Nocturnin Regulates Metabolic Flux Through Maintenance of Poly(A) Tail Length Dynamics

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Cyclic processes in both behavior and physiology are aligned to the external environment through the circadian clock. Nocturnin (Noc) is a rhythmically expressed gene regulated in part by the circadian clock and intimately linked to the metabolic state of an organism. Loss of Nocturnin (Noc-/-) in mice results in resistance to diet-induced obesity. Encoding a deadenylase, NOC protein is thought to regulate mRNA turnover through its ability to remove Poly(A) tails from mRNA transcripts. Though NOC has been linked with lipid and glucose metabolism, its specific targets have not been identified. I explored NOC's role in metabolism by exposing Wildtype (WT) and Noc-/- mice to nutrient challenges consisting of High Fat Diet (HFD) and fasting/refeeding. I demonstrated that Noc can be acutely reduced with a fast and induced with refeeding in WT mice. Hepatic Noc expression oscillates in WT mice fed a High Fat Diet (HFD) but with increased amplitude. I performed mRNA-seq from livers of Wildtype (WT) and Noc-/- mice and identified significant upregulation of both cholesterol and bile acid synthesis genes in Noc-/- mice under basal and nutrient-challenged conditions. This dysregulation results in Noc-/- mice having significantly increased gallbladder volumes during times of fasting. I subjected WT and Noc-/- to hyperinsulinemic-euglycemic clamps and found that HFD-fed Noc-/- mice develop more severe insulin resistance than HFD-fed WT mice. Under insulin-stimulated (clamped) conditions, HFD-fed Noc-/- mice fail to suppress endogenous glucose production and have reduced whole-body glucose turnover. Additionally, regular chow (RC) fed Noc-/- mice exhibit insulin resistance only during the dark phase. This deficit in glucose/insulin sensitivity can be partially rescued in Noc-/- mice through transgenic overexpression of WT NOC, but not a catalytically dead mutant NOC that cannot function as a deadenylase. The deadenylase activity of NOC is thus important for these metabolic phenotypes and I found that genes associated with bile acid, cholesterol and glucose metabolism have altered Poly(A) tail length regulation in Noc-/- mice and thus represent possible targets of NOC. This new understanding of the relationship between Nocturnin, the circadian system and metabolism will help guide the treatment of conditions such as obesity and diabetes.

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Pages 32-126 are incorrectly numbered as pages 31-125.
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