University of Illinois Urbana-Champaign

Molecular regulation of nutrient sensing and immunometabolism by calorie restriction

Hernandez Saavedra, Diego

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HERNANDEZSAAVEDRA-DISSERTATION-2018.pdf

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https://hdl.handle.net/2142/102889

Description

Title
Molecular regulation of nutrient sensing and immunometabolism by calorie restriction
Author(s)
Hernandez Saavedra, Diego
Issue Date
2018-09-05
Director of Research (if dissertation) or Advisor (if thesis)
Pan, Yuan-Xiang
Doctoral Committee Chair(s)
Loor, Juan J.
Committee Member(s)
  • Kemper, Jongsook Kim
  • Liang, Nu-Chu
Department of Study
Nutritional Sciences
Discipline
Nutritional Sciences
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Date of Ingest
2019-02-08T18:39:39Z
Keyword(s)
  • Caloric restriction
  • inflammation
  • nutrient sensing
  • protein recycling
  • epigenetics
Abstract
“‘You'll live longer and you'll be healthier too,’ he answered. ‘Because as we were saying today, there's nothing in the world like eating moderately to live a long life.’ ‘If that's the way things are,’ I thought to myself, ‘I never will die.’ Because I've always been forced to keep that rule, and with my luck I'll probably keep it all my life.”—Anonymous, The Life of Lazarillo de Tormes and of His Fortunes and Adversities 1554. Adaptive mechanisms in response to calorie restriction are evolutionarily conserved and necessary to promote longevity and increase health span. Caloric restriction (CR) without malnutrition, constitutes an effective strategy for weight reduction and ameliorates the chronic inflammatory burden of many chronic metabolic diseases. CR is known to impact nutrient sensing and immuno-metabolic processes in immune cells, but not much is known about skeletal muscle, the largest tissue in the body. We first delve into the literature that describes the interaction of CR and epigenetic mechanisms: DNA methylation, histone modifications, and microRNAs. We explore the impact of CR on nutrient sensing and immuno-metabolic processes and provide a comprehensive view of the adaptive and epigenetic machinery coordinated by CR. In our first study, we aimed to uncover the long-term effect of CR following early-life high fat-diet exposure. We analyzed physiological, biochemical, and transcriptional changes in muscle following chronic CR. Our results indicate that CR activates nutrient sensing pathways, promotes protein recycling, and stimulates myogenesis, possibly due to inhibition of cachexia-inducing inflammatory pathways. Then, our second experiment was designed to titrate the effects of CR by using a novel approach with clinical translatability. We used alternate-day CR (ADCR) in 1-3 days a week and 25-75 % energy restriction to delineate the physiological, biochemical, and transcriptional changes in muscle following chronic ADCR. Effective strategies with high translatable potential, such as 50% CR more than 2 days a week or 75% CR more than 1 day a week, produced similar effects to the gold standard of 25% chronic CR. Finally, on our third experiment we dissected the series of adaptive, epigenetic mechanisms employed by CR to decrease muscle inflammation. Chronic CR activates a series of inhibitors of inflammatory factor NF-kB, while increasing promoter DNA methylation and decreasing transcription factor binding of cytokine Tnf, as well as fine-tuning miRNA expression to prevent inflammation. Here we describe that CR orchestrates a series of adaptive nutrient sensing and anti-inflammatory checkpoints to inhibit inflammation and promote skeletal muscle maintenance.
Graduation Semester
2018-12
Type of Resource
text
Permalink
http://hdl.handle.net/2142/102889
Copyright and License Information
Copyright 2018 Diego Hernandez Saavedra

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Dissertations and Theses - Nutritional Sciences