Tissue specific regulation of BMAL1 gene by dietary fat

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Adipocytes play essential metabolic roles not only serving as massive energy reserves but also secreting hormones and cytokines that regulate metabolic activities. The link between metabolic activity in adipocytes and circadian rhythm has long been studied ; e.g. glucose and lipid homeostasis are well known to exhibit circadian variation. More recently, we reported that white adipose tissue contains functional molecular clock and that expression of several adipocytokines, including leptin, and plasminogen activator inhibitor-1 display circadian rhythm (Aoyagi, et. al. JHS 2005). Therefore, molecular clock may play important roles in the regulation of metabolic activity in adipocytes. BMAL1, a master component of circadian rhythm, is abundantly expressed in mature adipocytes in vivo and in vitro. This transcription factor regulates the expression of several factors involved in lipogenesis in adipocytes such as SREBP-1 (Shimba, et. al. PNAS 2005). Also, BMAL1 KO mice show phenotype of si … More gnificant reduction of adipose tissue, while the liver in KO mice is as intact as that in wild type. These characteristics of BMAL1 lead us to study the adipocytes-specific roles of this factor. In this study, we first examine the effects of dietary fat on BMAL1 expression and functions in mature adipocytes. The challenge to high fat diet results in significant induction of Bmal1 mRNA in mice adipose tissue. Interestingly, the induction of circadian gene by high-fat diet is observed only in adipose tissue, but not in other tissues tested. This adipose tissue specific induction of Bmal1 expression accompanied with enhanced expression of its targets genes such as Per and PAI-1. Tb determine whether dietary fats have a direct impact on Bmal1 expression, cultured adipocytes were treated with various saturated, unsaturated, and trans fatty acids and examined levels of Bmal1 mRNA One of the fatty acids significantly increased Bmal1 mRNA level in cultured adipocytes but not in primary hepatocytes. Inhibition of the fatty acid metabolism diminished the effect on Bmal1 expression. Tentative metabolites of the fatty acid increased Bmal1 mRNAlevel Finally, the fatty acid-treatment induced cyclic expression of circadian genes in cultured adipocytes. These results suggest that dietary fatty acids can modulate adipocytes specific circadian rhythm machinery. Less