Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity

Abstract

The mammalian circadian system consists of a central oscillator in the suprachiasmatic nucleus of the hypothalamus, which coordinates peripheral clocks in organs throughout the body. Although circadian clocks control the rhythmic expression of a large number of genes involved in metabolism and other aspects of circadian physiology, the consequences of genetic disruption of circadiancontrolled pathways remain poorly defined. Here we report that the targeted disruption of Nocturnin (Ccrn4l) in mice, a gene that encodes a circadian deadenylase, confers resistance to dietinduced obesity. Mice lacking Nocturnin remain lean on high-fat diets, with lower body weight and reduced visceral fat. However, unlike lean lipodystrophic mouse models, these mice do not have fatty livers and do not exhibit increased activity or reduced food intake. Gene expression data suggest that Nocturnin knockout mice have deficits in lipid metabolism or uptake, in addition to changes in glucose and insulin sensitivity. Our data support a pivotal role for Nocturnin downstream of the circadian clockwork in the posttranscriptional regulation of genes necessary for nutrient uptake, metabolism, and storage.C ircadian clocks are present in most tissues of the body, where they control the expression of 5-10% of the tissue-specific mRNAs through both transcriptional and posttranscriptional regulation (1, 2). The widespread importance of circadian clock regulation is evident in that generalized disruption of normal clock function results in tumor formation, sleep disorders, and metabolic problems (reviewed in refs. 3 and 4). For example, mutations in the central clock genes Clock or Bmal1 result in metabolic changes found in obesity and the metabolic syndrome (5-8), and numerous genes involved in fatty acid, cholesterol, and glucose metabolism in liver are regulated in circadian or diurnal patterns (9-15), indicating that the clock plays a broad role in regulating metabolism. Nonetheless, the large number of genes, metabolic pathways, and cell/tissue types that are under general circadian control impose a major challenge in understanding the molecular details. Further advances in this area require refined understanding of the specific circadian output pathways by which the clocks regulate physiology.For cycling mRNAs to closely reflect daily rhythmic transcriptional drive, their half-lives must be relatively short. There are several examples of rhythmic posttranscriptional regulation in which the mRNA half-life or adenylation state changes over the course of the day (16-19), but very little is known about the mechanisms responsible. A likely contributor is Nocturnin (Ccrn4l, Noc), which has been implicated in the posttranscriptional regulation of mRNA stability and/or translatability by the circadian clock (20). Noc is expressed rhythmically in many tissues, with particularly high-amplitude rhythms in liver where mRNA levels are increased 100-fold in early night (21). Noc is at a pivotal position to play a role in shaping the rhythmic pattern of gene ...

Regulatory roles of vertebrate Nocturnin: insights and remaining mysteries

“…Consistent with a role for NOCT in mediating lipid absorption and trafficking, intestines from NOCT -deficient mice accumulate excess lipids, and isolated enterocytes exhibit defects in lipid absorption and trafficking [19]. Together, these data indicate that NOCT activity may promote dietary lipid absorption and secretion, potentially forming the basis of NOCT knockout mouse resistance to high-fat diet-induced obesity and liver steatosis [9]; however, the mechanistic details of NOCT involvement in these processes is unclear. Moreover, the fate of unabsorbed dietary lipids is unclear as fecal lipid contents were reportedly unchanged between wild-type and NOCT knockout mice [19].…”

“…1). Consistent with this idea, the Drosophila NOCT ortholog curled has been implicated in the circadian light response [50]; however, NOCT knockout mice exhibit normal circadian behaviors, indicating that NOCT may function as a downstream effector of circadian signals in vertebrates [9]. …”

“…Although a comprehensive review of the specific functions attributed to each deadenylase is beyond the scope of this article (readers are instead referred elsewhere [13,21,24–26]), several lines of evidence support functional specialization amongst these proteins, even among the most closely-related of these enzymes. The strongest support for this idea comes from analyses of vertebrate NOCT, CNOT7, and CAF1z loss-of-function models that exhibit distinct phenotypes, indicating unique functions for these enzymes [9,27–30]. …”

“…Starvation has also been connected with increased curled mRNA abundance in Drosophila [14], as well as time- and tissue-dependent induction of noc-b and repression of noc-a mRNA expression in C. auratus [16]. The links between NOCT expression and nutrient availability suggest a role for NOCT in modulating metabolic activity, perhaps regulating the expression of genes involved in energy uptake, storage, and utilization [9,15,16,19,55]. Whether nutrient availability and feeding regulate NOCT expression in humans remains to be explored.…”

“…NOCT orthologs have been identified in invertebrates and vertebrates including Drosophila , fish, amphibians, and mammals, suggesting NOCT has an evolutionarily conserved function in metazoans [8–17]; however, it is absent from other organisms such as C. elegans and yeast. NOCT has been most extensively studied in mice, where loss of NOCT confers resistance to high-fat diet-induced obesity [9]. In addition to regulation of body mass, NOCT affects the regulation of intestinal lipid trafficking, and the differentiation of bone marrow mesenchymal stem cells into either adipocytes or osteoblasts (Fig.…”