The LncRNA11-hnRNPA1 functional axis maintains adipose tissue metabolic homeostasis by promoting mitochondrial respiration and lipid utilization.

Long noncoding RNAs (lncRNAs) are emerging as critical regulators of metabolic homeostasis and obesity pathogenesis. Mitochondrial dysfunction is a key driver of metabolic disorders, yet the underlying regulatory mechanisms remain incompletely understood. In this study, we unveil the metabolic function of a novel lncRNA GM44386 (LncRNA11), which is abundantly expressed in brown adipose tissue and functions as a protective molecule against obesity-related energy imbalance. Genetic deletion of LncRNA11 in mice led to exacerbated adipocyte hypertrophy, insulin resistance, and severe hepatic lipid accumulation under both normal and high-fat diet (HFD) conditions. Functionally, LncRNA11 deficiency compromised mitochondrial structure, quality, and oxidative phosphorylation capacity in adipocytes, resulting in defective fatty acid oxidation and impaired thermogenesis. Mechanistically, LncRNA11 forms a complex with Heterogeneous Nuclear Ribonucleoprotein A1 (hnRNPA1) to potentiate mitochondrial glycolysis in adipose tissue by upregulating pyruvate kinase M (PKM) expression. This enhancement supplies ATP required for UCP1-mediated uncoupling, thereby helping to maintain mitochondrial integrity and adaptive thermogenesis. Collectively, our findings identify LncRNA11 as a crucial upstream regulator that coordinates thermogenic capacity and mitochondrial stability, presenting a potential therapeutic target for combating obesity.