Time of Day and Nutrients in Feeding Govern Daily Expression Rhythms of the Gene for Sterol Regulatory Element-binding Protein (SREBP)-1 in the Mouse Liver

Abstract

Sterol regulatory element-binding protein-1 (SREBP-1) plays a central role in transcriptional regulation of genes for hepatic lipid synthesis that utilizes diet-derived nutrients such as carbohydrates and amino acids, and expression of SREBP-1 exhibits daily rhythms with a peak in the nocturnal feeding period under standard housing conditions of mice. Here, we report that the Srebp-1 expression rhythm shows time cue-independent and Clock mutation-sensitive circadian nature, and is synchronized with varied photoperiods apparently through entrainment of locomotor activity and food intake. Fasting caused diminution of Srebp-1 expression, while diabetic db/db and ob/ob mice showed constantly high expression with loss of rhythmicity. Time-restricted feedings during mid-light and mid-dark periods exhibited differential effects, the latter causing more severe damping of the oscillation. Therefore, "when to eat in a day (the light/dark cycle)," rather than "whenever to eat in a day," is a critical determinant to shape the daily rhythm of Srebp-1 expression. We further found that a high-carbohydrate diet and a high-protein diet, as well as a high-fat diet, cause phase shifts of the oscillation peak into the light period, underlining the importance of "what to eat." Daily rhythms of SREBP-1 protein levels and Akt phosphorylation levels also exhibited nutrientresponsive changes. Taken together, these findings provide a model for mechanisms by which time of day and nutrients in feeding shape daily rhythms of the Srebp-1 expression and possibly a number of other physiological functions with interindividual and interdaily differences in human beings and wild animals subjected to day-by-day changes in dietary timing and nutrients.The circadian timekeeping system for physiology and behavior in mammals consists of a whole-body network of cell-intrinsic oscillators that rely on activation/repression-alternating feedback loops of clock gene expression (1, 2). Daily expression rhythms of clock genes as oscillation generators are synchronized (entrained) to the light/dark cycle in the central pacemaker localized to the suprachiasmatic nucleus (SCN) 3 of the hypothalamus, whereas they are predominantly entrained to the feeding/fasting cycle in other brain regions and peripheral organs (3-5). On the other hand, it is poorly understood how daily rhythms of a large number of physiological functions as oscillation outputs are shaped and coordinated with each other.As a typical example of daily rhythms of liver functions exhibiting a wide spectrum of variety, we (6, 7) previously studied regulatory mechanisms for daily expression rhythms of the gene encoding Spot14 (8, 9) a regulatory protein stimulating lipid biosynthesis that is one of the most closely feeding-related functions in the liver. Because the Spot14 promoter is under the control (10) of sterol regulatory element-binding protein (SREBP)-1c (11, 12) a pivotal transcriptional regulator of genes for triglyceride synthesis, we here focused on Srebp-1 expression rhythms in the mous...

Diurnal regulation of RNA polymerase III transcription is under the control of both the feeding–fasting response and the circadian clock

“…S3C). Cluster 3 included 331 genes that peaked at the end of the day (ZT10) and were associated with steroid metabolic processes, as previously reported (Edwards et al 1972;Matsumoto et al 2010;Gilardi et al 2014), as well as glycogen metabolic process, circadian regulation of gene expression, circadian rhythm, and rhythmic processes. The rhythmic expression of these genes was altered in both CF mice and Arntl KO mice, although to a greater extent in the latter, as illustrated by blurring of the clusters (Fig.…”

Regulation of lipogenesis by cyclin-dependent kinase 8–mediated control of SREBP-1

“…Numerous studies have established a key role of nuclear SREBP-1c on lipogenic gene expression and de novo lipogenesis (6,16,28,44,48). In this regard, SREBP-1c levels are elevated in mice and humans under a variety of pathophysiologic states, including obesity, insulin resistance associated with hyperinsulinemia, high carbohydrate diet, excessive alcohol consumption, and non-alcoholic fatty liver disease (NAFLD) -in the case of the latter being directly shown to increase the proportion of liver VLDL triglyceride production by de novo lipogenesis from 2%-5% to 20%-30% (41,(49)(50)(51)(52).…”

Time-of-day of energy intake

“…Most of this evidence is derived from observational studies on breakfast skipping [7][8][9] and night eating [10][11][12], and from animal studies [11,[13][14][15][16][17][18][19]. In animal models, consumption of a high-fat diet at specific time points during the day induces tissue and gene-specific changes in the expression of core Clock genes [16].…”