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Nitric oxide required for transition to slower hepatic protein synthesis rates during long-term caloric restriction

ABSTRACT: Caloric restriction (CR) extends maximal lifespan and maintains cellular homeostasis in various animal models. We have previously shown that CR induces a global reduction in protein fractional synthesis rates (FSRs) across the hepatic proteome in mice, but the timing and regulatory mechanisms remain unclear. Nitric oxide (NO), a bioactive molecule upregulated during CR, is a potential regulator of protein synthesis. To explore the role of NO in hepatic proteome fluxes during CR, we used in vivo deuterium labeling from heavy water and LC/MS-based flux proteomics in wild-type and NO-deficient (NO-) mice. We found a transition to reduced global protein FSRs that occurred rapidly between days 25 to 30 of CR. NO deficiency, whether genetic or pharmacological, disrupted the slowing of proteome-wide fluxes and the beneficial effects on body composition and physiology. Administering the NO donor molsidomine restored the reduction in hepatic FSRs in NO-deficient mice. Further, inhibiting NO pharmacologically, whether starting on day 1, day 14, or day 24 of CR, mitigated the reduction in hepatic protein FSRs at day 32, highlighting NO's critical role during the transition period. These results underscore the importance of NO in CR-induced changes in proteostasis and suggest NO as a potential CR-mimetic target, while offering a specific time window for identifying other signals and testing therapeutic interventions.

ORGANISM(S): Mus musculus

PROVIDER: GSE274644 | GEO | 2025/10/04

REPOSITORIES: GEO

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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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Nitric oxide required for transition to slower hepatic protein synthesis rates during long-term caloric restriction

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