Study Background and Disease Burden
Obesity represents a significant and growing public health concern worldwide, particularly among older adults. It exacerbates age-related declines in metabolic regulation and physical function, increasing the risk for frailty, type 2 diabetes mellitus, cardiovascular disease, and disability. Older adults with obesity face unique challenges due to the combined effects of excess adiposity and age-related muscle loss (sarcopenia), which accelerate functional impairments and compromise quality of life. Weight loss through caloric restriction combined with exercise interventions is widely recommended to ameliorate these complications; however, the specific effects of distinct exercise modalities—namely aerobic exercise (AEX), resistance exercise (REX), or their combination (COMB)—on insulin secretion, neurotrophic factors, and anabolic signaling in this population remain incompletely understood.
Emerging evidence indicates that metabolic improvements induced by lifestyle therapies may be mediated by factors such as Ciliary Neurotrophic Factor (CNTF) and its receptor (CNTFRα), as well as Insulin-like Growth Factor-1 (IGF-1). CNTF is a cytokine involved in neuroprotection and energy homeostasis, while IGF-1 supports anabolic processes critical for muscle health and insulin sensitivity. Determining how these mediators respond to exercise during weight loss in older adults with obesity and frailty could provide mechanistic insights to optimize therapeutic interventions.
Study Design
This randomized controlled trial enrolled 160 older adults with obesity (criteria not detailed here) and assigned them to one of four groups: aerobic exercise (AEX), resistance exercise (REX), combined aerobic and resistance exercise (COMB), or a control group undergoing only diet-induced weight loss targeting approximately 10% reduction in body weight over six months. Key assessments included changes in body composition (truncal fat and appendicular lean mass via dual x-ray absorptiometry), plasma levels of CNTF, CNTFRα, and IGF-1 measured by enzyme-linked immunosorbent assay (ELISA), and insulin sensitivity and secretion metrics assessed through Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and Disposition Index (DI) during oral glucose tolerance testing.
Additionally, muscle biopsies from vastus lateralis muscle were analyzed for gene expression levels of CNTF and CNTFRα using quantitative polymerase chain reaction. Physical function assessments encompassed the Physical Performance Test (PPT), muscle strength measurements, and maximal oxygen consumption (VO2peak). Magnetic resonance imaging (MRI) was used to quantify body composition including visceral and intermuscular fat volumes. Plasma adipokines, including leptin and adiponectin, were also measured. Stepwise multiple regression analyses identified predictors of metabolic and functional changes.
Key Findings
The intervention resulted in differential effects across exercise modalities. Both AEX and COMB groups showed significantly greater reductions in truncal fat mass compared to other groups (p=0.001), highlighting the efficacy of aerobic components in fat loss. Conversely, appendicular lean mass, representing muscle mass in limbs, was better preserved in the REX group (p=0.001), reflecting resistance training’s role in muscle maintenance during weight loss.
Insulin sensitivity, as measured by HOMA-IR, improved more significantly in the COMB group relative to AEX or REX alone (p<0.001), indicating synergistic benefits of combined exercise on insulin resistance. The Disposition Index, assessing insulin secretion adjusted for insulin sensitivity, improved significantly only in the COMB group compared to controls (p=0.04), emphasizing enhanced pancreatic β-cell function with combined exercise.
Unexpectedly, plasma CNTF levels decreased across all exercise intervention groups versus controls (p<0.001). However, only the COMB group maintained circulating levels of CNTFRα (p=0.003) and exhibited the most marked reduction in the ratio of CNTF to CNTFRα—potentially reflecting changes in ligand-receptor dynamics relevant to metabolic regulation. Notably, muscle gene expression of CNTF and CNTFRα in vastus lateralis did not differ significantly among groups, suggesting systemic rather than localized muscular regulation.
IGF-1 levels increased significantly with REX and COMB interventions (p=0.004), consistent with resistance training’s anabolic effects and combined exercise’s comprehensive benefits. Regression analyses revealed that changes in visceral fat volume and plasma leptin collectively accounted for nearly half (49.6%) of plasma CNTF variation (p<0.009), linking adiposity-related signals to CNTF modulation.
Crucially, changes in CNTFRα levels emerged as key predictors of insulin secretion improvements measured by DI, explaining 38.3% of its variability alongside intermuscular fat changes (p=0.004). Moreover, CNTFRα alterations, together with intermuscular fat, muscle strength, VO2peak, and IGF-1 changes, jointly contributed to 61.2% of the variance in physical function improvements as assessed by PPT (p=0.03). These findings support the central role of CNTFRα and IGF-1 pathways in mediating the metabolic and functional benefits of combined lifestyle interventions.
Expert Commentary
This comprehensive trial provides compelling evidence that integrating aerobic and resistance exercise with diet-induced weight loss elicits superior improvements in metabolic parameters and physical function in older adults with obesity and frailty. The preservation of circulating CNTFRα and enhancement of IGF-1 levels highlight mechanistic pathways potentially responsible for the observed benefits. While CNTF levels decreased, the relevance of the receptor’s maintenance suggests nuanced regulation rather than simple ligand concentration effects.
The lack of difference in muscle CNTF and CNTFRα gene expression suggests peripheral tissues other than skeletal muscle or systemic regulation may be critical, warranting further exploration. The strong association between adipose tissue reductions (visceral and intermuscular) and changes in neurotrophic and growth factors underscores the intricate interplay between fat depots, inflammation, and metabolic signaling.
Limitations include population specificity to older adults with obesity and frailty, which may limit generalization to younger populations or those without frailty. The study duration of six months provides valuable mid-term insights but leaves open the question of long-term sustainability. Future research should aim to confirm causality in CNTF/CNTFRα pathways and explore therapeutic potential targeting these factors.
Conclusion
Combining aerobic and resistance exercise during diet-induced weight loss offers the most robust strategy to improve insulin secretion, insulin sensitivity, and physical function in older adults with obesity. Maintenance of circulating CNTFRα and increases in IGF-1 appear to be important mechanistic links underpinning these benefits. These findings advance understanding of the biological mediators driving favorable outcomes in lifestyle therapy and support integrated exercise prescriptions to optimize health in this vulnerable population.
References
Colleluori G, Viola V, Bathina S, Armamento-Villareal R, Qualls C, Giordano A, Villareal DT. 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. Clin Nutr. 2025 Aug;51:50-62. doi: 10.1016/j.clnu.2025.05.016. Epub 2025 May 28. PMID: 40527119; PMCID: PMC12241963.
Additional literature:
– Villareal DT, et al. Weight loss and exercise in obese older adults. JAMA. 2011;306(13):1346-1354.
– Kuk JL, et al. Resistance training improves insulin sensitivity in older adults: A randomized controlled trial. Ageing Res Rev. 2020;62:101121.
– Bathina S, et al. Role of CNTF and related pathways in obesity and metabolic disease. Neurobiol Dis. 2022;167:105667.
