Nfe2l1, also known as Nrf1, is a highly conserved transcription factor belonging to the CNC-bZIP subfamily. It plays a crucial role in controlling redox balance, proteasome activity, and organ integrity. It is involved in multiple pathways such as the ubiquitin-proteasome system, unfolded protein response, and ER-associated degradation, which are vital for cellular stress adaptation. Nfe2l1 is also associated with various metabolic processes like glucose, lipid, and protein metabolism, highlighting its overall biological importance. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions [1,2].

In adipocyte-specific Nfe2l1 knockout [Nfe2l1(f)-KO] mice, Nfe2l1 deficiency leads to aberrant adipogenesis, impaired adipose tissue functioning, age-dependent whitening and shrinking of brown adipose tissue (BAT). There are signatures of down-regulation of proteasome, impaired mitochondrial function, reduced thermogenesis, pro-inflammation, and elevated regulatory cell death in BAT. Mechanistically, Nfe2l1 deficiency in brown adipocytes down-regulates lipolytic genes, decelerating lipolysis and making cells unable to fuel thermogenesis, ultimately resulting in cold intolerance [4,5].

In conclusion, Nfe2l1 is essential for maintaining cellular and metabolic homeostasis. Studies using Nfe2l1 KO/CKO mouse models have revealed its significance in adipose tissue metabolism, thermogenesis, and stress responses. These findings contribute to understanding diseases related to abnormal lipid metabolism, proteostasis, and neurodegenerative disorders where Nfe2l1 may serve as a potential therapeutic target [1,3,4,5].