Postprandial Induction of Chaperone Gene Expression Is Rapid in Mice

Abstract

Molecular chaperones assist in the biosynthesis and processing of proteins. Most chaperones are induced by physiological stresses. We have shown that dietary energy restriction decreases the mRNA and protein levels of many endoplasmic reticulum chaperones in the livers of mice. Here, we have investigated the response of chaperone mRNA to feeding. Control and 50% energy-restricted C3B10RF1 mice were deprived of food for 24 h, fed, and killed 0, 1.5, 5 or 12 h after feeding. Chaperone mRNAs were strongly induced as early as 1.5 h after feeding in control and energy-restricted mice. The integrated levels of these mRNA over 24 h were significantly lower in energy-restricted mice. The mRNA response to energy intake was mirrored over the course of days in the level of chaperone protein. A similar but smaller response to feeding was found in kidney and muscle. Puromycin and cycloheximide failed to inhibit the feeding response, suggesting that feeding releases chaperone expression from an unstable inhibitor. Studies with dibutyryl-cAMP- and glucagon-supplemented, normal and streptozotocin-diabetic mice suggest that glucagon and insulin may be mediators of the feeding response. Adrenalectomy enhanced the feeding induction, but dexamethasone administration had no effect. Thus, postprandial changes in insulin and glucagon may link chaperone gene expression to feeding, possibly in several tissues including liver.

Temporal linkage between the phenotypic and genomic responses to caloric restriction

“…These early and intermediate genes were functionally associated with metabolism; signal transduction, growth factors, immune response, inflammation, stress response, and xenobiotic metabolism. These genes and their classes are consistent with those identified previously (7,(19)(20)(21). The metabolic genes included three urea cycle enzymes, Arg1 and As1, which are early genes, and Ass1, an intermediate gene.…”

“…However, elevated chaperones also decrease apoptotic responsiveness to genotoxic stress through both the endoplasmic stress and the mitochondrial apoptosis signaling pathways (36,37). CR and fasting reduce endoplasmic reticulum chaperone levels and enhance apoptosis in liver and other cycling cell types, perhaps accounting for their anticancer benefits (21,35,38,39). Importantly, CR appears to induce chaperone expression in nondividing cell types such as neurons, apparently enhancing their survival after stress (40).…”

Conserved and Tissue-Specific Genic and Physiologic Responses to Caloric Restriction and Altered IGFI Signaling in Mitotic and Postmitotic Tissues

“…Ames dwarf mice are homozygous for a loss-of-function mutation in the Prop1 gene, leading to reduced serum levels of insulin like growth factor I (IGFI) and other hormones produced by or released in response to signaling from the anterior pituitary (119). Fasting also downregulates and refeeding upregulates cytoplasmic and ER chaperones, possibly in response to changes in blood insulin and glucagon levels (20,21). Two chaperone genes recently were reported to be downregulated by CR in mouse heart, liver, and hypothalamus (37).…”

“…In mice, most chaperones are downregulated by LTCR at all times, especially before feeding (20,21,24,97). Feeding induces the expression of some chaperones, matching their abundance to that of their substrates, which are postprandially synthesized proteins (20,21).…”

Use of microarray biomarkers to identify longevity therapeutics

“…Chaperones were identified as a major effector shared by LTCR and MET. Some years ago, we found that LTCR, short-term CR, and fasting reduced the levels of most endoplasmic reticulum and some cytoplasmic chaperone mRNAs and proteins in the liver of mice (Spindler et al ., 1990;Dhahbi et al ., 2002;. In these studies, we found that MET and LTCR both negatively regulate the chaperones TRA1, HSPA5, GRP58 and DNAJB11, and the related transcription factor XBP1 (Dhahbi et al ., 2005b).…”