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

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.