In a randomized trial in prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles.

Erez Eitan,Sophia M Raefsky,Maja Mustapic,Beatrice Bertozzi,Luigi Fontana,Caitlin N Suire,Dimitrios Kapogiannis,Nicola Veronese,Edda Cava,Sean Berkowitz,Francesco Spelta,Valeria Tosti,Ryan Spangler,Mark P Mattson

doi:10.1111/acel.12657

Abstract

SummaryObesity, metabolic syndrome, and hyperleptinemia are associated with aging and age‐associated diseases including prostate cancer. One experimental approach to inhibit tumor growth is to reduce dietary protein intake and hence levels of circulating amino acids. Dietary protein restriction (PR) increases insulin sensitivity and suppresses prostate cancer cell tumor growth in animal models, providing a rationale for clinical trials. We sought to demonstrate that biomarkers derived from plasma extracellular vesicles (EVs) reflect systemic leptin and insulin signaling and respond to dietary interventions. We studied plasma samples from men with prostate cancer awaiting prostatectomy who participated in a randomized trial of one month of PR or control diet. We found increased levels of leptin receptor in the PR group in total plasma EVs and in a subpopulation of plasma EVs expressing the neuronal marker L1CAM. Protein restriction also shifted the phosphorylation status of the insulin receptor signal transducer protein IRS1 in L1CAM+ EVs in a manner suggestive of improved insulin sensitivity. Dietary PR modifies indicators of leptin and insulin signaling in circulating EVs. These findings are consistent with improved insulin and leptin sensitivity in response to PR and open a new window for following physiologic responses to dietary interventions in humans.

Highlights

Obesity and insulin resistance are associated with accelerated aging and increased risk of many age-related diseases (Mattson et al, 2016)
After establishing that extracellular vesicles (EVs) concentration is not changing in response to the protein restriction (PR) diet, we shifted our attention to their content, focusing on leptin receptor (LeR) and the insulin signaling protein IRS1
We previously demonstrated that they represent a distinct subpopulation that is enriched for several neuronal proteins and interestingly contain elevated levels of hormone receptors and intracellular signaling molecules like mTOR, IRS1, and leptinR (Mustapic et al, 2017) compared to total EVs, perhaps, a reflection of the high neuronal metabolic activity

Summary

Introduction

Obesity and insulin resistance are associated with accelerated aging and increased risk of many age-related diseases (Mattson et al, 2016). After establishing that EV concentration is not changing in response to the PR diet, we shifted our attention to their content, focusing on leptin receptor (LeR) and the insulin signaling protein IRS1.

Results

Conclusion