Characterization of a novel mouse model with adipocyte-specific disruption via the aP2 promoter

Circadian rhythms, the behavioral and physiological daily changes that occur in the majority of organisms, are partially generated via cell-autonomous molecular clock mechanisms. The functions of these molecular clocks vary with tissue and cell type. To examine clock function specifically within adipose tissue, a mouse model with a mutant Clock gene linked to the aP2 promoter (aP2 clock mutant, ACM) was created. The ACM model was verified with real-time quantitative PCR (qPCR) of mRNA levels for multiple circadian genes in several tissue types collected at different time points. These ACM mice were then assessed based on several physiological and behavioral parameters. Adult ACM animals weighed more (F[14, 2657]=9.70, p<.001) and have higher body fat percentages (t[46]=-2.71, p<.01) compared to wildtype animals. ACM mice exhibited increased food intake (F[1,752]=5.23, p<.05), higher respiratory exchange ratio (F[1,524]=33.32, p<.001), and higher energy expenditure (F[1,524]=88.51, p<.001), despite increased weight gain compared to wild-type mice. ACM animals also demonstrated higher levels of leptin (F[1,28]=4.72, p<.05) and non-esterified fatty acids (F[1,29]=8.23, p<.01). Tissue-specific disruption of the circadian clock appears to produce many of the phenotypes observed in global Clock mutant animals and suggests a critical role for tissues in which the aP2 promoter is active in regulating global metabolism and energy balance.