Understanding leptin's dual function in MAFLD pathogenesis

Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a predominant chronic liver condition globally, intricately linked with obesity, type 2 diabetes (T2DM), and metabolic syndrome. Its pathogenesis is complex, following a "multiple-hit" hypothesis that involves triglyceride accumulation, insulin resistance (IR), lipotoxicity, chronic inflammation, and oxidative stress. Among the various adipokines implicated, leptin, a hormone central to energy homeostasis, has been identified as a critical player. This review synthesizes the current understanding of leptin's structure, signaling, and its multifaceted-and often paradoxical-roles in the initiation and progression of MAFLD.

Leptin: Structure and receptor

Leptin is a 167-amino acid polypeptide hormone, primarily secreted by white adipose tissue, with levels correlating with body fat mass. It exerts its biological effects by binding to its receptor, Ob-R. Among several splice variants, the long isoform, Ob-Rb, is the primary signaling receptor, expressed both in the central nervous system (CNS) and peripheral tissues like the liver. The discovery of leptin-deficient (ob/ob) and receptor-deficient (db/db) mouse models, which exhibit severe hepatic steatosis and IR, was pivotal in elucidating leptin's metabolic functions.

Leptin receptor signaling and MAFLD

Upon leptin binding, Ob-Rb activates the JAK2-STAT3 signaling pathway, which regulates genes involved in metabolism and appetite. This pathway also induces SOCS3, a key negative feedback regulator that contributes to leptin resistance. Additionally, leptin signaling engages the PI3K/Akt and AMPK pathways, which are crucial for improving insulin sensitivity and promoting fatty acid oxidation in the liver. Dysregulation of these pathways is a hallmark of metabolic dysfunction in MAFLD.

Leptin resistance

A central concept in the pathophysiology of MAFLD is leptin resistance, a state commonly observed in obesity where elevated circulating leptin fails to elicit appropriate physiological responses. Mechanisms include impaired JAK-STAT signaling, increased SOCS3 expression, and defective transport across the blood-brain barrier. This resistance disrupts leptin's ability to regulate energy balance and metabolism, creating a vicious cycle that exacerbates IR and promotes hepatic lipid accumulation.

The dual role of leptin in MAFLD pathogenesis

The role of leptin in MAFLD is complex and context-dependent, acting as both a protector and a promoter of disease.

• Glucose metabolism and insulin resistance: Leptin improves glucose homeostasis through central and peripheral mechanisms. In the CNS, it enhances insulin sensitivity. In the liver, it inhibits gluconeogenesis. However, in states of hyperleptinemia, leptin can damage pancreatic β-cells and disrupt insulin signaling pathways, thereby worsening IR and creating a metabolic environment conducive to MAFLD progression.

• Lipid metabolism: Physiologically, leptin is anti-steatotic. It promotes hepatic fatty acid β-oxidation, inhibits lipogenesis, and enhances the export of very low-density lipoprotein triglycerides (VLDL-TC). This is evidenced by the reversal of steatosis in leptin-deficient mice upon leptin treatment. However, in the prevalent condition of leptin resistance, these beneficial effects are blunted, and high leptin levels may even promote lipogenesis via upregulation of SREBP-1, contributing to hepatic fat accumulation.

• Inflammation and fibrosis: Leptin exhibits potent pro-inflammatory properties. It promotes a pro-inflammatory M1 macrophage phenotype, stimulates the production of cytokines like TNF-α, IL-6, and IL-1β, and supports the proliferation of inflammatory T-cells while suppressing regulatory T-cells. Furthermore, leptin activates Kupffer cells and hepatic stellate cells (HSCs), upregulating pro-fibrogenic factors like TGF-β and VEGF, thereby driving the transition from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis.

• Oxidative stress: The evidence here is also dualistic. Leptin has been shown to enhance antioxidant defenses in some models. Conversely, it can induce reactive oxygen species (ROS) production in various cells, including HSCs and endothelial cells, primarily through NADPH oxidase activation. This oxidative stress further amplifies hepatic inflammation and injury.

Evidence from clinical studies

Clinical findings on leptin in MAFLD are heterogeneous. Many studies report a positive correlation between serum leptin levels and the presence and severity of MAFLD and liver fibrosis, even in lean individuals, suggesting a role for early leptin resistance. However, other studies have found no independent predictive value for leptin, and some Mendelian randomization analyses even suggest a protective causal effect. These discrepancies underscore the influence of confounding factors such as BMI, sex, age, and genetic background, highlighting that circulating leptin may not always reflect its activity within the liver.

Leptin as a potential therapeutic target

Leptin therapy has demonstrated remarkable efficacy in rare conditions of leptin deficiency, such as congenital lipodystrophy, significantly improving hepatic steatosis and IR. However, in the common scenario of obesity-associated hyperleptinemia and leptin resistance, exogenous leptin administration has largely been ineffective. This has shifted research focus towards developing leptin sensitizers and combination therapies aimed at restoring leptin responsiveness, which hold greater promise for treating MAFLD.

Future perspectives and conclusions

Future research must prioritize large-scale, long-term studies to clarify leptin's efficacy across diverse MAFLD phenotypes. Key directions include the development of leptin analogs that retain beneficial metabolic effects without pro-inflammatory actions, and the exploration of leptin sensitizers. Furthermore, leptin's potential as a diagnostic and prognostic biomarker, especially when integrated into multi-parameter profiles, warrants further investigation. In conclusion, leptin sits at a critical crossroads in MAFLD pathophysiology. Its dual role necessitates a nuanced understanding, as targeting the leptin signaling axis offers a compelling, though challenging, therapeutic strategy for this pervasive liver disease.