A nuclear ERK–ATF5 axis coordinates mitochondrial metabolism and thermogenic gene expression in brown adipocytes

Obesity and diabetes result from disrupted energy homeostasis, highlighting the importance of identifying molecular mechanisms that enhance energy expenditure. Brown adipose tissue (BAT) dissipates energy through mitochondria-dependent non-shivering thermogenesis, yet the transcriptional regulators coordinating this process remain incompletely defined. In this study, we identify activating transcription factor 5 (ATF5) as a key regulator of thermogenic gene expression and mitochondrial metabolism in brown adipocytes. Cold exposure and β3-adrenergic stimulation robustly induced Atf5 expression in BAT and differentiated brown adipocytes, coinciding with activation of canonical thermogenic programs. Mechanistically, ATF5 functions downstream of a nuclear PKA–ERK signaling axis, where nuclear ERK1/2 activation is required for ATF5 induction and subsequent upregulation of UCP1. Loss of Atf5 impaired thermogenic transcription, suppressed mitochondrial unfolded protein response (UPRmt) and lipolytic gene expression, and reduced mitochondrial oxidative capacity and metabolic flexibility. Transcriptomic profiling revealed broad downregulation of fatty acid oxidation, β-oxidation, oxidative phosphorylation, and thermogenic pathways in Atf5-deficient brown adipocytes. Collectively, these data establish ATF5 as a central transcriptional regulator that integrates mitochondrial metabolism, lipid catabolism, and thermogenic activation in brown adipocytes, providing mechanistic insight into energy expenditure regulation.