Weight Loss Via Alternate Day Fasting Increases Circulating Endogenous Secretory RAGE and is Associated with Markers of Adipocyte Health

Abstract

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor that upon binding of its ligand induces inflammation and promotes the development of complications associated with obesity, diabetes, and aging. Soluble isoforms of RAGE (sRAGE) produced by proteolytic cleavage (sRAGEc) or alternative splicing (endogenous secretory RAGE, esRAGE), inhibit RAGE signaling by scavenging RAGE ligands. RAGE plays a role in adipocyte hypertrophy and individuals with obesity present with lower circulating levels of sRAGE. This phenotype may permit RAGE signaling to persist, contributing to further adipose expansion and an increase in pro‐inflammatory adipokine production.PURPOSEThe purpose of this study was to determine if a 24‐week dietary weight loss intervention via alternate day fasting (ADF) could increase circulating sRAGE isoforms and if these changes in sRAGE were related to changes in fat mass and circulating adiopokines.METHODS42 participants (7 Males, 35 Females) were randomized to either control (CON) or ADF. The ADF group (BMI 33.8 ± 3.9 kg/m2) consumed 25% of their caloric requirements followed by ad libitum eating on alternating days whereas the CON group (BMI 33.3 ± 4.8 kg/m2) ate ad libitum every day. Total sRAGE, esRAGE, adiponectin, and IL‐6 were measured via ELISAs. sRAGEc was calculated by subtracting esRAGE from total sRAGE.RESULTSFollowing the intervention, the ADF group lost more body weight than the CON group (−7.1 ± 1.1 kg vs −0.72 ± 0.51 kg, p < 0.05) and the ADF group displayed a greater increase in esRAGE compared to CON (28.1 ± 79.9 pg/mL vs −30.9 ± 61.1 pg/mL p < 0.05). When changes in body weight or fat mass were stratified into tertiles, individuals with the greatest body weight and fat mass change displayed the greatest increases in esRAGE. In addition, changes in each of the sRAGE isoforms negatively correlated with changes in body weight and fat mass. Interestingly, changes in the sRAGEc:esRAGE ratio positively correlated with changes in fat mass (Rho = 0.327, p < 0.05) and negatively correlated with changes in adiponectin (Rho = −0.356, p <0.05). The baseline sRAGEc:esRAGE ratio was also negatively correlated to baseline levels of IL‐6 (Rho = −0.462, p <0.01).CONCLUSIONThese data are the first to demonstrate that weight loss, via caloric restriction, increases circulating esRAGE in obese individuals. Further, this is also the first evidence to relate reductions in fat mass loss to increases in sRAGE isoforms, suggesting a mechanistic link between adipose tissue and sRAGE. Additionally, the relationship between sRAGEc:esRAGE and adipopkines suggests that sRAGEc and esRAGE may be independently modulated with weight loss. Future research is warranted to investigate the mechanisms of caloric restriction on RAGE and sRAGE biology.