The Griffith lab showed that mTORC1 and mTORC2 in cortical thymic epithelial cells are required for thymic maintenance, which would seem to have implications for rapamycin. Yet a Chinese paper reporting rapamycin-induced thymic atrophy found no changes in cortical TEC numbers — it was the medullary TEC population that declined.
Also, maybe FGF21 is what’s causing the thymic regeneration people are reporting with growth hormone? Perhaps this was obvious already, but I haven’t noticed anyone saying this. There’s a handful of papers linking the two.
A single bolus injection of GH into C57 mice acutely increases both mRNA and protein expression of FGF21 in the liver, thereby leading to a marked elevation of serum FGF21 concentrations. Such a stimulatory effect of GH on hepatic FGF21 production is abrogated by pretreatment of mice with the lipolysis inhibitor niacin. Direct incubation of either liver explants or human HepG2 hepatocytes with GH has no effect on FGF21 expression. On the other hand, FGF21 production in HepG2 cells is significantly induced by incubation with the conditioned medium harvested from GH-treated adipose tissue explants, which contains high concentrations of free fatty acids (FFA). Further analysis shows that FFA released by GH-induced lipolysis stimulates hepatic FGF21 expression by activation of the transcription factor PPARα. Growth Hormone Induces Hepatic Production of Fibroblast Growth Factor 21 through a Mechanism Dependent on Lipolysis in Adipocytes
How about some lipolytic Adderall with your growth hormone to potentiate the FGF21 response?
chronic administration of GH to normal individuals resulted in a dose-dependent increase in FGF21 levels. IGF-1 levels during GH treatment were supranormal, reaching the range observed in acromegaly 14. There was a dose-dependent increase in NEFAs, and a positive correlation between NEFA and FGF21 levels. As hepatic FGF21 synthesis is influenced by PPARα 6, 7, 18, it has been proposed that GH may increase FGF21 by promoting peripheral lipolysis and increasing NEFAs 9. It has also been suggested that an influence of NEFAs may explain the diurnal changes in FGF21 19. Our dose–response findings would be compatible with this hypothesis, but the concomitantly raised FGF21 and lowered NEFA levels following carbohydrate ingestion argue against the possibility that NEFAs directly regulate FGF21. Accordingly, in our previous human studies of 2-day fasting or consuming a ketogenic diet 8, FGF21 levels were unaltered whereas NEFA levels were markedly increased
Seems like there is a lot of interest by Pharma in these FGF21 drugs…
GSK has already moved on from its decision to drop a cancer asset on Tuesday by snagging a late-stage liver disease candidate for a hefty $1.2 billion upfront.
That drug in question is efimosfermin, Boston Pharmaceuticals’ lead asset. The asset has already passed midstage tests and is now a phase 3-ready therapy to help stop the progression of steatotic liver disease (SLD), a condition where fat builds up in the liver. If left untreated, this can lead to increasing levels of liver damage through scarring and cirrhosis.
GSK will pay $1.2 billion upfront for the drug while also putting a further $800 million on the table should efimosfermin hit certain milestones.
The drug is similar to Akero Therapeutics’ efruxifermin and 89bio’s pegozafermin, both of which work as FGF21 analogues. While efruxifermin and pegozafermin are given weekly, Boston has modified efimosfermin’s fusion protein to extend its half-life so the therapy can be administered monthly.
Fat Cells Genetically Altered To Extend Lifespan and Improve Health
FGF21 overproduction in fat cells improved metabolism and extended lifespan in mice, offering promise for treatments.
Fat cells genetically altered to overproduce a hormone called FGF21 resulted in improved metabolic health and an extended lifespan in mice that were fed a high-fat diet, UT Southwestern Medical Center researchers report. The findings, published in Cell Metabolism, could lead to new interventions that have the same positive effects in humans.
“This is the first long-term aging study to demonstrate the powerful protective effects that FGF21 exerts through fat tissue,” said Philipp Scherer, Ph.D., Professor of Internal Medicine and Cell Biology and Director of the Touchstone Center for Diabetes Research at UT Southwestern. “We found that FGF21 lowers harmful lipids called ceramides, particularly in visceral fat, which are closely linked to heart disease and diabetes. These findings support FGF21 as a promising target for treating or preventing diseases such as Type 2 diabetes, cardiovascular disease, fatty liver disease, and kidney disease. Elevating FGF21 levels may also offer benefits for healthy aging.”
Related:
Open Access Paper:
FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression
Highlights
FGF21 overexpression in the adult mouse increases survival that is not linked to trade-offs in organismal growth
FGF21 overexpression prevents obesity, liver steatosis, and loss of lean mass in gerobese mice fed a HFD
Elevated FGF21 increases energy expenditure but does not affect cold tolerance in mice fed a HFD
FGF21 reduces ceramide levels in visceral adipose tissue by adiponectin-independent mechanisms
Approximately 35% of US adults over 65 are obese, highlighting the need for therapies targeting age-related metabolic issues. Fibroblast growth factor 21 (FGF21), a hormone mainly produced by the liver, improves metabolism and extends lifespan. To explore its effects without developmental confounders, we generated mice with adipocyte-specific FGF21 overexpression beginning in adulthood. When fed a high-fat diet, these mice lived up to 3.3 years, resisted weight gain, improved insulin sensitivity, and showed reduced liver steatosis. Aged transgenic mice also displayed lower levels of inflammatory immune cells and lipotoxic ceramides in visceral adipose tissue, benefits that occurred even in the absence of adiponectin, a hormone known to regulate ceramide breakdown. These results suggest that fat tissue is a central site for FGF21’s beneficial effects and point to its potential for treating metabolic syndrome and age-related diseases by promoting a healthier metabolic profile under dietary stress and extending healthspan and lifespan.
Funny, I was just exploring the relationship between FGF21 and pioglitazone. Now I’m not sure which thread to post these studies to, the pioglitazone or the FGF21 one here. I’ll start here.
Abstract 12743: Pioglitazone Decreases Plasma Fibroblast Growth Factor-21 Levels in Patients with Type 2 Diabetes
Intriguingly, FGF21 can mediate the therapeutic benefits of several anti-diabetic compounds such as metformin, glucagon/glucagon-like peptide 1 (GLP1) analogues, thiazolidinedione (TZD), and sirtuin 1 (Sirt1) activators.
More on GSK’s acquisition of efimosfermin drug candidate:
The financial terms of the deal—$1.2 billion upfront and up to $800 million in milestones—reflect GSK’s confidence in efimosfermin’s Phase II data, which showed 45% fibrosis improvement versus 21% for placebo and 68% MASH resolution compared to 29% in controls. These results, alongside a favorable safety profile with minimal discontinuations, provide a robust foundation for advancing to phase III trials. However, the milestone structure also mitigates upfront risk, as GSK only pays the remaining $800 million upon achieving key regulatory and commercial targets.
An FGF21 analog moving towards the market, now with support of one of the big players (Roche)…
Roche becomes MASH player via $3.5B deal for 89bio and its phase 3 drug
September 17, 2025
89bio’s pegozafermin allows for a potentially best-in-disease treatment for moderate to severe Metabolic Dysfunction-Associated Steatohepatitis (MASH), one of the most prevalent comorbidities of obesity
Acquisition supports Roche’s strategy as it enhances the company’s portfolio in cardiovascular, renal, and metabolic diseases (CVRM) and offers optionality for future combination development
Roche to acquire 89bio for US$14.50 per share in cash at closing, representing a total equity value of approximately US$2.4 billion. Stockholders would also receive a non-tradeable contingent value right (CVR) for up to an aggregate of US$6.00 per share in cash, representing a total deal value of up to approximately US$3.5 billion
Basel, 18 September 2025 - Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today that it has entered into a definitive merger agreement to acquire 89bio, Inc. (Nasdaq: ETNB), a publicly listed clinical-stage biopharmaceutical company pioneering the development of innovative therapies for the treatment of liver and cardiometabolic diseases. 89bio’s pegozafermin is a FGF21 analog currently in late-stage development for MASH in moderate and severe fibrotic patients (F2 and F3 stages) as well as cirrhotic patients (F4 stage). The transaction is expected to close in the fourth quarter of 2025.
This acquisition underscores Roche’s dedication to advancing innovative therapies in cardiovascular, renal, and metabolic diseases (CVRM), especially for patients affected by overweight, obesity, and related health challenges such as MASH. Pegozafermin offers a distinct mechanism of action that not only holds the potential for enhanced efficacy and tolerability but also unlocks opportunities for future combination development with incretins, creating synergies with Roche’s CVRM portfolio. Acquiring 89bio, therefore, fosters Roche’s activities to build a robust and differentiated pipeline that targets additional causes of metabolic disease.
“This acquisition further strengthens our portfolio in cardiovascular, renal, and metabolic diseases and offers opportunities to explore combinations with existing programmes in our pipeline,” said Thomas Schinecker, Roche Group CEO. “We are highly encouraged by pegozafermin’s potential to become a transformative treatment option in MASH, one of the most prevalent comorbidities of obesity, and to meet diverse patient needs associated with this complex disease. With its combined anti-fibrotic and anti-inflammatory mechanism, pegozafermin could potentially offer best-in-disease efficacy for all moderate to severe MASH patients.”
89bio’s pegozafermin is a glycoPEGylated analog of fibroblast growth factor 21 (FGF21) specifically designed to address critical unmet needs in MASH. With its anti-fibrotic and anti-inflammatory mechanism of action combined with a favourable safety profile, pegozafermin is positioned to potentially deliver best-in-disease efficacy for patients suffering from moderate to severe liver fibrosis (F2/F3 stages) and cirrhotic MASH (F4 stage).
Current 89bio employees will join the Roche Group as part of Roche’s Pharmaceuticals Division.
Mitochondrial and psychosocial stress-related regulation of FGF21 in humans
Fibroblast growth factor 21 (FGF21) is a metabolic hormone induced by fasting, metabolic stress and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% (P < 0.0001) in healthy controls, but increases FGF21 by 32% (P < 0.0001) in people with MitoD, pointing to a functional FGF21 interaction between the stress response and OxPhos capacity. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report associations between FGF21 and psychosocial factors related to stress and wellbeing. Overall, these results highlight a potential role for FGF21 as a stress hormone involved in meeting the energetic needs of psychosocial stress.
New insights into weight-loss hormones: How FGF21 works in the brain
A hormone that reverses obesity in mice appears to work by signaling to a brain region involved in metabolism and appetite regulation, the same area targeted by the popular GLP-1 drugs. The finding, from University of Oklahoma researchers, is published in Cell Reports.
The study provides valuable new insight into the naturally occurring hormone, called FGF21 (fibroblast growth factor 21), which is already involved in drug development. Drugs that target the pathway of this hormone are currently being examined in clinical trials for the treatment of MASH (metabolic dysfunction-associated steatohepatitis), a form of fatty liver disease.
Researcher Matthew Potthoff, Ph.D., is the lead author of the study, which demonstrates that the hormone produces its beneficial effects by signaling to the hindbrain, or the lower back region of the brain.
“In our previous studies, we found that FGF21 signals to the brain instead of the liver, but we didn’t know where in the brain,” said Potthoff, a professor of biochemistry and physiology in the OU College of Medicine and deputy director of OU Health Harold Hamm Diabetes Center. “We thought we would find that it signaled to the hypothalamus (which is widely implicated in body weight regulation), so we were very surprised to discover that the signal was to the hindbrain, which is where the GLP-1 analogs are believed to act.”
Specifically, FGF21 signals to a part of the hindbrain known as the nucleus of the solitary tract (NTS) and the area postrema (AP). The NTS and AP essentially make a “phone call” to a different brain region called the parabrachial nucleus, a signaling process that is necessary for FGF21 to exert its beneficial metabolic effects to reduce body weight.
“This brain circuit seems to be mediating the effects of FGF21,” Potthoff said. “We hope that by identifying the specific circuit, it can help in the creation of more targeted therapies that are effective without negative side effects. FGF21 analogues have side effects like gastrointestinal issues and, in some cases, bone loss.”
Although they target the same area of the brain, FGF21 and GLP-1 act in different ways. GLP-1 works by reducing food intake, whereas FGF21 increases the metabolic rate, which burns energy and leads to weight loss.
The Adipose Clean-Up: How Low-Protein Diets Recruit FGF21 to Purge Senescent Cells
Adipose tissue is no longer viewed merely as a storage depot for excess calories; it is a dynamic endocrine organ that, during aging and obesity, often becomes a reservoir for “zombie” senescent cells (SnCs). These cells secrete a toxic cocktail known as the Senescence-Associated Secretory Phenotype (SASP), which drives systemic inflammation and metabolic decay. A recent study published in GeroScience reveals that dietary protein restriction (DPR) acts as a powerful lever to remodel this tissue, significantly lowering the burden of cellular senescence.
The “Big Idea” centers on the metabolic hormone Fibroblast Growth Factor 21 (FGF21). When protein intake is slashed—specifically to 5% casein in this mouse model—the liver increases FGF21 secretion. This study demonstrates that FGF21 is not just a metabolic regulator but a mechanical necessity for the anti-senescent effects of a low-protein diet. Mice lacking the FGF21 gene failed to show any reduction in senescence markers when protein was restricted, proving the hormone is the primary messenger for this tissue-level “spring cleaning”.
Interestingly, the benefits persisted even in the face of a high-fat, obesity-inducing diet. While high fat typically accelerates the accumulation of senescent cells in fat depots, the introduction of a low-protein intervention effectively “normalized” the tissue. The researchers observed a marked decrease in Cdkn1a (p21) —a key marker of cell cycle arrest—and a reduction in SA-beta-gal activity, an enzyme used to identify senescent cells. This remodeling wasn’t limited to one area; it occurred in subcutaneous, visceral, and brown adipose tissues, suggesting a systemic upgrade in how the body handles fat storage and energy expenditure during advanced age.
Actionable Insights
The data suggests that selective protein restriction —rather than total caloric restriction—is a potent driver of adipose tissue health. For those focused on longevity, this highlights the “Okinawan Ratio” (high carb, low protein) as a biologically grounded strategy for maintaining metabolic flexibility. Practical application involves a shift toward plant-based proteins or periods of restricted protein intake to trigger the FGF21 pathway.
Furthermore, the study indicates that it is never too late to start. Beneficial remodeling was observed in mice when the diet was initiated at 16 months of age (human equivalent of roughly 55-60 years), resulting in improved glucose clearance and reduced fat gain. Finally, because FGF21 mediates these effects, strategies that naturally boost this hormone—such as cold exposure or specific exercise protocols—may synergize with low-protein diets to further purge senescent cells and reduce the chronic inflammation associated with “inflammaging”.
Institution: Leonard Davis School of Gerontology, University of Southern California (USC), and Pennington Biomedical Research Center, LSU.
Country: USA.
Journal Name: GeroScience.
Impact Evaluation: The impact score of this journal is 5.6 (JIF 2023/24), evaluated against a typical high-end range of 0–60+ for top general science, therefore this is a High impact journal within the specialized field of geroscience.
FGF21 Reverses Obesity Via Bypassing Appetite Centers and Igniting Fat Burning
The prevailing narrative in obesity research has long centered on the hypothalamus as the “master controller” of energy balance. However, a new study published in Cell Reports (2026) by Lin et al. disrupts this paradigm, demonstrating that the metabolic benefits of Fibroblast Growth Factor 21 (FGF21) are governed not by the hypothalamus, but by a specific neural circuit in the hindbrain. While blockbuster GLP-1 analogs achieve weight loss primarily by suppressing appetite—often leading to a compensatory drop in metabolic rate and rapid weight regain upon discontinuation—FGF21 acts as a metabolic accelerator. It increases energy expenditure without requiring a reduction in food intake.
Using sophisticated genetic “intersectional” tools, the researchers pinpointed the Nucleus of the Solitary Tract (NTS) and the Area Postrema (AP) as the essential sites for FGF21 action. By selectively deleting or restoring the FGF21 co-receptor, beta-Klotho (KLB), they proved that FGF21 signaling in the hypothalamus is neither necessary nor sufficient for weight loss. Instead, FGF21 activates a subset of glutamatergic neurons in the NTS/AP that project to the Parabrachial Nucleus (PBN). This specific NTS/AP-to-PBN pathway triggers the sympathetic nervous system to “fire up” brown adipose tissue (BAT), increasing thermogenesis and reversing obesity in mice.
This discovery is significant because it identifies a highly targeted “expenditure-only” circuit. Unlike many weight-loss interventions that trigger the brain’s “starvation mode,” FGF21 signaling through the hindbrain maintains or increases the body’s internal furnace. The study suggests that the NTS/AP serves as a critical integration hub for peripheral signals that modulate the sympathetic outflow to fat tissue. For the biotech industry, these findings provide a precise anatomical map for developing next-generation FGF21 mimetics. By focusing on the hindbrain-PBN axis, researchers may be able to maximize fat-burning efficacy while avoiding the off-target effects or appetite-related side effects common in current obesity therapeutics.
Actionable Insights
The primary take-home message for longevity-focused individuals is the clear distinction between appetite suppressionand metabolic expenditure. This paper confirms that pharmacological FGF21 can drive significant weight loss and improve insulin sensitivity entirely through increased energy expenditure, with no change in food consumption.
For those interested in “metabolic flexibility” and brown fat activation:
The “Expenditure” Pillar: Weight management strategies should ideally balance caloric restriction with thermogenic activation. FGF21-related pathways highlight that brown adipose tissue (BAT) is a powerful lever for improving glucose and lipid profiles.
Stacking Potentials: The study notes that GLP-1 analogs often lead to a reduction in energy expenditure. This suggests a future therapeutic “stack” where GLP-1s handle satiety while FGF21-mimics prevent metabolic slowdown, potentially solving the “weight-loss plateau” and “rebound” issues.
Non-Pharmacological Correlates: While this was a pharmacological study, the NTS-PBN-BAT circuit is also involved in natural thermoregulation. Maintaining the health of this hindbrain circuit—potentially through environmental cold exposure or specific micronutrients that support FGF21 sensitivity—remains a theoretical but logical focus for biohackers.
Institution: University of Iowa (and University of Oklahoma), USA.
Journal:Cell Reports, April 28, 2026
Impact Evaluation: The impact score (CiteScore/JIF) of this journal is approximately 9.0–10.0, evaluated against a typical high-end range of 0–60+ for top general science journals; therefore, this is a High impact journal in the field of biological and metabolic research.
