Nocturnin Regulates Circadian Trafficking of Dietary Lipid in Intestinal Enterocytes

Abstract

Summary Background Efficient metabolic function in mammals depends on the circadian clock, which drives temporal regulation of metabolic processes. Nocturnin is a clock-regulated deadenylase that controls its target mRNA expression post-transcriptionally through poly(A) tail removal. Mice lacking Nocturnin (Noc−/− mice) are resistant to diet-induced obesity and hepatic steatosis, yet are not hyperactive or hypophagic. Results Here we show that Nocturnin is expressed rhythmically in the small intestine, is induced by olive oil gavage and that the Noc−/− mice have reduced chylomicron transit into the plasma following the ingestion of dietary lipids. Genes involved in triglyceride synthesis, storage and chylomicron formation have altered expression and large cytoplasmic lipid droplets accumulate in the apical domains of the Noc−/− enterocytes. The physiological significance of this deficit in absorption is clear since maintenance of Noc−/− mice on diets that challenge the chylomicron synthesis pathway result in significant reductions in body weight, while diets that bypass this pathway do not. Conclusions Therefore we propose that Nocturnin plays an important role in the trafficking of dietary lipid in the intestinal enterocyes by optimizing efficient absorption of lipids.

Regulatory roles of vertebrate Nocturnin: insights and remaining mysteries

“…In addition to induction in response to dietary fat, NOCT mRNA exhibits circadian fluctuations in abundance in the proximal portion of the small intestine where dietary lipids are absorbed, and nighttime NOCT protein abundance is highest in this region. 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.…”

“…NOCT expression has been best characterized in mice, where NOCT mRNA abundance varies by tissue, and by time of day in several tissues [12,19,47]. Circadian variations in NOCT mRNA abundance are most dramatic in liver, followed by smaller fluctuations in heart and kidney; in each case, peak expression occurs at or soon after light offset [12,47,48].…”

“…Consistent with this idea, changes in NOCT mRNA abundance in response to feeding may be tissue specific. NOCT mRNA levels are constant in white adipose tissue from ad lib fed mice but become rhythmic in response to daytime feeding, and dietary fat induces NOCT mRNA expression in the proximal small intestine [19,55]. The connection between feeding and NOCT mRNA expression in certain contexts appears to be evolutionarily conserved, as several tissues in the goldfish Carassius auratus exhibit increased noc-a mRNA expression following a meal [16].…”

“…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.…”

“…1) [19]. In addition to induction in response to dietary fat, NOCT mRNA exhibits circadian fluctuations in abundance in the proximal portion of the small intestine where dietary lipids are absorbed, and nighttime NOCT protein abundance is highest in this region.…”