Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression

Abstract

In mammals, the circadian oscillator generates approximately 24-h rhythms in feeding behavior, even under constant environmental conditions. Livers of mice held under constant darkness exhibit circadian rhythm in abundance in up to 15% of expressed transcripts. Therefore, oscillations in hepatic transcripts could be driven by rhythmic food intake or sustained by the hepatic circadian oscillator, or a combination of both. To address this question, we used distinct feeding and fasting paradigms on wild-type (WT) and circadian clock-deficient mice. We monitored temporal patterns of feeding and hepatic transcription. Both food availability and the temporal pattern of feeding determined the repertoire, phase, and amplitude of the circadian transcriptome in WT liver. In the absence of feeding, only a small subset of transcripts continued to express circadian patterns. Conversely, temporally restricted feeding restored rhythmic transcription of hundreds of genes in oscillatordeficient mouse liver. Our findings show that both temporal pattern of food intake and the circadian clock drive rhythmic transcription, thereby highlighting temporal regulation of hepatic transcription as an emergent property of the circadian system. CREB ͉ metabolism ͉ mouse liver ͉ circadian rhythms

SWItch/sucrose nonfermentable (SWI/SNF) complex subunit BAF60a integrates hepatic circadian clock and energy metabolism

“…However, it has not escaped our attention that feeding rhythms alone can drive rhythmic gene transcription under constant darkness even in the complete absence of a functional clock. 5 In addition, only a small number of rhythmic transcripts in the liver are direct targets of clock regulators. 9 In fact, our results showed that several metabolic tissues such as skeletal muscle, heart, and kidney lack robust BAF60a rhythmicity, whereas they have nice oscillations of clock components.…”

“…5,9 Given that BAF60a is ubiquitously expressed, the specificity of BAF60a regulation should be achieved by simultaneously orchestrating BAF60a and other tissue-specific transcriptional factors, whose circadian expression is restricted to a subset of peripheral organs/tissues. One good example is the nuclear receptor PPARa, which is a clock-controlled metabolic sensor mostly expressed in the liver, where it regulates fatty acid boxidation.…”

“…4 Also, both food availability and the temporal pattern of feeding determine the repertoire, phase, and amplitude of the circadian transcriptome in mouse liver. 5 All these studies indicate that nutritional signals play a dominant role in the regulation of peripheral clock function. At the molecular level, Clock and Bmal1 are two basic helix-loop-helix transcription factors that activate the transcription of period (Per) and cryptochrome (Cry) genes.…”

Does the circadian system regulate lactation?

“…A total of 368 circadian clock-driven transcripts were identified under fasting conditions in WT mice. When WT mice were restricted to daytime feeding, 4960 transcripts displayed rhythmic expression (Vollmers et al, 2009), showing that there is a clear synergy between the circadian and metabolic systems in the regulation of rhythmic transcription in the liver. These studies also suggest that there is an independent but interactive organization that links metabolic controls with circadian clocks.…”

The role of clock genes and rhythmicity in the liver

“…The latter phenomenon can be achieved by the rhythmic expression of enzymes involved in the anabolic or catabolic reactions. A recent study revealed that up to 15% of the liver transcriptome is expressed in a rhythmic fashion (Vollmers et al, 2009) and food availability directly drives the expression of many of these genes. However, a relatively small subset of these transcripts remained rhythmic even under fasting conditions, i.e.…”