The effects of graded levels of calorie restriction: VI. Impact of short-term graded calorie restriction on transcriptomic responses of the hypothalamic hunger and circadian signaling pathways

Abstract

Food intake and circadian rhythms are regulated by hypothalamic neuropeptides and circulating hormones, which could mediate the anti‐ageing effect of calorie restriction (CR). We tested whether these two signaling pathways mediate CR by quantifying hypothalamic transcripts of male C57BL/6 mice exposed to graded levels of CR (10 % to 40 %) for 3 months. We found that the graded CR manipulation resulted in upregulation of core circadian rhythm genes, which correlated negatively with circulating levels of leptin, insulin‐like growth factor 1 (IGF‐1), insulin, and tumor necrosis factor alpha (TNF‐α). In addition, key components in the hunger signaling pathway were expressed in a manner reflecting elevated hunger at greater levels of restriction, and which also correlated negatively with circulating levels of insulin, TNF‐α, leptin and IGF‐1. Lastly, phenotypes, such as food anticipatory activity and body temperature, were associated with expression levels of both hunger genes and core clock genes. Our results suggest modulation of the hunger and circadian signaling pathways in response to altered levels of circulating hormones, that are themselves downstream of morphological changes resulting from CR treatment, may be important elements in the response to CR, driving some of the key phenotypic outcomes.

The effects of graded levels of calorie restriction: IX. Global metabolomic screen reveals modulation of carnitines, sphingolipids and bile acids in the liver of C57BL/6 mice

“…We also observed correlations between these metabolites and aspects of physiology of the CR mice, including Tb and FAA, but the correlation with respect to Tb was opposite that previously observed in the brain. One distinctive response in our mice was a large increase in FAA, and in addition the level of FAA was correlated with transcriptomic levels of several key hunger signalling neuropeptides in the hypothalamus (Derous et al ., 2016). The association of S1P and Tb is potentially significant in the context of the potential causal relationship between Tb and longevity.…”

Whey protein effects on energy balance link the intestinal mechanisms of energy absorption with adiposity and hypothalamic neuropeptide gene expression

“…The data suggest a signaling mechanism linking adiposity, hypothalamic neuropeptide gene expression, and intestinal growth, where the latter two changes may act to increase energy assimilation to counteract the energy loss in the adipose tissue. In fact, energy restriction, lactation, and cold exposure, each of which reduces adiposity and plasma leptin, also increased energy intake and the intestinal weight (8,30,40,46). By changing the protein to WPI, and bearing in mind the effect on the intestinal mechanisms of energy absorption and presumed energy loss, the above effects of the low sucrose were accentuated.…”

Calorie restriction in rodents: Caveats to consider

“…Efforts are now invested to further investigated this interplay between mouse strains, the level of restriction, and their impact on survival. The DBA results of Mitchell et al (2016) and those from John Speakman’s group in which the effects of different grades of CR in B6 mice elicit differential responses (Derous et al, 2016a; Derous et al, 2016b; Lusseau et al, 2015; Mitchell et al, 2015a; Mitchell et al, 2016a; Mitchell et al, 2015b; Mitchell et al, 2015c) open the door for new studies aimed at identify the underlying biological responses. Thus, one could predict that some of the recombinant inbred strains will have a beneficial response to CR if they were tested at a lower level of dietary restriction.…”

“…We know now that this level of CR may be excessive for some strains of mice. The interaction between the degree of CR and different aspects of physiology has been recently examined (Derous et al, 2016a; Derous et al, 2016b; Lusseau et al, 2015; Mitchell et al, 2015a; Mitchell et al, 2016a; Mitchell et al, 2015b; Mitchell et al, 2015c) and survival (Mitchell et al, 2016b). …”