Clcf1, or cardiotrophin-like cytokine factor 1, is a member of the interleukin-6 cytokine family [2,4,5]. It plays a role in various biological processes, with its signaling being involved in pathways such as the ciliary neurotrophic factor receptor (CNTFR)-signal transducer and activator of transcription 3 (STAT3) pathway. Genetic models, especially mouse models, have been crucial for understanding its functions.

In adipocyte-specific CLCF1 transgenic (CLCF1-ATG) mice, CLCF1 signaling led to loss of brown fat identity, impaired thermogenic capacity, reduced energy expenditure, and severe cold intolerance. It triggered whitening of brown adipose tissue by suppressing mitochondrial biogenesis via inhibiting peroxisome proliferator-activated receptor-γ coactivator (PGC) 1α and 1β through the CNTFR-STAT3 pathway [1]. In contrast, BAT-specific ablation of CLCF1 enhanced BAT function and energy expenditure under thermoneutral and cold conditions. CLCF1 was also found to negatively regulate the PERK-ATF4 signaling axis to modulate adenylate cyclase 3 (ADCY3) transcriptional activity, which activates PKA substrate phosphorylation [3]. In addition, in hyperthyroidism, serum CLCF1 levels were reduced, and T3-treated mice showed decreased CLCF1 expression in adipose tissue, suggesting thyroid hormone may regulate CLCF1 expression in adipose tissue [6].

In conclusion, Clcf1 plays a significant role in regulating brown fat thermogenesis and energy metabolism. Mouse models, including those with adipocyte-specific or BAT-specific manipulation of Clcf1, have provided valuable insights into its function in metabolic homeostasis and related diseases, such as obesity and hyperthyroidism. These findings suggest that targeting the CLCF1 pathway could potentially be used to restore metabolic balance in obesity [1,3].