Effect of aerobic or resistance exercise, or both on insulin secretion, ciliary neurotrophic factor, and insulin-like growth factor-1 in dieting older adults with obesity

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 (CNTFR alpha), 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 similar to 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, CNTFR alpha, 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 CNTFR alpha 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 CNTFR alpha plasma levels (p = 0.003) and exhibited the most significant reduction in CNTF/CNTFR alpha. In the vastus lateralis, CNTF and CNTFR alpha 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). CNTFR alpha 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 CNTFR alpha, and an increase in IGF-1 levels. These findings, along with identifying changes in CNTFR alpha as key predictors of enhanced insulin secretion and physical function and IGF-1 changes as a predictor of physical function, suggest that CNTF/CNTFR alpha and IGF-1 signaling may play a crucial role in mediating the health benefits associated with lifestyle therapy. NCT01065636, www.Clinicaltrials: gov. (c) 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).