Restricted feeding entrains rhythms of inflammation-related factors without promoting an acute-phase response

Abstract

A restricted schedule of food access promotes numerous metabolic and physiological adaptations to optimize the biochemical handling of nutrients. The restricted feeding activates responses in hypothalamic and midbrain areas, as well as in peripheral organs involved in energy metabolism. A restricted feeding schedule (RFS) is associated with marked behavioral arousal coincident with the food anticipatory activity (FAA) and extreme hyperphagia during food access. Food restriction is also accompanied by changes in an array of stress-related parameters, such as increase in corticosterone, slower rate in body weight gain, and reduction in retroperitoneal and epididymal adipose tissue. During RFS, the liver shows a diversity of biochemical and physiologically adaptations that are advantageous for food ingestion and processing, as well as for adequate nutrient distribution to other tissues. Taking into account the probable relationship between stressful conditions and the metabolic adaptations in the liver, we addressed whether an acute-phase response (APR), or a pro-inflammatory state, occurred after three weeks of 2 h food restriction. First, we compared the circulating levels of inflammation markers (interleukin-1alpha, interleukin-6, tumor necrosis factor-alpha), and APR proteins (C-reactive protein and fibrinogen) in rats under food restriction to those in rats treated with lipopolysacharide, a strong inducer of the APR. Second, the influence of RFS on the daily rhythms of systemic cytokines and APR proteins was characterized. Third, we tested if the feeding condition (22 h fasting and 2 h refeeding) influences these parameters. Finally, we assessed if a local stressed state was established in the liver associated with the restricted feeding by measuring the activation of the transcriptional factor NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells). The results showed that the following occurred during RFS: no APR was implemented; food restriction modified the rhythmic 24 h fluctuations of IL-1alpha, IL-6, TNF-alpha, and fibrinogen; simple fasting-refeeding modulated the level of IL-1alpha, IL-6, and fibrinogen, but this effect was not observed before and after food access in rats with restricted food; and food restriction produced a significant peak in NF-kappaB signal in the liver (including its translocation into the nuclei of hepatocytes) that was dependent on feeding condition, as it was coincident with the time after food access. In conclusion, the stress condition associated with RFS is not sufficient to induce an APR, but it could be related to a local stress-response within the liver.