Molecular regulation of nutrient sensing and immunometabolism by calorie restriction

Hernandez Saavedra, Diego

Permalink

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

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

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

Owning Collections