Inhibition of adipocyte lipolysis by vaspin impairs thermoregulation in vivo

Altered activity of brown adipose tissue (BAT) contributes to obesity, insulin resistance, and cardiovascular disease. BAT secretes endocrine factors ("batokines") that regulate thermogenesis. We identify the serpin vaspin as a batokine that modulates adrenergic control of lipolysis and thermogenesis. Adipocyte-specific vaspin overexpression in mice reduces BAT activation and impairs thermoregulation during cold exposure or fasting. Mechanistically, vaspin binds low-density lipoprotein receptors (LRP1, LDLR, vLDLR), inhibiting adrenergic signaling and lipolysis in brown and white adipocytes by modulating phosphodiesterase activity and endocytic lipid uptake. Gene set enrichment analyses in human subcutaneous adipose tissue and in vitro studies confirm vaspin's anti-lipolytic effects in humans. Overall, vaspin emerges as a regulatory BATokine that fine-tunes BAT thermogenic activity to limit excessive energy expenditure and preserve metabolic balance.