Adipose Tissue Browning in MASLD and Its Molecular Mechanisms and Metabolic Crosstalk

Abstract

Metabolic dysfunction–associated steatotic liver disease (MASLD) is an increasingly prevalent complication of obesity and metabolic dysregulation, with limited therapies targeting upstream drivers of disease. Adipose tissue has emerged as a central regulator of systemic metabolic homeostasis, where dysfunction contributes to excess free fatty acid flux, chronic inflammation, and hepatic steatosis. In this context, adipose tissue browning—the induction of thermogenically active beige adipocytes within white adipose depots—has gained attention as a potential therapeutic mechanism. Recent advances highlight that adipose browning modulates multiple pathways relevant to MASLD. These include enhanced mitochondrial β-oxidation and energy expenditure, leading to reduced lipid delivery to the liver, as well as endocrine signaling mediated by batokines such as fibroblast growth factor 21 (FGF21), irisin, and neuregulin 4 (Nrg4). Collectively, these pathways influence hepatic lipid metabolism, insulin sensitivity, and inflammatory and fibrotic processes. The preclinical studies consistently demonstrate metabolic and hepatoprotective benefits of browning; however, translational evidence in humans remains limited and heterogeneous. Factors such as reduced thermogenic capacity in obesity, inter-individual variability, and challenges in sustaining browning activation constrain clinical applicability. Overall, adipose tissue browning represents a promising component of a systems-based approach to MASLD. Future work should focus on integrating mechanistic insights with clinical investigation to clarify its therapeutic potential and to identify strategies that enable durable and patient-specific metabolic benefits.