2130-P: Transcription Factor NF-kB Regulates Thermogenic Function of Brown Adipocytes in UCP1-Independent Manner

Abstract

NF-kB is a transcription factor that is activated upon cellular response to endotoxin, TNF-a or oxidative stress, etc. The transcription factor is formed by two subunits, p65 and p50, in most cells. The transcription activity is mainly determined by the p65 subunit for the transactivation domain. The p50 subunit does not contain a transactivation domain in the protein structure. NF-kB is expressed in brown adipocytes and the expression of p65 is increased by differentiation of the adipocytes. However, the activity of NF-kB remains unknown in brown adipocytes, especially in the thermogenic function of the adipocytes. To address this issue, we generated brown adipocyte-specific NF-kB transgenic mice with gain-of-function and loss-of-function using the Cre-LoxP strategy. The gain-of-function was achieved by over expression of the p65 subunit in a knockin mice, and the loss-of-function was made by inactivation of p65 subunit in a floxed mice. The gene modification was achieved by crossing the p65 mice with UCP1-CreER mice. The gain-of-function led to an elevation of mitochondrial function in brown adipocytes with an increase in uncoupling activity. The gene alteration preserved the brown fat function in DIO mice. In contrast, NF-kB loss-of-function made the mice intolerant to cold exposure in the lean condition and obese condition. The thermogenic function was significantly decreased in the mice. UCP-1 is a dominant uncoupling protein in the mitochondria of brown adipocytes to mediate the cold-induced heat production. UCP-1 expression and post-translational modification were not altered in brown adipocytes of the two lines of transgenic mice. These results suggest that NF-kB is required for the thermogenic function of brown adipocytes, and its activity is not associated with regulation of UCP-1. Disclosure J. Ye: None.