Abstract
BACKGROUND AND AIMS: Obesity exacerbates age-related changes in metabolic and physical function. The effect of distinct exercise modalities combined with diet-induced weight loss on insulin secretion in older adults with obesity and frailty is unknown, and the potential mediators of the metabolic and functional improvements induced by lifestyle therapy still need to be identified. We aimed to assess the effects of various exercise therapies coupled with diet-induced weight loss on insulin secretion and sensitivity and on the levels of circulating Ciliary Neurotrophic Factor (CNTF), its receptor (CNTFRα), and Insulin-like Growth Factor-1 (IGF-1) in older adults with both obesity and frailty. METHODS: In this randomized controlled trial, we compared the effects of aerobic (AEX), resistance (REX), or combination (COMB) exercise during matched ∼10 % weight loss in 160 older adults with obesity. We compared 6-month changes in truncal fat and appendicular lean masses by dual x-ray absorptiometry; CNTF, CNTFRα, and IGF-1 levels by enzyme-linked immunosorbent assay; insulin sensitivity by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR); insulin secretion by Disposition Index (DI) during oral glucose tolerance test; and vastus lateralis muscle gene expression of CNTF and CNTFRα by quantitative polymerase chain reaction. Stepwise multiple regression analysis was employed to identify the main predictors of changes in plasma CNTF, DI, and physical function. This study also utilized additional data collected during the main trial, including Physical Performance Test (PPT) scores, muscle strength, maximal oxygen consumption (VO(2)peak), body composition by magnetic resonance imaging, and leptin and adiponectin plasma levels. RESULTS: Truncal fat mass was significantly more reduced in AEX and COMB (p = 0.001), while appendicular lean mass was better preserved in REX (p = 0.001). HOMA-IR showed more significant improvement in COMB compared to AEX and REX (p < 0.001), while DI improved significantly only in COMB compared to controls (p = 0.04). Plasma CNTF levels decreased across all intervention groups compared to controls (p < 0.001), while only COMB preserved CNTFRα plasma levels (p = 0.003) and exhibited the most significant reduction in CNTF/CNTFRα. In the vastus lateralis, CNTF and CNTFRα expression did not differ. IGF-1 improved more in REX and COMB (p = 0.004). Changes in visceral fat volume and plasma leptin explained 49.6 % of plasma CNTF variations (p < 0.009). CNTFRα changes were key predictors of DI variation, explaining 38.3 % of its variability, alongside intermuscular fat changes (p = 0.004). They also contributed 61.2 % of the variability in PPT changes, alongside intermuscular fat, muscle strength, VO(2)peak, and IGF-1 changes (p = 0.03). CONCLUSIONS: In older adults with obesity, combining aerobic and resistance exercise with diet-induced weight loss leads to the most significant improvements in metabolic and physical function, the preservation of circulating CNTFRα, and an increase in IGF-1 levels. These findings, along with identifying changes in CNTFRα as key predictors of enhanced insulin secretion and physical function and IGF-1 changes as a predictor of physical function, suggest that CNTF/CNTFRα and IGF-1 signaling may play a crucial role in mediating the health benefits associated with lifestyle therapy. NCT01065636, www. CLINICALTRIALS: gov.