Nitrate-Sialin2 Axis Couples ER-Mitochondrial Calcium Signaling with Fatty Acid Metabolism to Drive White Adipose Browning

ABSTRACT: Nutrient cues shape adipose homeostasis; however, the mechanism by which inorganic signals engage organelle networks to drive white fat browning remains unclear. Here, we identify a nitrate-Sialin2 pathway that converts dietary nitrate into a spatially confined thermogenic program. Sialin2 localizes to mitochondria and endoplasmic reticulum (ER) to strengthen ER-mitochondria contacts and engage the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1)-voltage-dependent anion channel 1 (VDAC1)-mitochondrial calcium uniporter 1 (MCU1) conduit, boosting 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 1A (CPT1A) to direct lipid-droplet-derived fatty acids into β-oxidation, thereby fueling the tricarboxylic acid (TCA) 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 indices in diet-induced obesity without adrenergic stimulation. These findings reveal an organelle-specific nitrate-sensing mechanism that couples ionic signaling with substrate routing to reprogram adipocytes, providing a non-hormonal strategy for restoring metabolic homeostasis.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS14192 | MetaboLights | 2026-05-17

REPOSITORIES: MetaboLights