Endogenous secretory RAGE increases with improvements in body composition and is associated with markers of adipocyte health

Abstract

Background and aims: The receptor for advanced glycation end products (RAGE) is implicated in obesogenesis. Conversely, soluble RAGE (sRAGE) competitively inhibits RAGE. Our aim was to determine the effects of weight-loss via alternate day fasting (ADF) on sRAGE isoforms and evaluate potential relationships with body composition.

Methods and results: 42 obese participants were randomized to control (CON) or ADF. For 24 weeks, the ADF group consumed 25% or 125% of their caloric requirements on alternating days while the CON group did not change their diet. Body fat was measured via DXA, visceral fat (VAT) via MRI and subcutaneous fat (SAT) was derived by subtracting VAT from total fat. sRAGE isoforms were measured via ELISAs. After 24 weeks, ADF -6.8 (-9.5, -3.5)kg (Median, IQR) lost more weight than CON -0.3 (-1.9, 1.0)kg (p < 0.05). The change in endogenous secretory RAGE (esRAGE) was different between ADF 15 (-30, 78)pg/mL and CON -21 (-72, 16)pg/mL after 24 weeks (p < 0.05). To examine the effect of changes in body composition, the cohort was stratified by median weight-, fat-, SAT-, and VAT-loss. The changes in all sRAGE isoforms were different between those above and below median weight-loss (p < 0.05) with sRAGE isoforms tending to decrease in individuals below the median. Changes in total sRAGE and esRAGE were different between individuals above compared to below median fat- and SAT-loss (p < 0.05). Those above median fat-loss increased esRAGE by 29 (-5, 66)pg/mL (p < 0.05).

Conclusion: Improvements in body composition are related to increased sRAGE isoforms, implicating sRAGE as a potential target for the treatment of obesity.

Clinical trial registration: NCT00960505.

Keywords: Adipokines; Alternate day fasting; Inflammation; Obesity; Soluble RAGE.

Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Figures

Figure 1.. Change in sRAGE isoforms by median weight-loss.

To examine the effect of weight-loss on the change in sRAGE isoforms following 12 (A-D) and 24 weeks (E-H) the entire cohort was stratified by median weight-loss after 12 and 24 weeks respectively. Change scores were compared via Mann-Whitney U-Test. # Significantly different between groups, (p<0.05). Data for each individual is presented with those in the “Above” group represented by open circles (o) and those in the “Below” group are represented by closed squares (∎). The bars identify the median value and the 25th and 75th percentiles of the median. Above: Individuals above the median weight-loss by week 12 or 24 (greater weight-loss), Below: Individuals below the median weight-loss by week 12 or 24.

Figure 2.. Correlations between the changes in weight and the changes in sRAGE Isoforms at weeks 12 and 24.

Spearman’s Rho correlations were performed to examine if weight-loss at 12 (A-D) and 24 (E-H) weeks was related to the change in sRAGE isoforms at corresponding time points in the study. Correlations presented are for the entire cohort (correlations were not run in individual groups). Data for each individual are presented with those in the “Above” group represented by open circles (o) and those in the “Below” group are represented by closed squares (∎). Above: Individuals above the median weight-loss by week 12 or 24 (greater weight-loss), Below: Individuals below the median weight-loss by week 12 or 24.

Figure 3.. Changes in sRAGE isoforms by median fat-loss.

To examine the effect of fat-loss on changes in sRAGE isoforms, the entire cohort was stratified by median fatloss achieved at week 24. Fat mass was quantified via dual x-ray absorptiometry (DXA) at weeks 1 and 24 only. Changes in Total sRAGE (A), cRAGE (B), esRAGE (C), and cRAGE:esRAGE (D) at week 24 were compared between groups via Mann Whitney UTest. # Significantly different between groups, (p<0.05). Data for each individual are presented with those in the “Above” group represented by open circles (o) and those in the “Below” group represented by closed squares (∎). The bars identify the median value and the 25th and 75th percentiles of the median. Spearman’s Rho correlations were performed to examine if fat-loss at 24 weeks was related to the change in Total sRAGE (E), cRAGE (F), esRAGE (G), and cRAGE:esRAGE (H) at week 24. Correlations presented are for the entire cohort (correlations were not run in individual groups). Data for each individual is presented with those in the “Above” group represented by open circles (o) and those in the “Below” group are represented by closed squares (∎). Data are presented as Mean±SEM. Above: Individuals above the median fat-loss by week 24, Below: Individuals below the median fat-loss by week 24.

Figure 4.. Changes in sRAGE isoforms by median visceral fat-loss.

To examine the effect of visceral fat-loss on changes in sRAGE isoforms, the entire cohort was stratified by median visceral fat-loss achieved at week 24. Visceral fat mass was quantified via dual x-ray absorptiometry (DXA) at weeks 1 and 24 only. Changes in Total sRAGE (A), cRAGE (B), esRAGE (C), and cRAGE:esRAGE (D) at week 24 were compared between groups via Mann Whitney U-Test. # Significantly different between groups, (p<0.05). Data for each individual are presented with those in the “Above” group represented by open circles (o) and those in the “Below” group represented by closed squares (∎). The bars identify the median value and the 25th and 75th percentiles of the median.. Spearman’s Rho correlations were performed to examine if visceral fat-loss at 24 weeks was related to the change in Total sRAGE (E), cRAGE (F), esRAGE (G), and cRAGE:esRAGE (H) at week 24. Correlations presented are for the entire cohort (correlations were not run in individual groups). Data for each individual is presented with those in the “Above” group represented by open circles (o) and those in the “Below” group are represented by closed squares (∎). Above: Individuals above the median visceral fat-loss by week 24, Below: Individuals below the median visceral fatloss by week 24.

Figure 5.. Changes in sRAGE isoforms by median subcutaneous fat-loss.

To examine the effect of subcutaneous fat-loss on changes in sRAGE isoforms, the entire cohort was stratified by median subcutaneous fat-loss achieved at week 24. Subcutaneous fat mass was quantified via dual x-ray absorptiometry (DXA) at weeks 1 and 24 only. Changes in Total sRAGE (A), cRAGE (B), esRAGE (C), and cRAGE:esRAGE (D) at week 24 were compared between groups via Mann Whitney UTest. # Significantly different between groups, (p<0.05). Data for each individual are presented with those in the “Above” group represented by open circles (o) and those in the “Below” group represented by closed squares (∎). The bars identify the median value and the 25th and 75th percentiles of the median. Spearman’s Rho correlations were performed to examine if subcutaneous fat-loss at 24 weeks was related to the change in Total sRAGE (E), cRAGE (F), esRAGE (G), and cRAGE:esRAGE (H) at week 24. Correlations presented are for the entire cohort (correlations were not run in individual groups). Data for each individual is presented with those in the “Above” group represented by open circles (o) and those in the “Below” group are represented by closed squares (∎). Above: Individuals above the median subcutaneous fat-loss by week 24, Below: Individuals below the median subcutaneous fat-loss by week 24.