Nocturnin: at the crossroads of clocks and metabolism

Abstract

Many aspects of metabolism exhibit daily rhythmicity under the control of endogenous circadian clocks, and disruptions in circadian timing result in dysfunctions associated with the metabolic syndrome. Nocturnin (Noc) is a robustly rhythmic gene that encodes a deadenylase thought to be involved in the removal of polyA tails from mRNAs. Mice lacking the Noc gene display resistance to diet-induced obesity and hepatic steatosis, due in part to reduced lipid trafficking in the small intestine. In addition, Noc appears to play important roles in other tissues and has been implicated in lipid metabolism, adipogenesis, glucose homeostasis, inflammation and osteogenesis. Therefore, Noc is a potential key post-transcriptional mediator in the circadian control of many metabolic processes.

Figure 1. The molecular circadian clock is responsive to environmental and metabolic cues while maintaining tight control over gene expression

(A) Cells from the suprachiasmatic nucleus (SCN) within the brain receive external environmental (e.g. light) and internal (e.g. nutrients and hormones) cues that influence gene expression of core “clock” genes. The CLOCK/BMAL1 heterodimer binds to E-box enhancer elements in the promoter of core clock genes, such as Period (Per) and Cryptochrome (Cry), and other clock-controlled genes (Ccg) responsible for clock output. PER and CRY proteins accumulate in the cytoplasm where they complex with Casein Kinase 1 (CK1) and translocate back into the nucleus inhibiting their own transcription. Clock output is responsible for synchronizing rhythms in peripheral clocks and influencing processes such as rhythmic nutrient metabolism and uptake, and the sleep/wake and body temperature cycles. Nutrient signals (e.g. NAD+, AMPK) participate in crosstalk with the core clock by feeding back and influencing nuclear receptors such as Rev-erbα and the retinoic acid-related orphan receptor α (RORα), thus contributing to molecular rhythm generation. Positive and negative regulatory mechanisms are represented with green and red broken lines, respectively. (B) The circadian clock generates rhythms in gene expression, but post-transcriptional mechanisms such as deadenylation can also alter rhythmic mRNA processing. mRNA stability is maintained in part through polyadenylation, a process involving the addition of 3’ adenosine residues creating a polyA tail on messenger transcripts. Conversely, polyA tail removal through deadenylation leads to transcript degradation or silencing. The clock and metabolic cues influence rhythmic expression of the gene Nocturnin (Noc), encoding a circadian deadenylase. This could be one mechanism whereby the clock exerts tight control over expression of genes involved in nutrient metabolism through regulating post-transcriptional modifications.

Figure 2. Nocturnin is rhythmically expressed throughout the body and is intimately linked with metabolism

The master pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) of the mammalian brain drives rhythms in gene/protein expression that synchronizes rhythmic behaviors and processes such as feeding and nutrient uptake and metabolism to the environment (1). Nutrients, especially lipid, are taken up by the body primarily in the small intestine. The deadenylase Nocturnin (Noc) is rhythmically expressed in the proximal small intestine and is involved in lipid processing into chylomicrons and the formation of cytoplasmic lipid droplets (CLD) (2). The highest amplitude expression of Noc is seen in the liver and it is here that NOC participates in lipogenesis (3). Noc expression in muscle has not been studied to date, but muscle is a key tissue in glucose metabolism and Noc^−/− mice show altered glucose/insulin processing, suggesting a role for NOC in this tissue (4). Adipose tissue does not exhibit rhythmic Noc expression under basal conditions. However, placing mice under a restricted feeding paradigm induces Noc rhythms. NOC is involved in adipogenesis through its interactions with PPARγ (5). Noc is also rhythmic in bone and it participates in lineage determination of mesenchymal stromal cells towards osteogenesis or adipogenesis (6). Crosstalk exists between the core clock in the brain and the periphery through metabolic signals resulting from nutrient metabolism.

Figure 3. Proposed working hypothesis for the development of resistance to DIO in Noc^−/− under high-fat diet feeding

In Noc^+/+ mice, fatty acids (FA) are processed from the lumen of the intestine to the peripheral blood circulation after undergoing chylomicron formation. This step requires the activity of diacylglycerol O-acyltransferase 2 (DGAT2) to transform FA into triglycerides (TG), adipose differentiation-related protein (ADRP) to transiently constitute a poolof TG, and adipose triglyceride lipase (ATGL) to release TG to the blood. In Noc^−/− mice, Dgat2, Adrp and Atgl mRNA levels are decreased, thus reducing chylomicron formation in the enterocytes. Lipid sequestration results in decreased TG release and distribution to the periphery. These alterations contribute to the development of resistance to DIO in Noc^−/− mice but could also lead to the development of insulin resistance via inflammatory mechanisms or disrupted nutrient sensing.