Nitrate-Sialin2 axis couples ER-mitochondrial calcium signaling with fatty acid metabolism to drive white adipose browning.

Abstract

White adipose browning is a promising route to restore energy balance; however, how inorganic anion signals engage intracellular organelle networks to drive this process remains unclear. Here, we identify Sialin2 as a nitrate sensor that converts dietary nitrate into a spatially confined thermogenic program by coupling ER-mitochondria Ca²⁺ transfer with lipid routing into mitochondrial oxidation. Sialin2 localizes to mitochondria and the endoplasmic reticulum (ER), where it strengthens ER-mitochondria contacts and engages the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1)-voltage-dependent anion channel 1 (VDAC1)-mitochondrial calcium uniporter 1 (MCU1) conduit to enhance inducible mitochondrial Ca²⁺ uptake. In parallel, Sialin2 associates with lysosomal acid lipase (LIPA), acyl-CoA synthetase long-chain family member 3 (ACSL3), and carnitine palmitoyltransferase 1 A (CPT1A) to channel lipid-droplet-derived fatty acids into β-oxidation, thereby fueling the tricarboxylic acid cycle and uncoupling protein 1 (UCP1)-dependent respiration. Loss of Slc17a5 abolishes nitrate-evoked browning and metabolic benefits, whereas nitrate supplementation improves adipose thermogenesis and systemic metabolic indices in male mice with diet-induced obesity without adrenergic stimulation. Together, these findings identify an organelle-specific nitrate-sensing mechanism that couples inorganic anion signalling to substrate routing in adipocytes and establish a non-hormonal pathway for restoring metabolic homeostasis.