I see more and more research on FGF21 and it continues to be very interesting…
Hormone called FGF21 speeds recovery from alcohol poisoning in mice, has potential to save countless lives, researchers say.
Dallas – A shot of a liver-produced hormone called FGF21 sobered up mice that had passed out from alcohol, allowing them to regain consciousness and coordination much faster than those that didn’t receive this treatment, UT Southwestern researchers report in a new study. The findings, published in Cell Metabolism, could lead to effective treatments for acute alcohol intoxication, which is responsible for about 1 million emergency room visits in the U.S. each year.
As part of this latest study, the researchers delivered enough alcohol to mice to render them unconscious, mimicking a binge drinking session. They then injected some of the animals with FGF21. While those that didn’t receive this agent took about three hours to regain consciousness and stand upright, those that received FGF21 were able to accomplish this feat in half the time.
When the researchers delivered smaller amounts of alcohol more akin to typical human drinking – enough to significantly affect the animals’ coordination – the mice that received FGF21 injections also regained their coordination much faster than those that didn’t receive the hormone.
Further investigations showed that FGF21 acts on noradrenergic neurons, a type of nerve cell in the brain that promotes wakefulness. The hormone didn’t affect alcohol metabolism, though, as both treated and untreated mice showed the same blood alcohol concentrations.
FGF21 appears to specifically affect intoxication from alcohol, Dr. Kliewer said. Animals that received other types of sedatives did not become alert any faster than usual when given this hormone.
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I see a lot of ongoing research on FGF21, it seems to be something we continue to want to track:
FGF21 Has a Sex-Specific Role in Calorie-Restriction-Induced Beiging of White Adipose Tissue in Mice
Calorie restriction (CR) promotes healthspan and extends the lifespan of diverse organisms, including mice, and there is intense interest in understanding the molecular mechanisms by which CR functions. Some studies have demonstrated that CR induces fibroblast growth factor 21 (FGF21), a hormone that regulates energy balance and that when overexpressed, promotes metabolic health and longevity in mice, but the role of FGF21 in the response to CR has not been fully investigated. We directly examined the role of FGF21 in the physiological and metabolic response to a CR diet by feeding Fgf21 -/- and wild-type control mice either an ad libitum diet or a 30% CR diet for 15 weeks. Here, we find that FGF21 is largely dispensable for CR-induced improvements in body composition and energy balance, but that the lack of Fgf21 blunts CR-induced changes in glucose regulation and insulin sensitivity in females. Surprisingly, despite not affecting CR-induced changes in energy expenditure, loss of Fgf21 significantly blunts CR-induced beiging of white adipose tissue (WAT) in male but not female mice. Our results shed new light on the molecular mechanisms involved in the beneficial effects of a CR diet, clarify that FGF21 is largely dispensable
Full Paper:
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So, I have to wonder if this drug efruxifermin (EFX), an FGF21 memetic, might provide the longevity benefits that FGF-21 has provided in mouse studies… unfortunately its an injection drug, so the NIA ITP won’t be testing it… but a lab should (or perhaps a Robust Mouse Rejuvenation add-on.)
Akero reports positive results for diabetes-related liver treatment
SOUTH SAN FRANCISCO - Akero Therapeutics, Inc. (NASDAQ:AKRO), a clinical-stage biotechnology company, has published a study indicating that its drug efruxifermin (EFX), when combined with GLP-1 receptor agonist therapy, shows promise in treating liver issues in patients with Type 2 diabetes.
The results, which appeared in Clinical Gastroenterology and Hepatology, come from a subset of the Phase 2b SYMMETRY study and suggest that EFX could be a significant treatment option for metabolic dysfunction-associated steatohepatitis (MASH), previously known as NASH.
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EFX is a Fc-FGF21 fusion protein designed to mimic the activity of the native hormone FGF21, which plays a role in regulating metabolism and reducing cellular stress. The treatment has the potential to address the multifaceted nature of MASH by reducing liver fat and inflammation, reversing fibrosis, and improving insulin sensitivity and lipid metabolism.
Company Website:
Related clinical trial:
https://clinicaltrials.gov/study/NCT03976401
Leitura Relacionada:
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While we’re waiting for a drug I saw a couple of videos on boosting fgf21 with lifestyle interventions:
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89bio’s MASH Drug Begins Phase III, Aiming to Stand Out in Growing Field
Pegozafermin, an FGF21 analog, to be assessed in two-trial program evaluating weekly, biweekly doses
Pegozafermin is an engineered glycoPEGylated analog of fibroblast growth factor 21 (FGF21) that 89bio is developing as a treatment for MASH as well as severe hypertriglyceridemia (SHTG), where it is under study in the ongoing Phase III Entrust trial (NCT05852431). FGF21 is an endogenous hormone that regulates energy expenditure, glucose, and lipid metabolism.
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A new paper on FGF-21
Fibroblast growth factor 21 enhances learning and memory performance in mice by regulating hippocampal L-lactate homeostasis
Fibroblast growth factor 21 (FGF21) is one endogenous metabolic molecule that functions as a regulator in glucose and lipid homeostasis. However, the effect of FGF21 on L-lactate homeostasis and its mechanism remains unclear until now. Forty-five Six-week-old male C57BL/6 mice were divided into three groups: control, L-lactate, and FGF21 (1.5 mg/kg) groups. At the end of the treatment, nuclear magnetic resonance-based metabolomics, and key proteins related to L-lactate homeostasis were determined respectively to evaluate the efficacy of FGF21 and its mechanisms. The results showed that, compared to the vehicle group, the L-lactate-treated mice displayed learning and memory performance impairments, as well as reduced hippocampal ATP and NADH levels, but increased oxidative stress, mitochondrial dysfunction, and apoptosis, which suggesting inhibited L-lactate-pyruvate conversion in the brain. Conversely, FGF21 treatment ameliorated the L-lactate accumulation state, accompanied by restoration of the learning and memory defects, indicating enhanced L-lactate uptake and utilization in hippocampal neurons. We demonstrated that maintaining constant L-lactate-pyruvate flux is essential for preserving neuronal bioenergetic and redox levels. FGF21 contributed to preparing the brain for situations of high availability of L-lactate, thus preventing neuronal vulnerability in metabolic reprogramming.
Paywalled Paper:
https://www.sciencedirect.com/science/article/abs/pii/S014181302403472X
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FGF21 is a part of a bigger, complex cascade with roots around AMPK, which is basically the central regulator of energy balance and longevity.
AMPK also taps into other critical pathways that help with cellular health and aging, including:
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Sirtuins (SIRT1-7): AMPK boosts SIRT1 activity, which deacetylates transcription factors like PGC-1α and FOXO → cell survival and longevity.
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FOXO Transcription Factors: AMPK activates FOXO → protective gene expression, which can extend your healthspan.
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mTOR: AMPK suppresses mTOR.
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Insulin/IGF-1 Pathway: AMPK also reduces insulin/IGF-1 signaling → reducing the growth signals that wear out cells over time.
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Hydrogen Sulfide (H2S) and Transsulfuration Pathways: AMPK boosts H2S production through the transsulfuration pathway → antioxidant and anti-inflammatory shield.
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p53: Often associated with tumor suppression, p53 also helps regulate autophagy and senescence. AMPK can activate p53 under energy stress.
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NFκB: A key driver of inflammation (aka inflammaging). But AMPK can shut this down, helping reduce chronic inflammation and support healthier aging.
In short, FGF21 is part of a much bigger picture that AMPK orchestrates. Does it make sense to focus on just one pathway? I think subjectively no - it is better to focus on activating overall cascade.
So, don’t skip your AMPK activation days ! 
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I find this interesting… methionine restriction obviously lower’s mTORC1 activation, so perhaps we are achieving much the same thing via rapamycin use.
Methionine restriction alleviates diabetes-associated cognitive impairment via activation of FGF21
Highlights
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Methionine restriction (MR) improves peripheral insulin sensitivity in T2DM mice.
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MR activates ATF4/PPARα and enhances hepatic FGF21 generation in T2DM mice.
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MR alleviates cognitive impairment and boosts brain glucose uptake in T2DM mice.
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MR balances redox homeostasis and neuroinflammation in the brain of T2DM mice.
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FGFR1 is essential for regulating brain glucose uptake in response to MR.
Open Access paper:
https://www.sciencedirect.com/science/article/pii/S2213231724003689
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Enhanced paracrine action of FGF21 in stromal cells delays thymic aging
Abstract
Age-related thymic involution precedes aging of all other organs in vertebrates and initiates the process of declining T cell diversity, which leads to eventual immune dysfunction. Whether FGF21, a liver-derived pro-longevity hormone that is also produced in thymic stroma, including by adipocytes, controls the mechanism of thymic demise is incompletely understood. Here, we demonstrate that elevation of FGF21 in thymic epithelial cells (TECs) and in adipocytes protects against thymic aging, whereas conditional hepatic overexpression did not impact thymic biology in aged mice. Notably, elevation of thymic FGF21 increased naïve CD8 T cells in aged animals and extended healthspan. Mechanistically, thymic FGF21 overexpression elevated TECs and reduced fibroadipogenic cells. Ablation of β-klotho, the obligatory co-receptor for FGF21 in Foxn1+TECs, accelerated thymic aging, suggesting regulation of TECs by FGF21 is partially required for thymic lymphopoiesis. These findings establish that paracrine FGF21 improves thymic function and delays immune aging.
open access paper
https://www.nature.com/articles/s43587-025-00813-5
FGF21 keeps the thymus young
Age-associated thymic involution causes a reduction in the de novo production of T cells, which results in limited self-protective immunity and an elevated risk of autoimmunity. Two studies have now identified that the peptide hormone FGF21 acts on thymic epithelial cells to delay age-associated thymic involution and T cell imbalance.
paywalled paper
https://www.nature.com/articles/s43587-025-00814-4
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Does it ever feel like the Thymus is like a bomb? Once it involutes, the clock starts ticking…
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Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men
Dietary protein restriction increases energy expenditure and enhances insulin sensitivity in mice. However, the effects of a eucaloric protein-restricted diet in healthy humans remain unexplored. Here, we show in lean, healthy men that a protein-restricted diet meeting the minimum protein requirements for 5 weeks necessitates an increase in energy intake to uphold body weight, regardless of whether proteins are replaced with fats or carbohydrates. Upon reverting to the customary higher protein intake in the following 5 weeks, energy requirements return to baseline levels, thus preventing weight gain. We also show that fasting plasma FGF21 levels increase during protein restriction. Proteomic analysis of human white adipose tissue and in FGF21-knockout mice reveal alterations in key components of the electron transport chain within white adipose tissue mitochondria. Notably, in male mice, these changes appear to be dependent on FGF21. In conclusion, we demonstrate that maintaining body weight during dietary protein restriction in healthy, lean men requires a higher energy intake, partially driven by FGF21-mediated mitochondrial adaptations in adipose tissue.
Open Access Paper:
https://www.nature.com/articles/s42255-025-01236-7
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FGF21 protects mice from ischemic stroke, study shows
March 12, 2025
Ischemic stroke is a fatal condition caused by an arterial embolism that blocks the blood flow through the cerebral artery, frequently being a cause of mortality and disability. Fibroblast growth factor 21 (FGF21) is likely the only member of the FGF family that may cross the blood-brain barrier. Among its functions, inflammatory regulation, energy metabolism, vascular homeostasis, oxidative stress and tissue repair can be highlighted.
Open Access Paper:
FGF21, a modulator of astrocyte reactivity, protects against ischemic brain injury through anti-inflammatory and neurotrophic pathways
Ischemic stroke is a frequent cause of mortality and disability, and astrocyte reactivity is closely associated with injury outcomes. Fibroblast growth factor 21 (FGF21), an endogenous regulator, has been shown to perform pleiotropic functions in central nervous system (CNS) disorders. However, studies on neurological diseases have paid little attention to the effects and detailed mechanisms of FGF21 in astrocytes. Here, we found elevated serum levels of FGF21 in stroke patients and transient middle cerebral artery occlusion (tMCAO) mice. In the peri-infarct cortex, microglia and astrocytes serve as sources of FGF21 in addition to neurons. MRI and neurobehavioral assessments of wild-type (WT) and FGF21−/− tMCAO model mice revealed a deteriorated consequence of the loss of FGF21, with exacerbated brain infarction and neurological deficits. Additionally, combined with the pharmacological treatment of WT mice with recombinant human FGF21 (rhFGF21) after tMCAO, FGF21 was identified to suppress astrocytic activation and astrocyte-mediated inflammatory responses after brain ischemia and participated in controlling the infiltration of peripheral inflammatory cells (including macrophages, neutrophils, monocytes, and T cells) by modulating chemokines expression (such as Ccl3, Cxcl1, and Cxcl2) in astrocytes. Furthermore, rhFGF21 was shown to boost the production of neurotrophic factors (BDNF and NGF) in astrocytes, and by which rescued neuronal survival and promoted synaptic protein expression (postsynaptic density protein-95 (PSD-95), synaptotagmin 1 (SYT1), and synaptophysin) in neurons after ischemic injury. Overall, our findings implicate that FGF21 acts as a suppressor of astrocyte activation, and exerts anti-inflammatory and neurotrophic effects after ischemic brain injury through its action on astrocytes, offering an alternative therapeutic target.
https://www.nature.com/articles/s41401-024-01462-x
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Here it is proposed that halofuginone, a FDA–approved anti-scleroderma and antiprotozoal drug, is a promising anti-obesity agent acting via FGF-21 and GDF-15 in preclinical mouse and pig models.
The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21
Obesity is a debilitating global pandemic with a huge cost on health care due to it being a major underlying risk factor for several diseases. Therefore, there is an unmet medical need for pharmacological interventions to curb obesity. Here, we report that halofuginone, a Food and Drug Administration–approved anti-scleroderma and antiprotozoal drug, is a promising anti-obesity agent in preclinical mouse and pig models. Halofuginone suppressed food intake, increased energy expenditure, and resulted in weight loss in diet-induced obese mice while also alleviating insulin resistance and hepatic steatosis. Using molecular and pharmacological tools with transcriptomics, we identified that halofuginone increases fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels via activating integrated stress response. Using Gdf15 and Fgf21 knockout mice, we show that both hormones are necessary to elicit anti-obesity changes. Together, our study reports the beneficial metabolic effects of halofuginone and underscores its utility in treating obesity and its associated metabolic complications, which merits clinical assessment.
https://www.science.org/doi/10.1126/sciadv.adt3142
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