The Impact of Varying Food Availability on Gene Expression in the Liver: Testing the Match-Mismatch Hypothesis

Abstract

Background: During early phases of life, such as prenatal or early postnatal development and adolescence, an organism's phenotype can be shaped by the environmental conditions it experiences. According to the Match-Mismatch hypothesis (MMH), changes to this environment during later life stages can result in a mismatch between the individual's adaptations and the prevailing environmental conditions. Thus, negative consequences in welfare and health can occur. We aimed to test the MMH in the context of food availability, assuming adolescence as a sensitive period of adaptation.

Methods: We have previously reported a study of the physiological and behavioral effects of match and mismatch conditions of high (ad libitum) and low (90% of ad libitum intake) food availability from adolescence to early adulthood in female C57BL/6J mice (n = 62). Here, we performed RNA-sequencing of the livers of a subset of these animals (n = 16) to test the effects of match and mismatch feeding conditions on the liver transcriptome.

Results: In general, we found no effect of the match-mismatch situations. Contrarily, the amount of food available during early adulthood (low vs. high) drove the differences we observed in final body weight and gene expression in the liver, regardless of the amount of food available to the animals during adolescence. Many of the differentially expressed genes and the corresponding biological processes found to be overrepresented overlapped, implicating common changes in various domains. These included metabolism, homeostasis, cellular responses to diverse stimuli, transport of bile acids and other molecules, cell differentiation, major urinary proteins, and immunity and inflammation.

Conclusions: Our previous and present observations found no support for the MMH in the context of low vs high food availability from adolescence to early adulthood in female C57BL/6J mice. However, even small differences of approximately 10% in food availability during early adulthood resulted in physiological and molecular changes with potential beneficial implications for metabolic diseases.

Keywords: Match-Mismatch hypothesis; RNA-sequencing (RNA-seq); differential expression (DE) analysis; food availability changes; immunity and inflammation; liver transcriptome; metabolism.

Figure 1

(A) Experimental design. Mice were kept at high (H) or low (L) food availability conditions during 6 weeks of adolescence. Upon reaching early adulthood, food availability either remained the same (match) or was changed (mismatch) for another 11 weeks. During the last 5 weeks, behavioral tests were conducted for a previous publication (24). Subsequently, final body weights and body length were assessed; liver samples were weighed and collected for RNA-sequencing. (B) Progressive increases in body weight were assessed at weeks 1, 2, 6, 7, 8, 12 and at the end of the experiment. Afterwards, liver weight was recorded. Significant differences (Tukey HSD adj. p < 0.05) between groups are denoted by (*). L, low food availability; H, high food availability.

Figure 2

(A) Plot of the first 2 principal components (PCs) of the normalized read counts. (B) Overlaps of differentially expressed genes (DEGs) and (C) the corresponding enriched Gene Ontology biological processes (GO_BPs) among all comparisons. No DEGs and/or GO_BP terms overlapping among all comparisons performed were identified. L, low food availability; H, high food availability.

Figure 3

Overview of differential expression results for all comparisons. MA plots show the statistically significant (adjusted p < 0.05) dysregulations obtained in each comparison marked in red.

Figure 4

(A) Top genes. Selection was based on the gene being differentially expressed within the top 20 most significant hits in more than one comparison, and belonging to a recognizable cluster of functional categories. TBA: transport of bile acids. (B) Representative top shared Gene Ontology biological processes (GO_BPs). Selected terms are representative of all different GO_BP terms enriched in at least four of the comparisons. Only significant (adjusted p < 0.05) genes and functional terms are shown.