Key result
Loss of ENPP1 cGAMP-hydrolysis exacerbates diet-induced weight gain and insulin resistance via brown fat cGAMP accumulation.
ENPP1 acts as an immunometabolic checkpoint that buffers extracellular cGAMP to maintain metabolic homeostasis, offering a potential mechanistic link to obesity and diabetes.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Brown adipose tissue has an immunometabolic checkpoint—in mice. Loss of ENPP1-mediated extracellular cGAMP hydrolysis worsened high-fat-diet weight gain and insulin resistance, while cGAMP impaired insulin-stimulated BAT glucose uptake through STING signaling. The work links extracellular nucleotide signaling, inflammatory macrophages, and brown-fat metabolism. It is mechanistic animal/cellular evidence, not a human therapeutic result.”
Animal findings only; leaves open whether ENPP1 hydrolysis is a viable target in human obesity or diabetes.
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 ( Enpp1 H362A ), 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.
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Wang et al. (2026) studied Metabolic disease, insulin resistance, and obesity. Loss of ENPP1 cGAMP-hydrolysis activity (Enpp1 H362A mutation) vs. Wild-type/normal ENPP1 activity was evaluated on High-fat diet-induced weight gain and insulin resistance. Selective loss of ENPP1 cGAMP-hydrolysis activity exacerbates high-fat diet-induced weight gain and insulin resistance by driving extracellular cGAMP accumulation in brown adipose tissue.
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