DUSP4 activates adipocyte thermogenesis via CRTC3 dephosphorylation-dependent UCP1 expression

Abstract Obesity arises when a chronic energy surplus overwhelms the storage capacity of adipocytes and subsequently causes systemic metabolic dysfunction. Adaptive thermogenesis, primarily mediated by uncoupling protein 1 (Ucp1) in adipocytes, serves to counteract obesity by dissipating excess energy as heat. Despite extensive studies on thermogenic regulation, the phosphatases that regulate this protective metabolic pathway remain poorly understood. Here we identify dual-specificity phosphatase 4 (Dusp4) as a critical modulator of adipocyte thermogenesis via direct modulation of CREB-regulated transcription coactivator 3 (Crtc3). Dusp4 -knockout mice exhibit impaired thermogenic capacity, diminished Ucp1 expression, and increased susceptibility to diet-induced obesity coupled with severe insulin resistance. Mechanistically, Dusp4 directly dephosphorylates serine residues on Crtc3, facilitating its nuclear translocation and subsequent transcriptional activation of Ucp1 . Depot-targeted restoration of catalytically active Dusp4 in inguinal adipose tissue rescues local thermogenic gene expression and reinstates Crtc3 dephosphorylation-dependent Ucp1 induction in Dusp4 -knockout mice. Collectively, these findings identify Dusp4 as a key upstream phosphatase orchestrating the Crtc3–Ucp1 thermogenic axis, and highlight its potential as a therapeutic target for obesity-associated metabolic disorders.