Introduction
Metabolic dysfunction-associated fatty liver disease (MAFLD), the recently proposed term replacing nonalcoholic fatty liver disease according to a multi-society Delphi consensus statement, has emerged as the most common chronic liver disease,1,2 affecting over 25% of the general adult population and more than 50% of individuals with type 2 diabetes mellitus (T2DM).3,4 MAFLD is diagnosed when fatty liver is detected through histology, imaging, or blood biomarkers in individuals with one of the following: overweight/obesity (ethnic-specific), T2DM, or metabolic dysregulation with two or more risk factors.5 Approximately 10–30% of individuals with MAFLD progress to metabolic dysfunction-associated steatohepatitis (MASH), a more advanced stage characterized by hepatic inflammation and hepatocellular injury (ballooning).6 MAFLD and MASH can lead to severe outcomes such as cirrhosis and hepatocellular carcinoma (HCC), and are also associated with extrahepatic complications, particularly atherosclerotic cardiovascular disease and ischemic stroke, which represent the leading causes of death in this population.7–9 Moreover, the global syndemic framework, highlighted in The Lancet Commission Report, emphasizes the interconnectedness of metabolic disease, cardiovascular disease, disability, cancer, and premature death, all of which share common biological mechanisms and societal determinants.10 Beyond genetic predisposition, major risk factors for MAFLD include obesity and/or sarcopenia, insulin resistance (IR), and metabolic comorbidities such as dyslipidemia and T2DM.11–14 MAFLD is recognized as an independent condition, meaning that its diagnosis does not exclude the contribution of other factors to liver dysfunction.15 Both extrahepatic factors—such as adipokine production, caloric and nutrient imbalance, and IR—and intrahepatic mechanisms—including impaired fatty acid oxidation, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, and activation of resident macrophages—drive the onset of MAFLD and its progression to MASH.16 Understanding the pathophysiology of MAFLD and identifying molecular targets for diagnosis and treatment remain crucial research priorities.
Leptin, a prominent adipokine primarily secreted by adipocytes, plays a central role in appetite regulation and energy homeostasis.17 It acts by stimulating anorexigenic pathways and suppressing orexigenic pathways within the central nervous system (CNS).18 Beyond appetite control, leptin regulates multiple physiological processes, including lipid and glucose metabolism and immune responses.18 Insights into leptin’s role in hepatic metabolism largely stem from studies using ob/ob (leptin-deficient) and db/db (leptin receptor-deficient) mice. These models exhibit hepatic IR, TC and lipid accumulation, steatosis, and inflammation—phenotypes that are partially reversed by leptin administration.19,20 Although leptin facilitates hepatic lipid clearance and mobilization, leptin resistance, commonly seen in obesity, may limit its effectiveness in reducing steatosis.19,20 Furthermore, elevated circulating leptin levels, frequently observed in obese individuals, are linked to hepatic inflammation and fibrosis, further implicating leptin in MAFLD progression.
This review provides a comprehensive overview of the interplay between leptin and MAFLD. We summarize experimental and clinical evidence linking leptin to MAFLD pathogenesis and evaluate its therapeutic potential, with a focus on its regulatory roles in IR, lipid metabolism, inflammation, and oxidative stress.
Leptin: Structure and receptor
The discovery of leptin began in the early 1950s with the identification of the ob/ob mouse, a model characterized by severe obesity and hyperphagia.21 In the 1960s, the db/db mouse, another hyperphagic and obese diabetic model, was described.22 In 1994, Jeffrey Friedman’s team successfully cloned the obese gene and named the protein it encoded leptin.23 The following year, the leptin receptor (Ob-R) was cloned and found to be mutated in the db/db mouse.24 Leptin is a polypeptide hormone composed of 167 amino acids, transcribed from the human OB gene located on chromosome 7, which contains three exons and two introns.23 Structurally, leptin exhibits the three-dimensional features of a four-helix bundle cytokine. It includes a short signal peptide (21 amino acids) and a longer functional segment of 146 amino acids. Although predominantly synthesized and secreted by subcutaneous white adipose tissue, leptin is also produced in several peripheral tissues and in the CNS.25 Leptin secretion is positively correlated with adipocyte size and is regulated by multiple factors, including body fat mass, metabolic state, circadian rhythm, and hormones such as insulin, glucocorticoids, and leptin itself.26–28 While classically regarded as a marker of long-term energy stores, leptin has pleiotropic functions: it modulates immune and inflammatory responses, neuroendocrine axes, autonomic nervous activity, cardiovascular function, reproduction, angiogenesis, osteogenesis, and hematopoiesis.29–34 In addition, leptin influences gluconeogenesis, insulin sensitivity, and lipid and carbohydrate metabolism in the liver; skeletal muscle regeneration; lipolysis in adipose tissue; and nutrient utilization in the small intestine by regulating mucus and hormone secretion, nutrient absorption, gastric emptying, and intestinal motility.35
Leptin exerts its effects by binding to its cell surface receptor, Ob-R, encoded by the Ob-R gene in rodents. Throughout this discussion, murine nomenclature and numbering are used.24,36–38 Alternative splicing of the Ob-R transcript produces several isoforms. These include the signaling-competent Ob-Rb (LepRb), which has a long intracellular tail; shorter isoforms with truncated intracellular domains (Ob-Ra, Ob-Rc, Ob-Rd); and a secreted form consisting of only the extracellular domain (Ob-Re).39,40 CNS-expressed Ob-R isoforms are critical for energy balance, metabolism, feedback regulation, and immune function.41 Ob-Rb is also expressed in peripheral tissues such as skeletal muscle, adipose tissue, liver, and pancreatic β-cells, suggesting autocrine and paracrine roles in energy regulation.42,43 Shorter isoforms, Ob-Ra and Ob-Rc, are involved in leptin transport across the blood-brain barrier.44 Leptin levels are inversely associated with the binding and clearance functions of these soluble receptors.45,46 However, only the long Ob-Rb isoform has a complete intracellular domain capable of transmitting signals upon ligand binding.47
Leptin receptor signaling and MAFLD
Upon leptin binding, Ob-Rb in hepatocytes activates intracellular signaling via JAK2 (Janus kinase 2) phosphorylation (Fig. 1). JAK2 then phosphorylates three tyrosine residues (Tyr1077, Tyr1138, and Tyr985) on the intracellular domain of Ob-Rb.20 Tyr1077 activates STAT5 (Signal transducer and activator of transcription 5), while Tyr1138 activates both STAT5 and STAT3 (Signal transducer and activator of transcription 3). Tyr985 engages the SHP2/MAPK (Tyrosine-protein phosphatase 2 containing SH2/ Mitogen-activated protein kinase) cascade.48–50 Activated STAT3 upregulates SOCS-3 (Cytokine signaling 3 suppressor), a negative feedback regulator of leptin and insulin signaling.32,51,52 Elevated SOCS-3 contributes to hormone resistance, suggesting that SOCS-3 inhibition could represent a therapeutic approach in liver disease. In addition, IRS1/IRS2 (Insulin receptor substrate) phosphorylation and PI3K (Phosphatidylinositol 3-kinase) activation modulate JAK2 activity, playing a central role in leptin’s regulation of food intake. Leptin also stimulates AMPK (5′-adenosine monophosphate-activated protein kinase) activity in peripheral tissues, promoting glucose uptake and fatty acid oxidation, while suppressing AMPK activity in the brain to regulate appetite.51 The PI3K/Akt (protein kinase B) pathway, which regulates mTOR signaling, is also activated and improves insulin sensitivity by reducing hepatic glucose output.53
Leptin resistance
For leptin to exert its physiological effects, circulating concentrations must remain within a functional range. Excessive leptin, however, can induce receptor desensitization—even in genetically leptin-deficient mice.54 In obesity, leptin resistance is characterized by impaired central and/or peripheral responsiveness despite elevated leptin levels.35 This may result from impaired receptor signaling or defective transport across the blood-brain barrier (BBB).55 Proposed mechanisms include suppression of the JAK-STAT pathway, downregulation of receptor expression, impaired post-receptor signaling, decreased histone deacetylase 5 activity in the hypothalamus, elevated C-reactive protein, endoplasmic reticulum stress, and hypothalamic inflammation.56 SOCS3 plays a central role in diet-induced obesity by inhibiting STAT3 and downstream Ob-Rb signaling.57,58
Leptin resistance increases the risk of diet-induced obesity and creates a feedback loop in which elevated leptin levels further exacerbate resistance. This resistance can manifest in the CNS and peripheral tissues and is referred to as central and peripheral leptin resistance, respectively.59 Peripheral leptin resistance occurs in tissues such as skeletal muscle, adipose tissue, and the liver; it diminishes leptin’s effectiveness in regulating lipid and carbohydrate metabolism and is closely associated with inflammation.60,61 Both leptin deficiency and leptin resistance are associated with hepatic lipid droplet accumulation, lymphocyte infiltration, and disturbances in glucose homeostasis.62 Disruptions in leptin signaling are also significantly associated with IR in MASH.63 In humans, leptin resistance is influenced by obesity, lipodystrophy, and genetic variations, including Ob-R polymorphisms linked to MAFLD.64,65 Typically, obesity induces hyperleptinemia, which promotes inflammation and leptin resistance, leading to sustained postprandial hyperinsulinemia and ultimately metabolic dysfunction.
Possible models of leptin function in MAFLD pathogenesis
Glucose levels and IR
Leptin regulates blood glucose levels both directly, through peripheral tissues, and indirectly, via the CNS (Fig. 2).66 In the CNS, these effects are mediated by leptin receptors (Ob-Rs) expressed on neurons.67 Leptin primarily modulates glucose homeostasis in the context of obesity and IR through pro-opiomelanocortin-expressing neurons in the hypothalamic arcuate nucleus.68,69 Notably, intracerebroventricular leptin administration in animal models produces minimal changes in circulating leptin levels but improves IR and glycemic control, supporting the hypothesis that leptin primarily regulates glucose metabolism via central mechanisms, independently of food intake or body weight.70 Peripherally, leptin regulates glucose levels by binding to receptors in multiple tissues and modulating pancreatic hormone secretion, lowering both insulin and glucagon.71 Although several studies show that leptin enhances glucose uptake, glycogenesis, and glucose oxidation in skeletal muscle, results have not been consistent across all investigations.72–74 Leptin reduces glucose uptake in adipocytes and decreases fatty acid and glycerol release, thereby limiting gluconeogenic substrate availability to the liver.75 In the liver, leptin inhibits gluconeogenesis via IRS-2 and reduces hepatic TC content.76,77 Leptin may also interfere with insulin action by altering adipocyte sensitivity to lipid accumulation, reducing insulin receptor binding in the liver, and suppressing insulin secretion from pancreatic islets.45,78,79 However, human studies suggest leptin does not directly affect insulin secretion from pancreatic β-cells.80 Serum leptin levels are not consistently associated with insulin or glucose concentrations, nor with the homeostasis model assessment of IR.81 Instead, leptin may lower blood glucose by reducing gluconeogenesis through substrate limitation. Furthermore, leptin-induced weight loss and reduced fat mass may improve insulin sensitivity, decrease glucose levels, and limit carbohydrate and lipid flux to the liver,80 thereby suppressing de novo lipogenesis and reducing hepatic fat accumulation.82
Hyperleptinemia, however, can damage pancreatic β-cells and impair JAK2/PI3K signaling in obese individuals with T2DM and MAFLD. Leptin resistance may further contribute to hyperinsulinemia and worsening IR, thereby increasing the risk of T2DM.83 IR inhibits lipid oxidation while promoting triglyceride and fatty acid synthesis.45,78,84 Consequently, the leptin–insulin signaling axis that normally regulates glucose metabolism becomes disrupted. Hyperleptinemia also upregulates hepatic sterol regulatory element-binding protein 1 (SREBP-1), promoting lipogenesis.85 Along with other pro-inflammatory adipokines, leptin has been strongly implicated in the development of IR, particularly in MAFLD.86,87
Lipid metabolism
Leptin plays a dual role in fatty liver disease (Fig. 2). In early MAFLD, leptin reduces hepatic lipid accumulation and promotes lipid oxidation.19,88 Rodent models with impaired leptin signaling—including leptin-deficient ob/ob and db/db mice—support these findings.89,90 Hepatic steatosis arises from disruptions in both glucose and lipid metabolism, and leptin limits TC storage in adipose and non-adipose tissues, including the liver, to prevent lipotoxicity.20 Leptin reduces hepatic lipid accumulation through vagal signaling by activating the JAK2–STAT3/AMPK pathway, independent of food intake.91 At physiological levels, leptin exerts anti-steatotic effects by suppressing lipogenesis and hepatic glucose production, thereby improving insulin sensitivity.52,92 These mechanisms explain the prevention or reversal of hepatic steatosis in ob/ob mice treated with leptin.93 Leptin’s anti-steatotic properties have also been demonstrated in non-obese mice with uncontrolled T1DM, in which leptin therapy reduced lipogenic and cholesterogenic transcription factors, lowering plasma and tissue lipid levels.94 Leptin regulates hepatic lipid synthesis by modulating key transcription factors such as carbohydrate-responsive element-binding protein.95 It may act synergistically with insulin and inhibit the production of very low-density lipoproteins (VLDL).94,96,97 Additionally, leptin may enhance VLDL-TC export, further reducing steatosis.98 Some studies even suggest that leptin improves steatosis and IR in lipodystrophic mice.99 Hackl et al. also reported leptin’s protective role against ectopic lipid accumulation in the brain, underscoring its therapeutic potential in obesity-related steatosis.100
Despite these beneficial effects, elevated leptin levels often fail to resolve hepatic steatosis because of leptin resistance, a central feature of MAFLD pathogenesis.52,101,102 Mechanisms such as Tyr985 phosphorylation on Ob-Rb and increased SOCS-3 expression impair leptin signaling, particularly in the arcuate nucleus.103 Leptin levels are positively correlated with steatosis severity, especially in individuals with high body mass index (BMI). In lean MAFLD patients, however, genetic and metabolic disorders (e.g., hypobetalipoproteinemia, celiac disease, cystic fibrosis) may play a greater role than leptin levels.104 Leptin may also promote hepatic IR, attenuating its own anti-steatotic effects.105 Cernea et al. reported increased MAFLD-related steatosis in T2DM patients,45 while Pavlidis et al. found higher leptin levels associated with more severe steatosis in chronic hepatitis C.106 Eshraghian et al. were the first to demonstrate that changes in leptin, adiponectin, and IR were associated with hepatic steatosis in liver transplant recipients.107
Inflammation
The severity of hepatic steatosis in MAFLD correlates with progressive liver damage, ranging from simple steatosis to MASH (Fig. 3). While most patients present with isolated steatosis, approximately one-third progress to MASH, increasing the risk of advanced stages of MAFLD.1 This progression is driven by inflammation, which arises when hepatic TC levels exceed the liver’s adaptive capacity, resulting in lipotoxicity. Lipotoxicity is characterized by the production of reactive oxygen species (ROS), endoplasmic reticulum stress, and hepatocellular injury.16 These cellular insults activate immune and apoptotic pathways, ultimately leading to cell death and contributing to fibrosis and cirrhosis over time.108 Although leptin possesses anti-steatotic properties, it also exhibits pro-inflammatory and fibrogenic effects.109 In animal models fed a high-fat diet, elevated leptin levels have been associated with inflammation and MASH.110 In the context of diet-induced obesity, leptin contributes to IR, T2DM, and chronic inflammation.111–113 Studies have shown that myeloid cells lacking leptin signaling demonstrate improved glucose tolerance in obese mice, underscoring leptin’s role in low-grade systemic inflammation.114 Furthermore, leptin resistance has been linked to low-grade inflammation and steatosis in obese individuals, implicating leptin in the transition from simple steatosis to MASH.115
Early studies in ob/ob and db/db mice revealed immune deficiencies, including impaired antibody production, reduced cytotoxic activity, and increased susceptibility to autoimmune and allergic diseases.116,117 Leptin enhances lipopolysaccharide-induced production of tumor necrosis factor-alpha (TNF-α) in monocytes and macrophages.118,119 It can also independently stimulate inflammation by promoting the M1 macrophage phenotype.120 Leptin deficiency exacerbates inflammatory cell infiltration and promotes MASH development.121 In murine preadipocytes and adipose-derived stromal cells, leptin facilitates lipid droplet formation and upregulates adipogenic and lipogenic signaling pathways, particularly through PPARγ and SREBP-1c activation. Leptin also reduces interleukin (IL)-10 production while increasing pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α.122 Conversely, TNF-α and IL-1 stimulate leptin secretion.123,124 Leptin supports pro-inflammatory CD4+ T-cell proliferation and inhibits regulatory T-cell expansion.125,126 It also plays a role in TH17 cell differentiation in human CD4+ T cells.127 In B cells, leptin has been shown to promote the release of inflammatory mediators and accelerate immunosenescence. B cells from young, lean individuals treated with leptin displayed inflammatory and aging markers typically observed in B cells from individuals with obesity or advanced age.128 In steatotic livers with active inflammation, OB-R expression is significantly increased in activated mouse CD4+CD8+ T cells and B cells. Leptin signaling promotes lymphocyte survival and function.129 These lymphocytes can release granzymes that generate ROS in mitochondria and activate caspases, ultimately inducing pyroptosis.130
Tissue inflammation frequently leads to additional tissue injury. Leptin levels are elevated in patients with liver fibrosis, particularly among those with high BMI, whereas leaner individuals exhibit reduced inflammation and fibrosis.104 Some studies suggest that leptin receptors on Kupffer cells (KCs) and sinusoidal endothelial cells contribute to the expression of matrix-remodeling enzymes, thereby initiating fibrosis through hepatic stellate cells (HSCs) activation.89,104,131 Leptin also induces vascular endothelial growth factor expression in HSCs, which may drive irreversible cirrhosis and MASH progression.132 In KCs, leptin upregulates transforming growth factor-β, likely activating HSCs through paracrine signaling.89,104,131 Activated HSCs exacerbate hepatic inflammation and fibrosis by secreting angiopoietin-1, collagen I, transforming growth factor-β1 (TGF-β1), and vascular endothelial growth factor (VEGF). These cells also produce leptin and express ObRb, forming a feedback loop that sustains HSCs proliferation and inhibits apoptosis, thereby amplifying hepatic inflammation and fibrosis.89 Moreover, leptin can activate KCs through oxidative stress mediated by peroxynitrite.133 This activation promotes the presence of CD8+CD57+ T cells, which are implicated in MASH progression.134 Prolonged hyperleptinemia may stimulate HSCs, KCs, and sinusoidal endothelial cells, triggering both pro-inflammatory and pro-fibrogenic signaling cascades.52
Oxidative stress
KCs are a major source of ROS in the liver, primarily through the activity of NADPH oxidase, the key enzyme responsible for ROS generation (Fig. 3).135 Danger-associated molecular patterns, such as ATP (Adenosine Triphosphate), activate KCs and stimulate ROS production.136 Additionally, lipid peroxidation products like 4-hydroxynonenal can activate HSCs,137 which also produce ROS via phagocytic activity and NADPH oxidase expression.138 The expression of cytochrome P450 2E1, an enzyme involved in fatty acid oxidation, is elevated in models of alcoholic steatohepatitis and MASH, contributing to oxidative liver damage.139 Increased oxidative stress also promotes auto-oxidation of excess cholesterol, forming oxysterols. Elevated oxysterol levels have been observed in biopsy-proven MAFLD patients and are associated with pro-inflammatory, pro-apoptotic, and pro-fibrogenic effects.140 A comparative study found that oxidative stress–related cellular damage in MAFLD aligns with the multiple parallel hits hypothesis.141 In this study, involving seven control subjects, 23 patients with MAFLD, and 17 with MASH, levels of 8-hydroxy-2′-deoxyguanosine and 4-hydroxynonenal were elevated in the MAFLD and MASH groups, indicating oxidative DNA damage and lipid peroxidation. Furthermore, compared with a non-hyperphagic rat model, obese hyperphagic rats showed increased hepatic oxidative stress.16,142
Watson et al. demonstrated that leptin treatment restored altered glutathione peroxidase levels in ob/ob mice, suggesting leptin’s role in regulating antioxidant enzyme activity.143In vitro studies have shown that leptin decreases malondialdehyde and ROS levels while increasing glutathione content.144 Additionally, leptin enhances natural antioxidant enzyme activity and suppresses inflammatory factor expression in 3T3-L1 preadipocytes, thereby reducing oxidative stress–induced cellular injury.145 Leptin supplementation has also been effective in mitigating oxidative stress induced by a high-fat diet.146 In one study, offspring of obese dams given oral leptin during the suckling period demonstrated greater antioxidant capacity and reduced inflammatory markers in the liver, retroperitoneal white adipose tissue, and plasma compared to those given vehicle control.147 Leptin-treated male offspring also exhibited increased plasma adiponectin and a higher adiponectin/leptin ratio, which enhances the liver’s anti-inflammatory and antioxidant functions.148 The absence of leptin in pigs led to reduced JAK2-STAT3 and AMPK phosphorylation, resulting in increased fatty acid β-oxidation and mitochondrial autophagy—both contributing to oxidative stress in liver cells.149 In human hepatoma cell lines, leptin treatment of ethanol-exposed cells reduced ROS generation.150 Furthermore, leptin was shown to suppress oxidative stress responses in blood and reduce endotoxemia-induced rises in pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α.151
However, leptin can also induce ROS formation in both phagocytic and non-phagocytic cells, including endothelial cells, cardiomyocytes, and HSCs.152–154 Elevated leptin levels have been linked to increased ROS production, primarily through NADPH oxidase activation.155 Hyperinsulinemia and hyperleptinemia are considered key contributors to oxidative stress in individuals with obesity or T2DM.156,157 Systemically elevated leptin levels exacerbate oxidative stress and weaken antioxidant defenses, thereby intensifying hepatic inflammation, especially in alcoholic liver disease.158 In mouse models with steatohepatitic lesions, high circulating leptin levels aggravated liver damage via NADPH oxidase activation, inducible nitric oxide synthase induction, and increased TNF-α and monocyte chemoattractant protein-1 release from KCs, all mediated through peroxynitrite-dependent pathways.133 Leptin promotes oxidative and inflammatory effects through three primary mechanisms: leptin-induced protein radical formation, tyrosine nitration, and KCs activation.133 It also upregulates CD14 expression on KCs, a receptor for the bacterial endotoxin lipopolysaccharide.159 This upregulation heightens cellular sensitivity to harmful stimuli and enhances oxidative stress. Notably, CD14 overexpression has been implicated in the progression of steatohepatitis and liver fibrosis, even in the absence of prior steatosis.160
Leptin in MAFLD: Evidence from clinical studies
Basal leptin levels correlate with BMI and reflect the body’s nutritional status. In severe obesity, the physiological set point for weight regulation may shift to a higher leptin threshold.115 When BMI decreases to below 25 kg/m2, fasting leptin levels fall by approximately 15 ng/dL, likely due to improved leptin delivery to the CNS and enhanced access to specific neuronal populations.130,161 Low circulating leptin levels and increased leptin sensitivity, both of which exert anti-steatotic effects, are associated with several interventions, including physical activity,162 bariatric surgery,163 dietary polyphenol intake,164,165 caloric restriction, and sustained weight loss.166,167 Leptin thresholds vary among individuals due to genetic factors,161 sex-related differences,115,168 and, more recently, the use of GLP-1 receptor agonists.169 Individuals with a history of obesity may retain elevated leptin levels even after returning to normal weight.170
Importantly, elevated leptin levels have been linked to MAFLD even in lean individuals and in the absence of IR.171 Multiple studies demonstrate that high leptin levels are associated with both the presence and severity of MAFLD in children and adults, suggesting that early-onset leptin resistance may contribute to disease pathogenesis.172–177 For instance, Marques et al. reported elevated leptin levels in MAFLD patients compared to healthy controls, with no significant difference between obese and non-obese groups—indicating that obesity is not a confounding factor.178 Moreover, reducing leptin levels with antibodies has been shown to restore leptin sensitivity, suggesting a potential therapeutic strategy for obesity and diabetes.179 These findings imply that early intervention to lower leptin levels in children could help prevent MAFLD.172 Previous studies also reported associations between elevated leptin and hepatic fibrosis in MAFLD. In one study, high serum leptin was identified as a significant risk factor for hepatic steatosis, and receiver operating characteristic analysis confirmed leptin as an independent predictor of liver fat accumulation.180
However, not all findings are consistent. Canbakan et al. found that leptin was not an independent predictor of MAFLD or fibrosis severity; their study reported higher leptin levels in patients with moderate fibrosis compared to those with advanced fibrosis.81 Similarly, in a pediatric cohort, children with prepubertal obesity and fatty liver disease had significantly lower leptin z-scores (adjusted for BMI) than peers with normal liver ultrasound findings,181 with these z-scores inversely correlated with fatty liver severity. In adults, normal-weight Caucasians with MAFLD, commonly referred to as lean MAFLD, showed significantly lower circulating leptin levels than obese MAFLD patients, though no difference was observed between lean MAFLD patients and lean healthy controls.182 A meta-analysis reported higher leptin levels in MAFLD patients with fibrosis compared to non-MAFLD controls; however, this association weakened after excluding one study involving morbidly obese individuals.183 No significant differences in leptin levels were found between MAFLD patients without fibrosis and healthy controls, or between MAFLD patients with and without fibrosis. Interestingly, a two-sample Mendelian randomization study provided strong evidence suggesting that elevated leptin levels may be causally linked to a reduced risk of MAFLD, indicating a potential protective effect.88
Taken together, these findings emphasize the importance of considering weight, sex, age, and other individual factors when interpreting leptin levels in MAFLD. A key unresolved question is whether fluctuations in circulating leptin accurately reflect changes in hepatic leptin levels. Subtle differences in liver leptin content could influence hepatic inflammation and fibrosis, even if such changes are not mirrored in systemic circulation. However, this relationship has yet to be clearly established.
Leptin as a potential therapeutic target for patients with MAFLD
The ob/ob mouse model carries a mutation in the leptin gene, resulting in leptin deficiency.23 This deficiency causes severe obesity, primarily due to hyperphagia (overeating) and, to a lesser extent, reduced energy expenditure and physical activity. These mice also develop metabolic abnormalities, including elevated lipid, glucose, insulin, and hepatic fat levels.184,185 Their metabolic and endocrine profiles closely resemble those of humans with congenital leptin deficiency. Notably, leptin administration corrects all metabolic and endocrine abnormalities in these animals. In contrast, the aP2-nSREBP-1c mouse model, which exhibits impaired adipocyte differentiation and reduced white adipose tissue mass, is commonly used to study lipodystrophy.186 These mice develop hyperglycemia, hyperinsulinemia, mild hyperphagia, and hepatic steatosis. Leptin treatment reduces appetite, body weight, and liver steatosis while improving glucose levels and insulin sensitivity—benefits that occur independently of caloric restriction.186 Conversely, diet-induced obesity models—characterized by high body fat and elevated circulating leptin—exhibit minimal or no weight loss even when administered high doses of leptin.187,188 Collectively, these findings suggest that leptin therapy is more effective in conditions of leptin deficiency—such as congenital leptin deficiency, lipodystrophies, or fasting-induced hypoleptinemia—than in conditions associated with hyperleptinemia.185
In clinical studies, an open-label trial of patients with relative leptin deficiency and MASH, one year of metreleptin treatment improved liver fat content and MASH scores in five of seven patients with available liver biopsies, with additional improvements in inflammation, ballooning, and fibrosis in some cases.189 Similarly, Akinci et al. reported that metreleptin significantly reduced overall MASH scores in obese adults with relative leptin deficiency.190 In a placebo-controlled crossover study, a single leptin dose administered to lean individuals post-fasting enhanced VLDL-TC export and may have prevented the hepatic fat accumulation typically associated with fasting.98 Improved insulin sensitivity and appetite suppression could reduce the flux of free fatty acids and carbohydrates to the liver, thereby decreasing de novo lipogenesis and hepatic fat accumulation.82 However, despite these promising findings, existing studies are limited by small sample sizes. To date, no clinical trial has demonstrated fibrosis improvement without worsening MASH or MASH resolution without increasing fibrosis. Even in insulin-resistant patients, insulin therapy can effectively reduce blood glucose, suggesting that pharmacological doses of leptin might promote weight loss and improve liver fat content. Yet randomized controlled trials using pegylated recombinant human leptin or metreleptin at various doses have not shown significant benefits in energy expenditure, body composition, weight loss, adrenal hormones, sympathetic nervous system activity, lipid metabolism, or macronutrient utilization.191–195 Strategies to overcome leptin resistance—such as leptin sensitization or co-treatment with amylin analogs—have been proposed, but to date, they have not produced significant advances in common obesity patients with relatively low leptin levels.
Future perspectives
Numerous studies and clinical cases have demonstrated that MAFLD imposes substantial long-term health, social, and economic burdens, largely due to its high global prevalence.5 Without effective policy interventions, these consequences will continue to escalate. Given the increased cardiovascular and mortality risks associated with MAFLD, a multidisciplinary strategy is essential.2 There remains an urgent need for non-invasive diagnostic tools to replace liver biopsy, enabling earlier detection and monitoring in broader populations. Both extrahepatic factors and intrahepatic mechanisms contribute to MAFLD onset and its progression to MASH.16 Elucidating the underlying pathophysiology and identifying precise molecular targets for diagnosis and treatment remain crucial research priorities.
Leptin, a hormone closely associated with adiposity and IR, has been identified as an independent predictor of MAFLD onset and progression.177,180,183 Although leptin exhibits anti-steatotic properties, it is also implicated in hepatic steatosis and the progression of MAFLD to more advanced stages, including MASH and fibrosis.16 In the early stages of MAFLD, leptin helps regulate glucose homeostasis, reduce hepatic lipid accumulation, and promote lipid oxidation. However, hyperleptinemia can damage pancreatic β-cells and disrupt JAK2/PI3K signaling, contributing to elevated insulin levels and worsening IR.83 This IR, in turn, inhibits lipid oxidation while promoting TC and fatty acid synthesis.45,78,84 Leptin can also directly stimulate inflammation by promoting the M1 macrophage phenotype120 and increasing pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α.122 It supports the proliferation of pro-inflammatory CD4+ T cells and B cells while inhibiting regulatory T-cell expansion.125,126 These lymphocytes release granzymes that generate mitochondrial ROS and activate caspases, ultimately inducing pyroptosis.130 Leptin can further promote ROS formation in both phagocytic and non-phagocytic cells, including endothelial cells, cardiomyocytes, and HSCs.152–154 The effects of leptin on cirrhosis and HCC in MAFLD remain poorly defined, and its role in other cirrhosis etiologies is still debated.20 Nonetheless, substantial evidence suggests a pro-tumorigenic role for leptin in HCC associated with liver diseases unrelated to MAFLD.
Leptin therapy has proven effective in individuals with congenital leptin deficiency; however, its broader therapeutic potential remains controversial.185 This underscores the need for further research into the development of leptin analogs that preserve anti-steatotic properties while avoiding pro-inflammatory and fibrogenic effects. Investigating leptin sensitizers and their use in combination with other therapeutic agents should also be prioritized.56
Conclusions
Large-scale observational studies and long-term clinical trials are necessary to establish leptin’s efficacy across diverse MAFLD phenotypes. Finally, leptin shows promise as a biomarker for MAFLD diagnosis and monitoring, particularly when combined with glucose, lipid, and metabolic profiling. Future research should explore not only leptin’s therapeutic potential but also preventive strategies targeting leptin signaling to mitigate MAFLD development.
Declarations
Acknowledgement
The graphics in this article were supported by Figdraw free of charge.
Funding
This work was supported by grants from the Chengde Science and Technology Agency (Grant No. 202109A193).
Conflict of interest
The authors have no conflict of interests related to this publication.
Authors’ contributions
Manuscript preparation and drafting (JLW, YX, MLL), study conception and design (JLW, JLL), and drafting of the manuscript (JLW). All authors contributed to the manuscript by revising and editing it for important intellectual content. They gave final approval of the version and agreed to be accountable for all aspects of the work presented here.