Orai1-mediated Ca2+ entry regulates lipolysis and mitochondrial activation in brown adipose thermogenesis.

Cold-induced thermogenesis in brown adipose tissue is essential for maintaining energy homeostasis, yet the Ca2+-dependent mechanisms underlying this process remain incompletely understood. Here, we identify Orai1, a component of the store-operated Ca2+ entry pathway, as a regulator of thermogenic activation in brown adipose tissue. Using a brown adipocyte-specific Orai1 knockout mouse model, we demonstrate that cold exposure is associated with Orai1-dependent Ca2+ influx through a non-canonical mechanism. Orai1 deficiency impairs cAMP-protein kinase A signalling, reduces the expression of lipolytic enzymes and thermogenic genes, and diminishes mitochondrial Ca2+ uptake and uncoupling. These defects culminate in cold intolerance, lipid accumulation and decreased energy expenditure. Mechanistically, Orai1 facilitates Ca2+-dependent activation of adenylyl cyclase 3, linking membrane Ca2+ entry to cAMP production, and promotes mitochondrial remodelling and oxidative metabolism. These findings support a key role for Orai1 in coordinating Ca2+ entry to lipolytic and mitochondrial pathways in brown adipocytes and highlight Orai1 as a potential therapeutic target in metabolic diseases characterized by impaired energy metabolism.