ENPP1 buffers extracellular cGAMP in brown adipose tissue to limit insulin resistance.

The mechanism underlying the role of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) in metabolic disease remains unsolved. Using a 2'3'-cyclic GMP-AMP (cGAMP)-hydrolysis-deficient mouse (Enpp1H362A), we show that selective loss of this activity exacerbates high-fat diet (HFD)-induced weight gain and insulin resistance. An in vivo glucose-uptake screen identifies brown adipose tissue (BAT) as a key site of metabolic impairment, marked by extracellular cGAMP accumulation and defective insulin-stimulated glucose uptake. Mechanistically, nutrient excess drives mitochondrial DNA leakage in brown adipocytes, triggering cGAMP synthesis and export. Excess extracellular cGAMP directly suppresses glucose uptake in brown adipocytes via stimulator of interferon genes (STING) pathway. Furthermore, impaired cGAMP clearance acts as a paracrine signal that recruits and polarizes BAT macrophages toward a pro-inflammatory M1-like phenotype. Finally, the human ENPP1 K173Q variant associated with obesity and diabetes displays reduced cGAMP hydrolysis activity. Together, these findings establish ENPP1 as an immunometabolic checkpoint that buffers extracellular cGAMP to maintain metabolic homeostasis.