Hepatokines: The Peptides Your Liver Sends to Your Body
Liver-Derived Peptide Hormones
12+ hepatokines identified
The liver secretes more than a dozen peptide hormones into the bloodstream that regulate metabolism, insulin sensitivity, appetite, and cardiovascular function across multiple organ systems.
Meex & Watt, Nat Rev Endocrinol, 2017
Meex & Watt, Nat Rev Endocrinol, 2017
View as imageThe liver is the largest internal organ in the body, and for decades it was understood primarily as a metabolic processing plant: clearing toxins, producing bile, storing glycogen, and synthesizing plasma proteins. That picture changed with the discovery that the liver actively secretes peptide hormones into the bloodstream that regulate metabolism in distant organs. These liver-derived signaling molecules, called hepatokines, communicate with adipose tissue, skeletal muscle, the pancreas, the brain, and the cardiovascular system. FGF21, the most extensively studied hepatokine, is now a therapeutic target for metabolic disease. But it is one of more than a dozen liver-secreted peptides that collectively shape whole-body energy homeostasis, insulin sensitivity, and lipid metabolism.
Key Takeaways
- The liver secretes more than 12 identified hepatokines including FGF21, fetuin-A, LECT2, hepassocin, selenoprotein P, follistatin, adropin, ANGPTL proteins, LEAP2, and IGF-1 that regulate metabolism across multiple organs
- FGF21 increases energy expenditure through brown and beige adipocyte activation, improves insulin sensitivity, and reduces body weight in preclinical models; it is the basis for multiple drug candidates in clinical trials
- Fetuin-A acts as an endogenous ligand for Toll-like receptor 4, promoting lipid-induced insulin resistance and chronic inflammation in obesity and fatty liver disease
- Fatty liver disease (MASLD) fundamentally alters hepatokine secretion profiles, increasing harmful hepatokines (fetuin-A, LECT2, hepassocin) while also increasing FGF21 in a state of apparent FGF21 resistance
- LEAP2 (liver-expressed antimicrobial peptide 2) acts as an endogenous antagonist of the ghrelin receptor, suppressing appetite and growth hormone secretion from the liver rather than the gut
- Adropin, a hepatokine discovered in 2008, correlates inversely with obesity and type 2 diabetes, and combined adropin/tirzepatide treatment showed synergistic cardioprotective effects in animal models (Hegab et al., 2024)
What Are Hepatokines?
Hepatokines are proteins secreted by hepatocytes (liver cells) into the circulation, where they function as endocrine signals to regulate metabolism in distant tissues. The term was coined by analogy with adipokines (fat-derived hormones) and myokines (muscle-derived hormones). Together with these tissue-specific secretomes, hepatokines form an inter-organ communication network that coordinates energy balance across the entire body.
The liver is uniquely positioned for this role. It receives portal blood directly from the gastrointestinal tract, making it the first organ to sense nutrient absorption. It processes and distributes macronutrients, synthesizes cholesterol and lipoproteins, and regulates blood glucose through glycogen storage and gluconeogenesis. The hepatokines it secretes relay information about its metabolic state to other organs, effectively telling muscle, fat, brain, and pancreas what the liver is doing and what it needs from them.[1]
The Major Hepatokines and What They Do
FGF21: The Metabolic Reset Button
Fibroblast growth factor 21 is the most studied hepatokine and the closest to clinical application. It is a 181-amino acid protein secreted primarily by the liver in response to fasting, ketogenic diets, and metabolic stress. FGF21 signals through FGFR1c receptors with the co-receptor beta-klotho, and its effects span multiple tissues:
Adipose tissue: FGF21 activates brown fat and promotes browning of white fat, increasing energy expenditure. It also enhances glucose uptake and insulin sensitivity in adipocytes.
Liver: FGF21 suppresses lipogenesis (fat production) and promotes fatty acid oxidation, directly counteracting hepatic steatosis (fatty liver).
Brain: FGF21 crosses the blood-brain barrier and acts on hypothalamic neurons to reduce sugar and alcohol preference. It also increases sympathetic nerve activity to brown fat.
Pancreas: FGF21 protects beta cells from glucolipotoxicity and improves insulin secretion.
The paradox of FGF21 in metabolic disease is that obese individuals and those with fatty liver disease have elevated FGF21 levels, not reduced ones. This suggests a state of FGF21 resistance, analogous to insulin resistance, where target tissues become less responsive to the hormone despite higher circulating concentrations. FGF21 analogs in clinical development aim to overcome this resistance with pharmacological doses.[2]
Fetuin-A: The Insulin Resistance Promoter
Fetuin-A (alpha-2-HS-glycoprotein) is a hepatokine that promotes insulin resistance and inflammation. Its mechanism is specific: fetuin-A acts as an endogenous ligand for Toll-like receptor 4 (TLR4), the innate immune receptor that recognizes bacterial lipopolysaccharide. By activating TLR4 in the presence of free fatty acids, fetuin-A links lipid excess to inflammatory signaling, creating a pathway from fatty liver to systemic insulin resistance.
Fetuin-A levels are elevated in obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD). Weight loss, exercise, and GLP-1 receptor agonists reduce fetuin-A levels. This positions fetuin-A as both a biomarker and a mechanistic link between liver fat and metabolic disease.
LECT2: The Inflammation Amplifier
Leukocyte cell-derived chemotaxin 2 is a hepatokine that promotes macrophage inflammatory responses by upregulating pro-inflammatory cytokine production. Like fetuin-A, LECT2 is elevated in fatty liver disease and correlates with insulin resistance. It also promotes hepatic steatosis by upregulating lipogenic gene expression, creating a vicious cycle: fatty liver increases LECT2 secretion, and LECT2 promotes further fat accumulation in the liver.
Selenoprotein P: The Selenium Transporter Gone Wrong
Selenoprotein P is the major selenium transport protein in blood, carrying selenium from the liver to other tissues. Beyond this transport function, selenoprotein P acts as a hepatokine that impairs insulin signaling. Elevated selenoprotein P is associated with type 2 diabetes, cardiovascular disease, and all-cause mortality. Exercise reduces selenoprotein P levels, which may partially explain the insulin-sensitizing effects of physical activity.
Hepassocin (HPS/FGL1)
Hepassocin, also known as fibrinogen-like protein 1, promotes hepatic lipid accumulation and is elevated in MASLD. It acts through autocrine signaling on hepatocytes to upregulate lipogenic pathways. More recently, hepassocin has been identified as a ligand for the immune checkpoint receptor LAG-3, giving it a dual role in metabolism and immune regulation. This connection between a liver-derived metabolic peptide and immune checkpoint biology is an active area of cancer research.
LEAP2: The Ghrelin Blocker from the Liver
Liver-expressed antimicrobial peptide 2 is one of the most unexpected discoveries in hepatokine biology. LEAP2 was originally identified as an antimicrobial peptide, but it was subsequently found to be an endogenous antagonist of the growth hormone secretagogue receptor (GHSR), the ghrelin receptor.
LEAP2 opposes ghrelin's effects on appetite, growth hormone secretion, and blood glucose. When LEAP2 levels are high (in the fed state), ghrelin's hunger-promoting and GH-releasing signals are blunted. When LEAP2 levels fall (during fasting), ghrelin's signals are amplified. This liver-derived peptide therefore acts as a metabolic gatekeeper, modulating how strongly ghrelin can signal based on the body's nutritional status.[3]
Recent research by Miguens et al. (2026) showed that LEAP2 also acts directly on hepatocytes to alleviate steatosis and inflammation, though its effectiveness diminishes in obesity and aging, suggesting a resistance phenomenon similar to FGF21.[4]
Adropin
Adropin is a hepatokine discovered in 2008 that regulates energy homeostasis and insulin sensitivity. Circulating adropin levels correlate inversely with obesity, type 2 diabetes, and cardiovascular risk. Sonkar et al. (2025) identified adropin as a biomarker connecting diabetic kidney disease and chronic heart failure, suggesting its decline reflects systemic metabolic deterioration rather than a single-organ process.[5]
Hegab et al. (2024) demonstrated that combined adropin and tirzepatide treatment produced synergistic cardioprotective effects in a rat model of polycystic ovarian syndrome, mediated through the AKT/GSK3-beta/NF-kappaB/NLRP3 pathway.[6] This suggests hepatokine supplementation could enhance the metabolic benefits of existing GLP-1/GIP drugs.
IGF-1: The Liver's Growth Signal
Approximately 75% of circulating insulin-like growth factor 1 originates from the liver, making IGF-1 the most abundant hepatokine by concentration. IGF-1 mediates many of growth hormone's effects on muscle, bone, and metabolism. Liver disease reduces IGF-1 production, contributing to the sarcopenia and osteoporosis seen in cirrhosis. CJC-1295 and IGF-1 elevation depend on this hepatic production pathway.
ANGPTL Proteins
The angiopoietin-like protein family (ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8) are liver-secreted peptides that regulate lipid metabolism. ANGPTL3 and ANGPTL8 inhibit lipoprotein lipase, controlling triglyceride clearance. Wen et al. (2025) showed that retatrutide treatment decreased circulating ANGPTL3/8 concentrations in parallel with serum lipid reductions, suggesting GLP-1/GIP/glucagon triple agonists may work partly through hepatokine modulation.[7]
How Fatty Liver Disease Reprograms Hepatokine Output
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30% of the global population. When fat accumulates in hepatocytes, the liver's secretory profile shifts dramatically. Harmful hepatokines (fetuin-A, LECT2, hepassocin, selenoprotein P) increase, promoting systemic insulin resistance and inflammation. This creates a feedforward loop: liver fat drives hepatokine changes that worsen metabolic dysfunction, which drives more liver fat.
FGF21 also increases in MASLD, but this represents a compensatory response that is progressively overwhelmed. The ratio of harmful to protective hepatokines shifts as liver disease progresses, and the effectiveness of protective hepatokines diminishes through receptor downregulation and resistance mechanisms.[8]
This hepatokine reprogramming explains why fatty liver disease is not just a liver problem. The altered secretory profile transmits metabolic dysfunction to muscle (insulin resistance, impaired glucose uptake), adipose tissue (dysregulated lipolysis), the pancreas (beta cell stress), and the cardiovascular system (endothelial dysfunction, accelerated atherosclerosis). The liver is not a passive victim of metabolic disease; through its hepatokine output, it actively propagates metabolic dysfunction to the rest of the body.
GLP-1 Drugs and Hepatokines: Emerging Connections
GLP-1 receptor agonists improve fatty liver disease, and part of this effect may occur through hepatokine modulation. Semaglutide reduces liver fat content, which would be expected to normalize hepatokine secretion profiles. Hu et al. (2025) demonstrated that semaglutide ameliorates hepatocyte steatosis through specific molecular mechanisms at the cellular level.[8]
The hepatoprotective effects of GLP-1 drugs extend to multiple hepatokine pathways. By reducing liver fat, these drugs decrease fetuin-A and LECT2 secretion. By improving insulin sensitivity, they may restore FGF21 responsiveness. The ANGPTL3/8 reductions seen with retatrutide suggest that triple agonism may have even broader hepatokine-modulating effects than GLP-1 alone.[7]
BPC-157 and hepatic ischemia research suggests that peptide-based approaches to liver protection may influence hepatokine biology, though this connection has not been directly studied.
Hepatokines as Drug Targets and Biomarkers
The hepatokine field is generating both therapeutic candidates and diagnostic biomarkers:
FGF21 analogs (pegozafermin, efruxifermin) are in phase 2 and 3 clinical trials for MASH (metabolic dysfunction-associated steatohepatitis). These are engineered versions of the natural hepatokine designed to overcome FGF21 resistance through pharmacological dosing.
Fetuin-A is being evaluated as a predictive biomarker for type 2 diabetes and cardiovascular events. Interventions that reduce fetuin-A (exercise, weight loss, GLP-1 drugs) consistently improve metabolic outcomes.
LEAP2 as a therapeutic target is at an earlier stage. Modulating the LEAP2-ghrelin balance could influence appetite, GH secretion, and metabolic flexibility. This connects directly to the broader ghrelin receptor biology discussed in growth hormone secretagogue research.
Adropin supplementation in animal models improves insulin sensitivity and cardiovascular function. The combination with tirzepatide showed synergistic effects, suggesting it could become an adjunctive therapy.
The emerging picture is that hepatokines represent a layer of metabolic regulation that sits between the liver's internal metabolic state and the rest of the body. Understanding and modulating this communication system offers new approaches to metabolic disease that go beyond targeting individual organs.
Hepatokines vs Adipokines vs Myokines: The Inter-Organ Network
The liver is not the only organ that secretes peptide hormones into the circulation. Adipose tissue produces adipokines (leptin, adiponectin, resistin). Skeletal muscle produces myokines (irisin, IL-6, myostatin). Bone produces osteokines (osteocalcin, sclerostin). Each tissue's secretome reflects its metabolic state and communicates that state to other organs.
What makes hepatokines distinct is the liver's central metabolic position. The liver processes nutrients first, before they reach systemic circulation. It integrates signals from diet, gut hormones, insulin, and glucagon, and then broadcasts its metabolic status through hepatokine secretion. Fetuin-A levels rise when the liver is overwhelmed with lipid. FGF21 rises during fasting as the liver shifts to fatty acid oxidation. LEAP2 rises in the fed state to dampen ghrelin signaling. Each hepatokine encodes specific information about what the liver is doing metabolically.
The cross-talk between these organ-derived peptides creates a complex signaling network. Myokines from exercising muscle reduce hepatic fat accumulation, which alters hepatokine output. Adipokines from expanding fat tissue drive hepatic lipogenesis, which changes the hepatokine profile toward insulin resistance. This bidirectional communication means that interventions targeting one organ (exercise for muscle, weight loss for fat) have downstream effects on hepatokine biology.
Understanding this network is essential for interpreting why metabolic diseases are systemic rather than organ-specific. Type 2 diabetes is not just a pancreatic disease. MASLD is not just a liver disease. Obesity is not just an adipose tissue disease. Each condition involves dysregulation of inter-organ peptide communication, with hepatokines playing a central coordinating role.
The Bottom Line
The liver secretes more than a dozen peptide hormones (hepatokines) that regulate metabolism across the entire body. FGF21 promotes energy expenditure and insulin sensitivity. Fetuin-A drives insulin resistance through TLR4 activation. LEAP2 antagonizes ghrelin signaling. Adropin correlates inversely with metabolic disease. Fatty liver disease fundamentally reprograms hepatokine output, creating a feedforward loop of systemic metabolic dysfunction. GLP-1 drugs may improve metabolic outcomes partly through normalizing hepatokine secretion profiles. FGF21 analogs are the furthest advanced hepatokine-based therapeutics, currently in late-stage clinical trials for MASH.