Dataset Information

Transcriptomics and Metabonomics Identify Essential Metabolic Signatures in Calorie Restriction (CR) Regulation across Multiple Mouse Strains.

ABSTRACT: Calorie restriction (CR) has long been used to study lifespan effects and oppose the development of a broad array of age-related biological and pathological changes (increase healthspan). Yet, a comprehensive comparison of the metabolic phenotype across different genetic backgrounds to identify common metabolic markers affected by CR is still lacking. Using a system biology approach comprising metabonomics and liver transcriptomics we revealed the effect of CR across multiple mouse strains (129S1/SvlmJ, C57BL6/J, C3H/HeJ, CBA/J, DBA/2J, JC3F1/J). Oligonucleotide microarrays identified 76 genes as differentially expressed in all six strains confirmed. These genes were subjected to quantitative RT-PCR analysis in the C57BL/6J mouse strain, and a CR-induced change expression was confirmed for 14 genes. To fully depict the metabolic pathways affected by CR and complement the changes observed through differential gene expression, the metabolome of C57BL6/J was further characterized in liver tissues, urine and plasma levels using a combination or targeted mass spectrometry and proton nuclear magnetic resonance spectroscopy. Overall, our integrated approach commonly confirms that energy metabolism, stress response, lipids regulators and the insulin/IGF-1 are key determinants factors involved in CR regulation.

SUBMITTER: Collino S

PROVIDER: S-EPMC3937836 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Transcriptomics and Metabonomics Identify Essential Metabolic Signatures in Calorie Restriction (CR) Regulation across Multiple Mouse Strains.

Collino Sebastiano S Martin François-Pierre J FP Montoliu Ivan I Barger Jamie L JL Da Silva Laeticia L Prolla Tomas A TA Weindruch Richard R Kochhar Sunil S

Metabolites 20131011 4

Calorie restriction (CR) has long been used to study lifespan effects and oppose the development of a broad array of age-related biological and pathological changes (increase healthspan). Yet, a comprehensive comparison of the metabolic phenotype across different genetic backgrounds to identify common metabolic markers affected by CR is still lacking. Using a system biology approach comprising metabonomics and liver transcriptomics we revealed the effect of CR across multiple mouse strains (129S ...[more]

PMID: 24958256

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Project description:Calorie restriction (CR) enhances longevity and mitigates aging phenotypes in numerous species. Physiological responses to CR are cell-type specific and variable throughout the lifespan; however, the mosaic of molecular changes responsible CR benefits remain unclear, particularly in brain regions susceptible to deterioration throughout aging. Thus, we examined the influence of long-term CR on the CA1 hippocampal region, a key learning and memory brain area that is vulnerable to age-related pathologies, such as Alzheimerâs disease (AD). Through mRNA sequencing and NanoString nCounter analysis, we demonstrate that one year of CR feeding suppresses an age-dependent signature of 882 genes functionally associated with synaptic transmission-related pathways, including calcium signaling, long-term potentiation (LTP), and Creb signaling in wild-type mice. By comparing the influence of CR on hippocampal CA1 region transcriptional profiles at younger- (5 months) and older-adult (15 months) timepoints, we identify conserved upregulation of proteome quality control and calcium buffering genes, including heat shock 70 kDa proteins 1b and 5 (Hspa1b and Hspa5), protein disulfide isomerase family A members 4 and 6 (Pdia4 and Pdia6), and calreticulin (Calr). Expression levels of putative neuroprotective factors, klotho (Kl) and transthyretin (Ttr), are also elevated by CR throughout adulthood, although the global CR-specific expression profiles at young and older timepoints are highly divergent. At a previously unachieved resolution, our results demonstrate conserved activation of neuroprotective gene signatures and broad CR-suppression of age-dependent hippocampal CA1 region expression changes, indicating that CR functionally maintains a more youthful transcriptional state within hippocampal CA1 throughout aging. Hippocampal CA1 region mRNA profiles of younger- (5 months) and older-adult (15 months) mice on calorie-restricted (CR) and normal (AD) diets were generated by deep sequencing using Illumina HiSeq 2500.

Project description:Ghrelin is a gut hormone that signals to the hypothalamus to stimulate growth hormone release, increase food intake and promote fat deposition. The ghrelin receptor, also known as growth hormone secretagogue receptor (GHS-R), is highly expressed in the brain, with the highest expression in agouti-related peptide (AgRP) neurones in the hypothalamus. Compelling evidence indicates that ghrelin serves as a survival hormone with respect to maintaining blood glucose and body weight during nutritional deficiencies. Recent studies have demonstrated that AgRP neurones are involved in metabolic and behavioural adaptation to an energy deficit to improve survival. In the present study, we used a neuronal subtype-specific GHS-R knockout mouse (AgRP-Cre;Ghsrf/f ) to investigate the role of GHS-R in hypothalamic AgRP neurones in metabolic and behavioural adaptation to hypocaloric restricted feeding. We subjected the mice to a restricted feeding regimen of 40% mild calorie restriction (CR), with one-quarter of food allotment given in the beginning of the light cycle and three-quarters given at the beginning of the dark cycle, to mimic normal mouse intake pattern. The CR-fed AgRP-Cre;Ghsrf/f mice exhibited reductions in body weight, fat mass and blood glucose. Metabolic profiling of these CR-fed AgRP-Cre;Ghsrf/f mice showed a trend toward reduced basal metabolic rate, significantly reduced core body temperature and a decreased expression of thermogenic genes in brown adipose tissue. This suggests a metabolic reset to a lower threshold. Significantly increased physical activity, a trend toward increased food anticipatory behaviour and altered fuel preferences were also observed in these mice. In addition, these CR-fed AgRP-Cre;Ghsrf/f mice exhibited a decreased counter-regulatory response, showing impaired hepatic glucose production. Lastly, hypothalamic gene expression in AgRP-Cre;Ghsrf/f mice revealed increased AgRP expression and a decreased expression of genes in ?-oxidation pathways. In summary, our data suggest that GHS-R in AgRP neurones is a key component of the neurocircuitry involved in metabolic adaptation to calorie restriction.

Dataset Information

Transcriptomics and Metabonomics Identify Essential Metabolic Signatures in Calorie Restriction (CR) Regulation across Multiple Mouse Strains.

Publications

Transcriptomics and Metabonomics Identify Essential Metabolic Signatures in Calorie Restriction (CR) Regulation across Multiple Mouse Strains.

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