ELOVL3 regulates phospholipid homeostasis and thermogenesis in brown adipose tissue

Nonshivering thermogenesis plays an important role in maintaining body temperature and energy homeostasis. Elongation of very long-chain fatty acid protein 3 (ELOVL3), which catalyzes the synthesis of C20-C24 fatty acids, is induced in brown adipose tissue (BAT) by cold exposure and regarded as a thermogenic gene. However, its precise role in thermogenesis remains elusive. BAT-specific KO mice of Elovl3 were generated by the Cre/LoxP approach and phenotypically analyzed under cold exposure. Gene expression changes in BAT were characterized by quantitative RT-PCR and Western blotting, BAT remodeling was evaluated by histological examination, and lipid composition was examined by lipidomic analysis. BAT-specific deletion of the Elovl3 gene resulted in cold intolerance because of impaired BAT thermogenesis, without a significant effect on muscle shivering thermogenesis. Mechanistically, Elovl3 deficiency impaired cold-induced BAT remodeling and Ucp1 expression, with a defect in mitochondrial cristae remodeling. Lipidomics analysis showed a marked reduction in the contents of lysophosphatidylcholine, cardiolipin, and acylcarnitine in BAT in the absence of Elovl3. Taken together, our findings reveal the critical role of ELOVL3 in BAT thermogenesis and provide new ideas for the intervention and treatment of obesity-related diseases.