Submitted to: Obesity
Publication Type: Abstract Only
Publication Acceptance Date: 8/1/2007
Publication Date: 9/1/2007
Citation: Zanquetta, M.M., Jeong, W.M., Garcia, R.A., Chow, C., Young, M.E., Bray, M.S. 2007. A novel animal model linking adiposity to altered circadian rhythms [abstract]. Obesity. 15:85-OR. Interpretive Summary:
Technical Abstract: Researchers have provided evidence for a link between obesity and altered circadian rhythms (e.g., shift work, disrupted sleep), but the mechanism for this association is still unknown. Adipocytes possess an intrinsic circadian clock, and circadian rhythms in adipocytokines and adipose tissue metabolism are well established. We hypothesize that disruption of the adipocyte-specific circadian clock may contribute to the development of adiposity via altered adipocyte metabolism and/or alterations in energy balance. To identify those genes/processes regulated by circadian clock within the adipocyte, we generated an adipose tissue-specific, circadian clock mutant mouse model (ACM) in which a dominant negative CLOCK protein (dnCLOCK) is overexpressed within adipocytes through use of the ap2 promoter. The specificity of dnCLOCK for adipose tissue was confirmed by quantitative RT-PCR in different tissues, obtained from 6 week-old wildtype (WT) and AMC animals (collected 9 hours following the dark/light transition). Whole genome differential gene expression in visceral adipose was performed using microarray technology (Illumina, Inc.). ACM animals showed altered expression of clock component genes, including increased (19x, P < 0.0001) and bmall (6.5x, P < 0.0002), and decreased rev-erba (3.7x, P < 0.05), per3 (2.1x, P < 0.05), and dbp (1.5x, P < 0.01). A total of 2973 genes were differentially expressed in ACM animals compared to WT. Thirty genes related to lipogenesis were overexpressed in ACM adipose, including acly, alox12, elov14, ptgs1, prkag1. Conversely, 25 genes involved with lipolysis were downregulated in ACM mice, e.g. adipoR2, adrb2, fabp5, lipe, lpl, lyplal, pparg. Functional pathways represented by these genes included signaling cascades (insulin, adipocytokine, Wnt, MAPK, mTOR and JAK-STAT), along with factors related to type 2 diabetes, cytokine-cytokine receptor interaction, and circadian rhythm. Although body weight was not significantly different between ACM and WT animals at 6 weeks of age, weights begin to deviate by 11 weeks of age. The circadian clock within the adipocyte appears to alter adipocyte metabolism and function. The ACM mouse model is an important tool to understand the link between obesity and circadian clocks.