Research Progress on Leptin in Metabolic Dysfunction-associated Fatty Liver Disease

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) poses a significant challenge in modern medicine due to its high prevalence. The pathogenesis of MAFLD involves a complex dysmetabolic process consistent with the "multiple-hit" hypothesis. This process includes excessive triglyceride (TC) accumulation within hepatocytes, lipotoxicity, insulin resistance (IR), chronic low-grade inflammation, and increased oxidative stress. The role of leptin in the liver has been extensively studied, demonstrating both direct effects on hepatic cells and indirect actions mediated through the central nervous system (CNS). In MAFLD, leptin modulates several physiological processes: it improves glucose metabolism by enhancing insulin sensitivity and lowering glucose levels; regulates lipid metabolism by promoting β-oxidation and TC export while inhibiting lipogenesis; and contributes to fibrogenesis by upregulating transforming growth factor-β (TGF-β) expression and activating hepatic stellate cells (HSCs) and the immune response. This review explores the structure of leptin, its primary physiological functions, its potential role in MAFLD pathogenesis, and its promise as a novel therapeutic target.

Keywords: Inflammation; Insulin resistance; Leptin; Lipid metabolism; MAFLD; Metabolic dysfunction-associated fatty liver disease.

Fig. 1. Signal transduction of the leptin receptor in hepatic cells.

Akt, protein kinase B; AMPK, 5′-adenosine monophosphate-activated protein kinase; ERK, extracellular signal-regulated kinase; Grb2, growth factor receptor-bound protein 2; IRS, insulin receptor substrate; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; PTP, protein tyrosine phosphatase; SHP2, tyrosine-protein phosphatase 2 containing SH2; STAT, signal transducer and activator of transcription; SOCS3, suppressor of cytokine signaling 3.

Fig. 2. Mechanisms of insulin resistance and lipid metabolism of leptin in MAFLD.

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, leading to elevated insulin levels and worsening IR. This IR inhibits lipid oxidation while promoting triglyceride and fatty acid synthesis. VLDL, very low-density lipoproteins; TC, Triglyceride; JAK, Janus kinase; PI3K, phosphatidylinositol 3-kinase; IR, insulin resistance; T2DM, type 2 diabetes mellitus; MAFLD, metabolic dysfunction-associated fatty liver disease.

Fig. 3. Mechanisms of inflammation and oxidative stress of leptin in MAFLD.

Leptin can independently stimulate inflammation by promoting the M1 macrophage phenotype while increasing pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α. Leptin supports pro-inflammatory CD4⁺ T-cell and B-cell proliferation while inhibiting regulatory T-cell (Treg) expansion. These lymphocytes can release granzymes that produce ROS in mitochondria and activate caspases, ultimately inducing pyroptosis. It can also induce ROS formation in both phagocytic and non-phagocytic cells, including endothelial cells, cardiomyocytes, and HSCs. IL-6, interleukin-6; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-alpha; ROS, reactive oxygen species; M1, macrophage phenotype 1; KCs, Kupffer cells; HSCs, hepatic stellate cells; TGF-1β, transforming growth factor-beta; VEGF, vascular endothelial growth factor; MAFLD, metabolic dysfunction-associated fatty liver disease; ↑, increase.