state and rise during fasting, reaching peak levels after 24–48 hours of food deprivation. This pattern supports the view of FGF21 as a fasting‑induced hormone that orchestrates metabolic adaptations to energy deficit.

Beyond the liver, FGF21 is also produced in white and brown adipose tissue, the pancreas, and skeletal muscle. In obesity and type 2 diabetes, circulating FGF21 concentrations are often two‑ to three‑fold higher than in lean, healthy individuals. This elevation is thought to represent a compensatory response to metabolic stress, but it also signals the development of FGF21 resistance—a condition in which target tissues become less responsive to the hormone. Understanding the balance between FGF21 production and signaling efficiency is critical for developing effective therapeutics.

FGF21 and Energy Homeostasis: Effects on Energy Expenditure and Lipid Metabolism

One of the most well‑characterized actions of FGF21 is its ability to increase energy expenditure. In animal models, administration of FGF21 leads to a significant rise in oxygen consumption and heat production, an effect mediated primarily through the browning of white adipose tissue. Browning refers to the transformation of energy‑storing white adipocytes into beige or brite adipocytes that express uncoupling protein 1 (UCP1). UCP1 allows mitochondria to dissipate the proton gradient as heat rather than producing ATP, thereby increasing energy expenditure. FGF21 stimulates browning both directly, by acting on adipocyte FGFR1/β‑klotho complexes, and indirectly, via activation of the sympathetic nervous system and secretion of other factors such as irisin and norepinephrine.

FGF21 also promotes fatty acid oxidation in the liver and adipose tissue. During fasting, elevated FGF21 signals the liver to increase the β‑oxidation of fatty acids derived from adipose tissue lipolysis. This process generates ketone bodies (acetoacetate and β‑hydroxybutyrate), which serve as alternative fuel sources for the brain and other tissues. In obese animals, FGF21 treatment reduces hepatic steatosis and lowers circulating triglycerides, partly by increasing the expression of genes involved in fatty acid oxidation (e.g., CPT1A, ACOX1) and decreasing lipogenic gene expression (e.g., SREBP‑1c, FAS). These effects collectively reduce fat mass and improve metabolic health.

Furthermore, FGF21 influences lipid trafficking by enhancing clearance of very low‑density lipoproteins (VLDL) and reducing cholesterol synthesis. Human studies with FGF21 analogs have consistently demonstrated reductions in triglycerides and LDL cholesterol, along with increases in HDL cholesterol. The combination of increased energy expenditure, enhanced fat oxidation, and improved lipid profile positions FGF21 as a powerful agent for combating obesity‑related dyslipidemia.

The Role of FGF21 in the Central Nervous System

FGF21 can cross the blood‑brain barrier and act directly on the brain, particularly the hypothalamus and hindbrain areas involved in energy balance. Central administration of FGF21 suppresses appetite and enhances energy expenditure. Surprisingly, however, peripheral FGF21 administration often does not lead to marked anorexia in humans; instead, the primary effect on energy balance appears to be through increased thermogenesis rather than reduced caloric intake. Nonetheless, FGF21 signaling in the brain contributes to the regulation of circadian rhythms, stress responses, and dietary preference. For example, FGF21 has been shown to reduce the preference for simple sugars and alcohol, suggesting it may help curb cravings for high‑calorie foods. This central action adds another layer of metabolic control and therapeutic potential.

The Paradox of FGF21 Resistance in Obesity

Although FGF21 levels rise in obesity, the expected metabolic benefits are often blunted. This phenomenon, known as FGF21 resistance, mirrors the well‑established insulin resistance seen in type 2 diabetes. In resistant states, target tissues such as white adipose tissue and the liver fail to respond adequately to FGF21, despite high circulating concentrations. The precise mechanisms underlying FGF21 resistance are complex and multifactorial, involving receptor downregulation, impaired co‑receptor availability, and intracellular signaling defects.

Molecular Mechanisms of Resistance

One major contributor is the reduction in β‑klotho expression in adipose tissue. β‑klotho is the obligate co‑receptor for FGF21; without it, FGF21 cannot bind effectively to FGFRs. In obese mice and humans, β‑klotho mRNA and protein levels are decreased in subcutaneous and visceral adipose tissue, limiting FGF21 signaling. Additionally, chronic exposure to high FGF21 levels may promote internalization and degradation of the FGF21 receptor complex. There is also evidence of impaired downstream signaling, such as reduced phosphorylation of ERK1/2 and STAT3, and increased activity of negative regulators like SOCS3 (suppressor of cytokine signaling 3).

Inflammation is another key player in FGF21 resistance. Obesity is characterized by a state of chronic low‑grade inflammation, with elevated tumor necrosis factor‑α (TNF‑α), interleukin‑6 (IL‑6), and other inflammatory cytokines. These cytokines can interfere with FGF21 signaling pathways, particularly by activating c‑Jun N‑terminal kinase (JNK) and IκB kinase (IKK), which impair insulin and FGF21 action. Furthermore, endoplasmic reticulum stress, common in obesity, may reduce β‑klotho expression and FGF21 sensitivity.

The existence of FGF21 resistance has important implications for therapy. Simply raising FGF21 levels further with supplements or gene therapy may be ineffective if target tissues are unresponsive. This has driven the development of FGF21 analogs and variants that have enhanced potency, longer half‑life, and the ability to bypass resistance mechanisms. Some engineered versions have shown efficacy even in models of established resistance, possibly because they bind to a broader range of FGFR subtypes or interact with β‑klotho with higher affinity.

FGF21 and Glucose Metabolism: Implications for Diabetes

FGF21 exerts profound effects on glucose homeostasis, making it a promising target for diabetes therapy. The hormone improves insulin sensitivity, stimulates glucose uptake in peripheral tissues, and suppresses hepatic glucose production. These actions are mediated through coordinated signaling in the liver, adipose tissue, and pancreas.

Effects on the Liver

In the liver, FGF21 suppresses gluconeogenesis by reducing the expression of key enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose‑6‑phosphatase (G6Pase). This effect is partly mediated by activation of the ERK1/2 pathway and downstream inhibition of CREB and FoxO1 transcriptional activity. FGF21 also promotes glycogen synthesis, helping to store glucose as a reserve. Together, these actions lower hepatic glucose output and contribute to fasting glucose reduction. In animal models of obesity and diabetes, FGF21 treatment normalizes fasting blood glucose and improves oral glucose tolerance.

Additionally, FGF21 reduces hepatic steatosis, which is often associated with insulin resistance and non‑alcoholic fatty liver disease (NAFLD). By increasing fatty acid oxidation and decreasing de novo lipogenesis, FGF21 alleviates liver fat accumulation—a primary driver of hepatic insulin resistance. Clinical trials with FGF21 analogs have shown significant reductions in liver fat content and improvements in biomarkers of liver injury, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This dual benefit—glucose lowering and liver fat reduction—positions FGF21 as a potential therapy for type 2 diabetes complicated by NAFLD.

Effects on Adipose Tissue

FGF21 stimulates glucose uptake in adipose tissue via translocation of glucose transporter type 4 (GLUT4) to the cell membrane. This effect is independent of insulin, making FGF21 particularly valuable in states of severe insulin resistance. In white adipose tissue, FGF21 also suppresses lipolysis under some conditions, reducing circulating free fatty acids that would otherwise worsen insulin resistance (a phenomenon known as lipotoxicity). At the same time, FGF21 promotes expansion of metabolically healthy adipose tissue, which may help sequester lipids away from the liver and muscle. In brown and beige adipose tissue, FGF21 enhances glucose uptake to fuel thermogenesis.

Effects on the Pancreas

FGF21 receptors and β‑klotho are expressed on pancreatic islet cells, including α and β cells. In animal studies, FGF21 protects β‑cells from apoptosis induced by glucolipotoxicity, oxidative stress, and endoplasmic reticulum stress. It also stimulates insulin secretion under conditions of hyperglycemia, though the effect is moderate compared to incretin hormones. Importantly, FGF21 suppresses glucagon secretion from α‑cells, which may contribute to improved glucose tolerance. Thus, FGF21 has a dual action on the pancreas: enhancing insulin secretion and preserving β‑cell mass while reducing glucagon release. These pancreatic effects are additive to its actions on liver and adipose tissue, making FGF21 a multi‑organ regulator of glucose metabolism.

Therapeutic Development: FGF21 Analogs in Clinical Trials

Given its broad metabolic benefits, several FGF21 analogs have been developed and tested in human clinical trials. These analogs are designed to improve pharmacokinetics—native FGF21 has a short half‑life of about 1–2 hours—and to enhance potency. Most analogs incorporate modifications such as pegylation, fusion to an antibody Fc domain, or amino acid substitutions to reduce proteolysis or improve receptor binding.

Pegbelfermin (BMS‑986036)

Pegbelfermin is a pegylated recombinant human FGF21 analog developed by Bristol‑Myers Squibb. In phase 2 trials for non‑alcoholic steatohepatitis (NASH) and type 2 diabetes, pegbelfermin significantly reduced liver fat content, improved fibrosis markers, and lowered HbA1c and fasting glucose. Patients also experienced weight loss and improvements in lipid profiles. However, some trials noted gastrointestinal side effects, including nausea and diarrhea, and the drug did not always meet primary endpoints for fibrosis resolution. The development of pegbelfermin for NASH was eventually halted after mixed phase 2b results, but it provided proof‑of‑concept for FGF21‑based therapy.

Efruxifermin (AKR‑001, formerly AMG 876)

Efruxifermin is an Fc‑FGF21 fusion protein developed by Akero Therapeutics. In phase 2b trials for NASH (e.g., the HARMONY study), efruxifermin achieved significant rates of NASH resolution without worsening fibrosis, and also improved liver fat, HbA1c, and body weight. Once‑weekly doses were well tolerated, with mild to moderate gastrointestinal effects. Akero is now proceeding with phase 3 trials. This success suggests that FGF21 analogs may become a cornerstone of NASH and diabetes treatment.

Other Analogs in Development

Several other FGF21‑based therapies are in earlier stages. LL‑F22 (long‑acting FGF21) from LG Chem has shown promise in animal models. NNC0194‑0499 is a long‑acting FGF21 analog from Novo Nordisk that was tested in obesity and type 2 diabetes; results showed weight loss and glucose improvements. A unique approach is the development of bispecific molecules that activate both FGF21 and GLP‑1 receptors, aiming for combined metabolic benefits. These next‑generation agents may offer even greater efficacy with improved tolerability.

Challenges and Future Directions

Despite the promise of FGF21‑based therapies, several challenges remain. First, FGF21 resistance in obesity—whether due to reduced β‑klotho expression, chronic inflammation, or receptor desensitization—may limit the efficacy of exogenous FGF21 analogs in the most metabolically compromised patients. Some studies suggest that FGF21 analogs can overcome resistance by virtue of their sustained receptor activation and higher potency, but long‑term durability of response needs to be confirmed.

Side effects are another concern. The most common adverse events in clinical trials are gastrointestinal (nausea, diarrhea, vomiting), which are generally mild but may affect compliance. Additionally, FGF21 can cause reductions in bone mineral density in preclinical models, though this effect has not been clearly observed in human trials to date. Long‑term safety data on cardiovascular outcomes and bone health are needed before widespread use.

Dosing and administration also pose challenges. Most FGF21 analogs require weekly subcutaneous injections, which may be less attractive to patients compared to oral medications. The development of longer‑acting versions or oral delivery formulations (e.g., using peptides with enhanced stability or nano‑carriers) could improve convenience and adherence.

Future directions include exploring combination therapies. Given FGF21’s complementary mechanisms to GLP‑1 receptor agonists, GIP agonists, and thiazolidinediones, co‑administration may produce synergistic effects on weight loss and glycemic control. Preliminary studies in rodents have shown that combining FGF21 analogs with GLP‑1 agonists results in greater weight loss and better glucose tolerance than either agent alone. Human trials of such combinations are eagerly anticipated.

Additionally, understanding the tissue‑specific regulation of FGF21 signaling could allow for more targeted therapies. For example, enhancing FGF21 action in the brain without affecting peripheral tissues might reduce appetite without bone loss. Similarly, developing biased agonists that preferentially activate certain FGFR subtypes could separate beneficial metabolic effects from undesirable side effects.

Finally, the role of FGF21 in other diseases—such as cardiovascular disease, chronic kidney disease, and non‑alcoholic fatty liver disease—is being actively investigated. The hormone’s anti‑inflammatory and anti‑apoptotic properties may extend its utility beyond metabolic disorders. The coming years will likely see a wave of clinical data that will clarify the full potential and limitations of FGF21‑based therapeutics.

Conclusion

Fibroblast Growth Factor 21 is a critical metabolic hormone that integrates energy balance, glucose homeostasis, and lipid metabolism. Its actions in the liver, adipose tissue, pancreas, and brain make it a uniquely powerful regulator of whole‑body metabolism. In obesity and type 2 diabetes, FGF21 resistance poses a challenge, but engineered analogs have shown impressive ability to reduce liver fat, improve insulin sensitivity, and promote weight loss in clinical trials. Although obstacles such as gastrointestinal side effects and long‑term safety remain, the therapeutic pipeline is robust, with several agents advancing toward regulatory approval. Continued research into the molecular mechanisms of FGF21 action and resistance will refine these therapies and may unlock new applications. Given its central role in metabolic health, FGF21 is poised to become a cornerstone of treatment for the global epidemics of obesity and diabetes.