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.
Subject(s)
Adipocytes/metabolism , Adiposity , Fasting , Intra-Abdominal Fat/metabolism , Obesity/blood , Obesity/diet therapy , Receptor for Advanced Glycation End Products/blood , Subcutaneous Fat, Abdominal/metabolism , Weight Loss , Absorptiometry, Photon , Adult , Biomarkers/blood , Chicago , Energy Intake , Enzyme-Linked Immunosorbent Assay , Female , Humans , Intra-Abdominal Fat/diagnostic imaging , Intra-Abdominal Fat/physiopathology , Magnetic Resonance Imaging , Male , Middle Aged , Obesity/diagnosis , Obesity/physiopathology , Subcutaneous Fat, Abdominal/diagnostic imaging , Subcutaneous Fat, Abdominal/physiopathology , Time Factors , Treatment Outcome , Up-RegulationABSTRACT
Fetuin-A (FetA) is a 64-kDa glycoprotein that is secreted from both the liver and adipose tissue. Circulating FetA is elevated in obesity and related disorders including type 2 diabetes mellitus, nonalcoholic fatty liver disease and the metabolic syndrome; and a FetA-related parameter, caliciprotein particle, is highly relevant to vascular calcification in overweight/obese patients with chronic kidney disease. FetA level is also associated with impaired insulin sensitivity and glucose tolerance. Accumulating evidence suggests that elevated FetA level causes impaired glycemic control, as FetA has been implicated in impairment of insulin receptor signaling, toll-like receptor 4 activation, macrophage migration and polarization, adipocyte dysfunction, hepatocyte triacylglycerol accumulation and liver inflammation and fibrosis. Weight loss, aerobic exercise, metformin and pioglitazone have each been shown to be effective for reducing FetA level.
