Uncoupling Protein 1 (UCP1) in Non-Adipose Tissue

UCP1, a mitochondrial protein traditionally regarded as exclusive to thermogenic adipocytes, and Ucp1-promoter-driven Cre is widely used in gene manipulation in thermogenic adipocytes. However, new evidence suggests that Ucp1-promoter-driven Cre is also active in non-adipocyte types. The presence and role of UCP1 in non-adipose tissues during development, and its potential non-thermogenic functions, remain under debate. This study systematically investigated UCP1 expression patterns from embryogenesis to adulthood using Ucp1 GFP/+ (knock-in), Ucp1 CreERT2/+ (knock-in) and Ucp1 Cre/+ (transgenic) mice crossed with Ai9-tdTomato-Red mice, complemented by single-cell RNA sequencing and immunostaining analyses. Ucp1 CreERT2/CreERT2 knockout mice were utilized to evaluate developmental consequences of UCP1 deficiency. Significantly, UCP1 expression initiated in non-thermogenic tissues by embryonic day 10.5, before adipose tissue formation, notably in the brain, eye, ear, mammary gland, kidney, and reproductive systems. UCP1 was more broadly expressed in non-adipose tissues during embryonic stages compared to adulthood, particularly in the epithelial cells of these non-adipose tissues. UCP1 knockout mice exhibited retinal developmental defects, suggesting physiological roles for UCP1 beyond thermogenesis in non-adipose tissues. This study highlights that using Ucp1-promoter-driven tamoxifen-inducible Cre can minimize off-target effects in gene manipulation of thermogenic adipocytes compared to the traditional transgenic Cre strategy.