Quantitative proteomics of rat livers shows that unrestricted feeding is stressful for proteostasis with implications on life span

Abstract

Studies in young mammals on the molecular effects of food restriction leading to prolong adult life are scares. Here, we used high-throughput quantitative proteomic analysis of whole rat livers to address the molecular basis for growth arrest and the apparent life-prolonging phenotype of the food restriction regimen. Over 1800 common proteins were significantly quantified in livers of ad libitum, restriction- and re-fed rats, which summed up into 92% of the total protein mass of the cells. Compared to restriction, ad libitum cells contained significantly less mitochondrial catabolic enzymes and more cytosolic and ER HSP90 and HSP70 chaperones, which are hallmarks of heat- and chemically-stressed tissues. Following re-feeding, levels of HSPs nearly reached ad libitum levels. The quantitative and qualitative protein values indicated that the restriction regimen was a least stressful condition that used minimal amounts of HSP-chaperones to maintain optimal protein homeostasis and sustain optimal life span. In contrast, the elevated levels of HSP-chaperones in ad libitum tissues were characteristic of a chronic stress, which in the long term could lead to early aging and shorter life span.

Effect of Nutrition on Statural Growth

“…Our results showed that IGFBP-1 synthesis was increased during food restriction and reduced upon re-feeding, in agreement with previous findings [51, 52]. In contrast, the acid-labile subunit was found to be reduced following food restriction, but after re-feeding increased to a level similar to that of the controls although lower [53]. These results suggest that the decrease in plasma IGF-1 and local IGF-1R and GHR expression may result from the body’s effort to adapt to food restriction/malnutrition by shunting calories away from nonessential processes, including growth [58].…”

“…As a result, cell catabolism is upregulated in order to generate energy for cell survival. In our proteomic study, described earlier, we indeed found a general across-the-board degradation, or slower replenishment, of the most abundant proteins in the endoplasmic reticulum and the cytosol, with the ribosomal proteins and chaperones acting as the core components of the protein homeostasis machineries [53]. …”

“…In contrast, there are numerous studies describing changes of IGFPB-1 levels secondary to a rapid change of nutritional status, possibly related to changes in glucose and insulin [51]. IGFBP-1 production is suppressed by insulin and increased by food restriction [52, 53], energy restriction, and dietary restriction of proteins or specific amino acids [54]. IGFBP-1 binds both IGF-1 and -2 with high affinity and inhibits their binding to their receptor; both IGF-1 and -2, in turn, cause suppression of IGFBP-1 levels, probably at the transcriptional level [55].…”

“…performed on the livers of the AL, RES, and CU rats [53, 57], we found a dramatic reduction in the production of IGF-1 in the livers of the RES rats, with a significant increase of IGF-1 levels found already after 1 day of re-feeding (CU group), although IGF-1 levels were still lower than in the controls (AL) [47]. Our results showed that IGFBP-1 synthesis was increased during food restriction and reduced upon re-feeding, in agreement with previous findings [51, 52].…”

How Milk and Its Proteins Affect Growth, Bone Health, and Weight

“…When 10 days of the RES regimen were followed by a single day of unlimited re-feeding (leading to CU), there was a dramatic increase in liver weight. Analysis of liver proteins by mass spectrometry showed a fundamental difference between the RES and the CU groups: re-feeding led to massive protein synthesis, necessitating high levels of ribosomes and chaperones; many ribosomal and chaperone proteins became significantly more abundant in the CU rats, implying that they were massively and preferably synthetized during the single day of re-feeding [20]. …”