Orai1-mediated Ca2+ entry regulates lipolysis and mitochondrial activation in brown adipose thermogenesis
Obesity and related metabolic disorders, such as type 2 diabetes and fatty liver disease, remain significant public health challenges. This study explores the role of Orai1, a calcium channel, in brown adipose tissue (BAT) thermogenesis, an area gaining attention for its potential to enhance energy expenditure. Using a brown adipocyte-specific Orai1 knockout model, the authors demonstrate that Ora
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.