Skeletal Muscle DPT Ameliorates Obesity and Metabolic Dysfunction via the PERK/eIF2α/ATF4-GDF15 Axis

Skeletal muscle plays a pivotal role in maintaining metabolic homeostasis by acting as a primary site for glucose disposal and insulin-mediated energy use. Here, through RNA sequencing of skeletal muscle from individuals with normal weight versus obesity, we identified that the extracellular matrix–related gene dermatopontin (DPT) was significantly upregulated in the individuals with obesity. By establishing muscle-specific overexpression, knockdown, and knockout Dpt mouse models, we demonstrated that DPT ameliorated metabolic dysfunction by improving muscular mitochondrial function and exercise capacity, systemic insulin sensitivity, and glucose tolerance while reducing hepatic steatosis, suppressing appetite, and synergistically boosting energy expenditure under high-fat-diet feeding. Mechanistically, DPT activated a compensatory increase in the PERK/eIF2α/ATF4 endoplasmic reticulum stress pathway, leading to the transcriptional upregulation of growth differentiation factor (GDF) 15 expression and secretion. Importantly, the metabolic benefits of DPT were abolished in Gdf15−/− mice. Collectively, our study identified DPT as a novel, compensatorily expressed regulator in muscle during obesity, highlighting its potential as a therapeutic target for treating metabolic disorders. Article Highlights We identified dermatopontin (DPT) as a previously unrecognized compensatory regulator that is upregulated in skeletal muscle in obesity and preserves muscle function and systemic metabolic homeostasis, offering a potential therapeutic target for metabolic disorders. Mechanistically, DPT activates an adaptive PERK/eIF2α/ATF4 endoplasmic reticulum stress axis specifically under metabolic stress, but not under normal conditions, which enhances muscle function and directly counteracts metabolic deterioration, revealing a protective signaling cascade. This DPT-driven endoplasmic reticulum stress axis transcriptionally upregulates growth differentiation factor (GDF) 15 expression and secretion in muscle. Muscle-derived GDF15 exerts both local muscle-autonomous and systemic protective effects, uncovering a previously unrecognized muscle-to-organ cross-talk axis.