HACD3 integrates central leptin sensitivity and peripheral thermogenesis to oppositely regulate energy balance.

The enzyme 3-hydroxyacyl-CoA-dehydratase 3 (HACD3) is involved in fatty acid synthesis, but its systemic role in metabolism is unknown. This study investigated the physiological function of HACD3 in energy homeostasis. Systemic HACD3 deficiency protected mice from diet-induced obesity by increasing energy expenditure and activating adipose thermogenesis. Conversely, deleting HACD3 specifically in leptin receptor-expressing neurons caused obesity, hyperphagia, and leptin resistance. In adipocytes, HACD3 cell-autonomously repressed thermogenesis by forming a complex with Keratin 1 (KRT1), which sequestered thermogenic transcription factors and maintained repressive chromatin. HACD3 ablation disrupted this complex, enabling nuclear translocation of PPARγ/PGC-1α and increasing transcription of thermogenic genes. In neurons, HACD3 is required for leptin receptor stability and signaling. HACD3 acts as a critical, tissue-specific regulator that simultaneously governs both sides of the energy balance equation-suppressing energy expenditure in adipose tissue while facilitating anorexigenic signaling in the brain. This dual function identifies HACD3 as a novel, multifaceted target for therapeutic intervention in metabolic disorders.