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Genome-wide effects of acute progressive feed restriction in liver and white adipose tissue

ABSTRACT: Acute progressive feed restriction (APFR) represents a specific form of caloric restriction in which feed availability is increasingly curtailed over a period of a few days to a few weeks. It is often used for control animals in toxicological and pharmacological studies on compounds causing body weight loss to equalize weight changes between experimental and control groups and thereby, intuitively, to also set their metabolic states to the same phase. However, scientific justification for this procedure is lacking. In the present study, we analyzed by DNA microarrays the impact on hepatic gene expression in rats of two APFR regimens that caused identical diminution of body weight (19%) but differed slightly in duration (4 vs. 10 days). In addition, white adipose tissue (WAT) was also subjected to the transcriptomic analysis on day-4. The data revealed that the two regimens led to distinct patterns of differentially expressed genes in liver, albeit some major pathways of energy metabolism were similarly affected (particularly fatty acid and amino acid catabolism). The reason for the divergence appeared to be entrainment by the longer APFR protocol of peripheral oscillator genes, which resulted in derailment of circadian rhythms and consequent interaction of altered diurnal fluctuations with metabolic adjustments in gene expression activities. WAT proved to be highly unresponsive to the 4-day APFR as only 17 mRNA levels were influenced by the treatment. This study demonstrates that body weight is a poor proxy of metabolic state and that the customary protocols of feed restriction can lead to rhythm entrainment. Keywords: physiological state comparison

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE9121 | GEO | 2008/03/01

SECONDARY ACCESSION(S): PRJNA102657

REPOSITORIES: GEO

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Project description:When puberty starts before males reach harvest size, animal welfare and sustainability issues occur in Atlantic salmon (Salmo salar) aquaculture. Hallmarks of male puberty are an increased proliferation activity in the testis and elevated androgen production. Examining transcriptional changes in salmon testis during the transition from immature to maturing testes may help understanding the regulation of puberty, potentially leading to procedures to modulate its start. Since differences in body weight influence, via unknown mechanisms, the chances for entering puberty, we used two feed rations to create body weight differences. Maturing testes were characterized by an elevated proliferation activity of Sertoli cells and of single undifferentiated spermatogonia. Pituitary gene expression data suggest increased Gnrh receptor and gonadotropin gene expression, potentially responsible for the elevated circulating androgen levels in maturing fish. Transcriptional changes in maturing testes included a broad variety of signaling systems (e.g. Tgfβ, Wnt, insulin/Igf, nuclear receptors), but also, activation of metabolic pathways such as anaerobic metabolism and protection against ROS. Feed restriction lowered the incidence of puberty. In males maturing despite feed restriction, plasma androgen levels were higher than in maturing fish receiving the full ration. A group of 449 genes that was up-regulated in maturing fully fed fish, was up-regulated more prominently in testis from fish maturing under caloric restriction. Moreover, 421 genes were specifically up-regulated in testes from fish maturing under caloric restriction, including carbon metabolism genes, a pathway relevant for nucleotide biosynthesis and for placing epigenetic marks. Undifferentiated spermatogonia and Sertoli cell populations increased at the beginning of puberty, which was associated with the up-regulation of metabolic pathways (e.g. anaerobic and ROS pathways) known from other stem cell systems. The higher androgen levels in males maturing under caloric restriction may be responsible for the stronger up-regulation of a common set of (449) maturation-associated genes, and the specific up-regulation of another set of (421) genes. The latter opened regulatory and/or metabolic options for initiating puberty despite feed restriction. As a means to reduce the incidence of male puberty in salmon, however, caloric restriction seems unsuitable.

Project description:Moderate caloric restriction (CR) and weight loss are beneficial for the promotion of health; however, there is controversy regarding the effects of dieting regimens on behavior. In this study, we investigated two different dieting regimens: repeated fasting and refeeding (RFR) and daily feeding of half the amount of food consumed by RFR mice (CR). Mice in both regimens were subjected to 20% reduction in food intake and transiently reduced their body weights during the first 12 days of the study. Open field, light-dark transition, elevated plus maze, and forced swimming tests indicated that CR, but not RFR, reduced anxiety- and depressive-like behaviors, with a peak on day 8. Using a mouse whole genome microarray, we analyzed gene expression in the prefrontal cortex, amygdala, and hypothalamus. In addition to the caloric restriction-responsive genes commonly modified by RFR and CR, each regimen differentially changed the expression of distinct genes in each region. The most profound change was observed in the amygdala of CR mice: 884 genes were specifically up-regulated. Ingenuity pathway analysis showed that these 884 genes significantly modified 9 canonical pathways in the amygdala. alpha-adrenergic and dopamine receptor signaling were the two top-scoring pathways. Quantitative real-time RT-PCR confirmed the up-regulation of 6 genes in these pathways. Ppp1r1b encoded Darpp-32 including dopamine receptor signaling, and the increased protein was specific for CR mice. Our results suggest that moderate CR may modify anxiety- and depressive-like behaviors and alter gene expression especially in the mouse amygdala. Experiment Overall Design: We tested three feeding regimens. One group of mice had ad libitum (AD) access to food, and was used as a control group. The repeated fasting and refeeding (RFR) group of mice were fasted on day 0 and allowed to feed ad libitum on day 1. Amounts of food consumed by the three mice on day 1 were measured. The half amount of food consumed by the RFR mice was given to three mice in another cage for two days (days 0 and 1) (CR group). The fasting followed by refeeding (RFR) and the restriction of food (CR) were repeated up to day 16. Body weights and consumed chow were measured at 20:00 every day, and then the fasting or feeding period was started. In RFR mice, fasting was started on day 0.Total RNA was prepared from the prefrontal cortex, hypothalamus, and amygdala in the mice of each group on day 8. An equal amount of RNA from 4 mice in each group was pooled and used for microarray analysis.

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Genome-wide effects of acute progressive feed restriction in liver and white adipose tissue

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