Uncoupling protein 1 in nonadipose tissue

Uncoupling protein 1 (UCP1), a mitochondrial protein traditionally regarded as exclusive to thermogenic adipocytes, and <i>Ucp1</i>-promoter-driven Cre is widely used in gene manipulation in thermogenic adipocytes. However, new evidence suggests that <i>Ucp1</i>-promoter-driven Cre is also active in nonadipocyte types. The presence and role of UCP1 in nonadipose tissues during development, and its potential nonthermogenic functions, remain under debate. This study systematically investigated UCP1 expression patterns from embryogenesis to adulthood using <i>Ucp1^GFP/+</i> (knock-in), <i>Ucp1^CreERT2/+</i> (knock-in), and <i>Ucp1^Cre/+</i> (transgenic) mice crossed with Ai9-tdTomato-Red mice, complemented by single-cell RNA sequencing and immunostaining analyses. <i>Ucp1^{CreERT2/CreERT2}</i> knockout mice were used to evaluate the developmental consequences of UCP1 deficiency. Significantly, UCP1 expression initiated in nonthermogenic tissues by <i>embryonic day 10.5</i>, before adipose tissue formation, notably in the brain, eye, ear, mammary gland, kidney, and reproductive systems. UCP1 was more broadly expressed in nonadipose tissues during embryonic stages compared to adulthood, particularly in the epithelial cells of these nonadipose tissues. UCP1 knockout mice exhibited retinal developmental defects, suggesting physiological roles for UCP1 beyond thermogenesis in nonadipose tissues. This study highlights that using <i>Ucp1</i>-promoter-driven tamoxifen-inducible Cre can minimize off-target effects in gene manipulation of thermogenic adipocytes compared with the traditional transgenic Cre strategy.<b>NEW & NOTEWORTHY</b> Our findings reveal UCP1 expression begins from E10.5, particularly in the brain, kidney, ear, eye, mammary gland, and reproductive system. During embryonic development, UCP1 expression is more prevalent in nonadipose tissues, compared to adulthood, especially in epithelial cells. Notably, UCP1-knockout mice exhibit developmental defects in retinas, suggesting UCP1 has physiological functions beyond thermogenesis. Our study highlights using Ucp1-promoter-driven tamoxifen-inducible Cre can minimize off-target effects in gene manipulation within thermogenic adipocytes compared to traditional Cre methods.