Our study provides novel insights into the complex relationship between BMI and mortality in patients with CRD. The findings confirm the existence of the “obesity paradox,” where higher BMI is associated with lower all-cause and non-CVD mortality. This paradox has been previously observed in various chronic diseases, including COPD15,16. The underlying mechanisms remain incompletely understood, but several hypotheses have been proposed to explain this phenomenon. One potential explanation is that individuals with higher BMI may have greater energy reserves, which could be beneficial during acute exacerbations of CRD. This is particularly relevant in the context of COPD, where exacerbations can significantly impact mortality rates. Research indicates that patients with higher BMI may possess a metabolic advantage, allowing them to better withstand the physiological stress associated with acute respiratory events17,18. Furthermore, the presence of additional adipose tissue may provide a protective effect by serving as an energy reservoir during periods of increased metabolic demand, such as during exacerbations or infections19. Additionally, obese individuals may possess a more favorable immune profile, which could contribute to their improved survival. Studies have suggested that obesity can lead to alterations in immune function, potentially enhancing the body’s ability to respond to infections and inflammatory processes20. For instance, the presence of certain adipokines, which are signaling molecules secreted by adipose tissue, may modulate immune responses and reduce the severity of inflammation associated with CRD. This immune modulation could play a critical role in the observed survival advantage among obese patients with chronic respiratory conditions. Moreover, the obesity paradox has been documented in other chronic diseases, reinforcing the notion that higher BMI may not always correlate with poorer health outcomes. This suggests that the relationship between BMI and health outcomes is complex and may be influenced by various factors, including comorbidities and the overall health status of the individual.

Our study highlights the mediating role of the TyG index in the association between BMI and mortality in patients with CRD. The TyG index, a reliable measure of insulin resistance, was found to mediate a significant proportion of the observed associations. This finding suggests that insulin resistance may be an important factor contributing to the “obesity paradox” in CRD patients, where higher BMI is paradoxically associated with lower mortality rates. Insulin resistance is characterized by elevated levels of triglycerides and glucose, which can lead to a chronic pro-inflammatory state. This pro-inflammatory state may exacerbate respiratory conditions and contribute to mortality risk, as inflammation plays a critical role in the pathophysiology of CRD21. Our results indicate that the protective effect of higher BMI may be partially explained by its association with lower insulin resistance, as measured by the TyG index. The TyG index has been shown to be a reliable biomarker for assessing insulin resistance and has been linked to various adverse health outcomes, including CVDs and metabolic disorders22,23. Elevated levels of triglycerides and glucose, which comprise the TyG index, are indicative of metabolic dysregulation and can lead to systemic inflammation, further complicating the clinical picture for patients with CRD24. Moreover, the relationship between the TyG index and mortality risk underscores the importance of metabolic health in understanding the obesity paradox. Previous studies have suggested that individuals with higher BMI may have greater energy reserves, which could be beneficial during acute exacerbations of CRD. This is particularly relevant in the context of COPD, where exacerbations can significantly impact mortality rates25. Furthermore, the presence of insulin resistance, as indicated by the TyG index, may influence the severity of respiratory conditions and the overall health status of patients, thereby affecting their mortality risk26.

Recent evidence emphasizes the heterogeneity of adipose tissue, revealing that different fat depots exert distinct metabolic effects. Epicardial adipose tissue (EAT), for example, plays a dual role; in moderate amounts, it acts as a cardioprotective metabolic buffer by storing free fatty acids and secreting anti-inflammatory adipokines like adiponectin, which can mitigate vascular inflammation and stabilize coronary arteries27. However, excessive EAT volume is associated with detrimental outcomes, such as coronary plaque progression, arrhythmias, and heart failure, primarily due to the secretion of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)28. In addition to EAT, visceral abdominal fat is strongly linked to insulin resistance and heightened cardiovascular risk, while subcutaneous fat may exhibit a neutral or even protective metabolic profile29. Our findings, grounded on BMI as a general measure of adiposity, do not differentiate between these various fat depots. However, the observed inverse association between BMI and non-CVD mortality may suggest a predominance of metabolically favorable adipose tissue—such as subcutaneous or moderate EAT—in CRD patients. This aligns with the concept of “protective fat,” wherein certain fat depots enhance energy reserves and immune modulation while reducing systemic inflammation30. For instance, subcutaneous adipose tissue may function as a benign energy reservoir during acute respiratory exacerbations, in contrast to visceral or ectopic fat, which tends to exacerbate insulin resistance and inflammatory processes. The elevated TyG index, noted in higher BMI groups yet paradoxically associated with improved survival, reflects potential metabolic adaptations in CRD patients that could mitigate some adverse effects related to adipose dysfunction.

Recent studies indicate that inflammation in adipose tissue significantly drives insulin resistance and metabolic abnormalities associated with obesity, creating a complex interrelationship that impacts CRD31. In this context, inflamed adipose tissue releases pro-inflammatory cytokines, such as TNF-α and IL-6, which impair insulin signaling in skeletal muscle and liver, leading to reduced glucose uptake and increased hepatic glucose production32. This inflammatory environment also contributes to dysfunctional adipocytes that exhibit elevated lipolytic activity, thus increasing circulating triglyceride levels and affecting TyG index33 The interaction between these metabolic changes creates a vicious cycle where increased inflammation perpetuates insulin resistance, linking obesity to heightened cardiovascular risks and metabolic dysfunction, ultimately influencing CRD progression. Our findings align with this framework, as higher BMI was associated with elevated TyG index values, yet paradoxically linked to improved survival. This suggests that in CRD patients, the benefits of energy reserves and adipokine-mediated immune modulation may outweigh the detrimental effects of adipose tissue dysfunction. However, the absence of a significant association between BMI and CVD mortality implies that the cardiometabolic risks of obesity (e.g., atherosclerosis, hypertension) may counterbalance these protective mechanisms in cardiovascular contexts.

Our findings hold significant clinical implications for the management of CRD patients. First, they emphasize the importance of considering metabolic health in the management of these patients. Given the significant role that insulin resistance, as measured by the TyG index, plays in the relationship between BMI and mortality, interventions aimed at improving insulin sensitivity may be beneficial. Lifestyle modifications, such as dietary changes and increased physical activity, have been shown to enhance insulin sensitivity and may lead to improved outcomes in patients with CRD. Additionally, pharmacological treatments that target insulin resistance, such as metformin or thiazolidinediones, could be explored as potential adjunct therapies in this population. Second, the study suggests that the traditional focus on weight reduction in obese patients with CRD may need to be reconsidered. While weight loss has been a common recommendation for managing obesity-related health issues, our findings indicate that a more nuanced approach is warranted. This approach should take into account not only BMI but also metabolic health indicators, such as the TyG index. For instance, some obese individuals may have a favorable metabolic profile and experience better health outcomes despite their weight. Therefore, clinicians should consider individual metabolic health when developing treatment plans, rather than solely focusing on weight reduction as a primary goal. Moreover, the implications of these findings extend to public health initiatives aimed at preventing and managing CRD. Strategies that promote metabolic health, such as community-based programs encouraging physical activity and healthy eating, could play a crucial role in improving the overall health of individuals at risk for or currently living with CRD. In summary, the findings of this study underscore the need for a paradigm shift in the management of patients with CRD. By prioritizing metabolic health and considering the complexities of the obesity paradox, healthcare providers can better tailor interventions to improve patient outcomes and enhance quality of life.

The strengths of this study include the use of a large, nationally representative dataset from NHANES, which allows for generalizability of the findings. Additionally, the study utilized robust statistical methods, including mediation analysis and survival analysis, to assess the associations between BMI, the TyG index, and mortality. However, there are also several limitations. The cross-sectional design of the study limits the ability to establish causality. Additionally, the study relied on self-reported data for some variables, which may introduce bias. Future longitudinal studies are needed to further explore the underlying mechanisms of the “obesity paradox” and the role of insulin resistance in CRD patients.