Neutrophil serine proteases inhibit thermogenic capacity of visceral white adipose tissue.

Neutrophils and neutrophil-derived serine proteases (NSPs), including neutrophil elastase (NE) and proteinase 3 (PR3), are present in visceral fat of individuals and rodents with obesity, yet their roles in energy metabolism remain elusive. Here we show that neutrophil infiltration and NSP activation impair visceral fat browning in response to β-adrenergic receptor stimulation or cold exposure in male mice. Genetic deletion or local pharmacological inhibition of NE with sivelestat rescued visceral fat browning and enhanced thermogenesis. Mechanistically, NE/PR3 directly suppresses beige adipogenesis by arresting cell cycle via CDK4/cyclin D1 downregulation, impairs beige adipocyte differentiation by degrading insulin-like growth factor binding protein-3, and indirectly promotes M1 macrophage polarization. Administration of sivelestat suppressed diet-induced neutrophil infiltration, enhanced cold-induced visceral fat browning and decreased visceral fat content in mice. These findings reveal an unexpected inhibitory role of NSPs in visceral fat browning and suggest the potential of repurposing sivelestat as an anti-obese drug.