Abstract
Asthma is a heterogeneous condition influenced by multiple clinical and biological factors, and obesity has emerged as a major modifier that worsens symptoms and increases the risk of exacerbations. This review aimed to examine the mechanisms by which obesity contributes to reduced responsiveness to corticosteroids, which remain the cornerstone of guideline-based asthma management. We reviewed evidence from clinical and experimental studies describing how adipose tissue dysfunction, chronic low-grade inflammation, oxidative stress, and systemic comorbidities alter glucocorticoid receptor signalling and downstream pathways. Particular attention was given to immune mechanisms such as neutrophilic inflammation and interleukin-17 signalling, as well as metabolic disturbances including hyperleptinaemia and vitamin D deficiency. We also considered the role of lifestyle factors, such as physical inactivity and dietary patterns, in sustaining corticosteroid insensitivity. Based on these insights, we evaluated both established and emerging therapeutic strategies, including weight loss, structured exercise, dietary modification, and drug repurposing with agents such as metformin, low-dose theophylline, and glucagon-like peptide-1 receptor agonists. A comprehensive synthesis of these findings highlights the need for integrated lifestyle and pharmacological interventions, and provides a framework for the development of targeted treatments to improve outcomes in patients with obesity-associated, corticosteroid-insensitive asthma.
1 Introduction
Asthma is a heterogeneous disease characterised by diverse clinical manifestations, inflammatory profiles, and responses to treatment. Among the factors influencing its pathophysiology, obesity has been recognised as a significant contributor to adverse outcomes. Patients with asthma and obesity are at higher risk of acute exacerbations, experience more severe symptoms, and are more likely to require ventilatory support (1–5). Although the epidemiological association between obesity and poor asthma outcomes is well established, the underlying mechanisms remain only partly understood.
Currently, at least two distinct phenotypes have been identified among patients with asthma and obesity (6, 7). The first is a late-onset, non–type 2 phenotype, which is more prevalent in women and is characterised by pronounced oxidative stress. In this phenotype, adipose tissue–derived cytokines and oxidative stress contribute to airway inflammation. Obesity-related alterations in autonomic nervous system function, particularly increased parasympathetic tone, also promote airway narrowing (7). Weight loss in these patients can lead to substantial improvement in asthma control (8). Because the pathophysiological changes driven by obesity appear to directly induce asthma in this group, it has been described as “asthma consequent to obesity.” The second phenotype is early-onset, with elevated immunoglobulin E (IgE) levels and prominent type 2 inflammation (7). This phenotype is interpreted as typical allergic asthma whose disease course is modified by the presence of obesity, and is therefore termed “asthma complicated by obesity.” Although obesity has been reported to amplify eosinophilic inflammation, the precise mechanisms underlying asthma worsening in this phenotype remain incompletely understood (9).
A particularly concerning feature of obesity-associated asthma is the reduced responsiveness to inhaled corticosteroids (ICS), which are a cornerstone of guideline-based asthma management. Reduced corticosteroid responsiveness leads to more frequent exacerbations, often necessitating the use of systemic corticosteroids. The use of systemic corticosteroids can, in turn, contribute to further weight gain and metabolic dysfunction, thereby reinforcing a vicious cycle of poor asthma control and progressive obesity. A clearer mechanistic understanding of corticosteroid resistance in patients with asthma and obesity is crucial for breaking this cycle and developing more effective therapeutic strategies.
In this review, we examine the mechanisms by which obesity may reduce corticosteroid sensitivity in asthma. We first outline obesity-related changes in adipose tissue biology and their potential effects on corticosteroid sensitivity. We then discuss cellular, molecular, and systemic pathways proposed to contribute to corticosteroid insensitivity in patients with asthma and obesity. Finally, we highlight emerging therapeutic approaches aimed at restoring corticosteroid sensitivity and improving clinical outcomes in patients with asthma associated with obesity.
2 Corticosteroid resistance in obese asthma: clinical data
Reduced responsiveness to corticosteroid therapy in patients with asthma and obesity has been demonstrated in multiple clinical studies. In a clinical trial involving 3,073 adults with moderate asthma, the response to inhaled beclomethasone decreased with increasing body mass index (BMI), whereas the response to montelukast was observed irrespective of BMI (10). Similarly, a study of 72 patients with mild to moderate persistent asthma reported that overweight individuals exhibited attenuated symptom improvement and reduced fractional exhaled nitric oxide responses to inhaled budesonide compared with normal-weight patients (11). Another study enrolled 1,242 corticosteroid-naïve patients with moderate asthma and evaluated asthma control following treatment with either fluticasone alone or a combination of fluticasone and salmeterol. While the combination therapy was effective overall, obese patients were significantly less likely than non-obese patients to achieve adequate asthma control with either treatment regimen (12). To et al. further assessed corticosteroid sensitivity using peripheral blood mononuclear cells (PBMCs) from patients with asthma and demonstrated that individuals with excessive body fat exhibited significantly reduced corticosteroid sensitivity compared with controls (13). These clinical findings highlight consistent evidence that obesity is linked to impaired corticosteroid responsiveness in asthma, providing a strong foundation for investigating the underlying mechanisms and developing targeted interventions.
3 Overview of factors linking pathogenic changes in obese adipose tissue and corticosteroid insensitivity
Adipose tissue plays a fundamental role in maintaining energy homeostasis. Under conditions of energy surplus, adipocytes store excess nutrients as triglycerides, whereas during fasting or starvation, they release fatty acids to meet systemic energy demands. Once regarded as a passive energy reservoir, adipose tissue is now recognised as an active endocrine and immunological system that influences distant organs through the secretion of adipokines, cytokines, and metabolic mediators.
As obesity develops, adipocytes undergo marked hypertrophy due to triglyceride accumulation. This expansion increases lipid droplet size disproportionately relative to cytoplasmic volume, placing mechanical stress on the plasma membrane and straining intracellular organelles such as mitochondria and the endoplasmic reticulum (14–16). These biomechanical and metabolic stresses induce local hypoxia and endoplasmic reticulum stress (17), which alter adipokine production and create an inflammatory microenvironment (18, 19). This inflammatory state is further intensified by a phenotypic shift of resident macrophages from anti-inflammatory M2 to pro-inflammatory M1 phenotypes (20, 21). M1 macrophages secrete cytokines such as interleukin (IL)-1β, IL-6, and tumour necrosis factor-alpha (TNF-α), thereby amplifying local inflammation. The inflammation within adipose tissue exerts systemic effects that contribute to the development of obesity-related complications (22).
In addition to promoting inflammation, adipocyte dysfunction in obesity induces pronounced oxidative stress (23). This arises through several interrelated mechanisms within adipose tissue. Elevated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity enhances the production of reactive oxygen species (ROS) (23). Excessive mitochondrial fatty acid oxidation further contributes to ROS accumulation. At the same time, the expression of key antioxidant enzymes—such as superoxide dismutase and catalase—is reduced (23), thereby diminishing the cell's capacity to counteract oxidative damage. These processes establish a pro-oxidant environment that disrupts adipocyte homeostasis. Importantly, increased oxidative stress is observed in individuals with obesity even in the absence of external factors such as cigarette smoking, affecting both adipose tissue and the systemic circulation (23–26).
Several of these alterations in the adipose tissue environment are thought to impair corticosteroid sensitivity. For example, increased oxidative stress and elevated pro-inflammatory cytokines can diminish glucocorticoid receptor (GR) function. Obesity-related oxidative stress can also suppress key regulatory molecules of corticosteroid sensitivity including phosphoinositide 3-kinase (PI3K) and histone deacetylase 2 (HDAC2) (27). Although direct evidence linking obesity-related factors to regulatory molecules of corticosteroid sensitivity remains limited, obesity-induced changes provide a plausible mechanistic link between adipose tissue dysfunction and corticosteroid resistance in asthma.
4 Molecular and cellular mechanisms of corticosteroid insensitivity in obese asthma
4.1 Glucocorticoid receptor alterations
GRs, the primary binding sites for corticosteroids, exist in multiple isoforms with distinct functions. Among these, GRα is the transcriptionally active form and mediates the classical anti-inflammatory actions of corticosteroids. In contrast, GRβ lacks transcriptional activity and acts as a dominant negative inhibitor of GRα (28). An increased GRβ/GRα ratio has been implicated in the development of corticosteroid insensitivity, and obesity has been reported to be associated with an increased GRβ/GRα ratio (29). One study demonstrated lower GRα expression in obese patients with asthma compared with their non-obese counterparts (30), suggesting a potential link between GR isoform imbalance and reduced corticosteroid responsiveness in this population.
4.2 Modification of intracellular signalling pathways
4.2.1 Oxidative stress–related modification of phosphoinositide 3-kinase–Akt and mitogen-activated protein kinase signalling
The PI3K signalling pathway has been widely implicated in the pathogenesis of corticosteroid insensitivity (31–34). Oxidative stress is a key upstream regulator of this pathway. Increased oxidative stress disrupts cell membrane integrity, subsequently activating the PI3K–AKT pathway (32, 35). Once activated, this pathway phosphorylates (HDAC2, inhibiting its enzymatic activity (36). When the glucocorticoid–GR complex translocates into the nucleus, HDAC2 is recruited to suppress pro-inflammatory transcription factors such as NF-κB, thereby attenuating inflammation (37). However, when HDAC2 activity is reduced, GR deacetylation is impaired, diminishing its capacity to repress pro-inflammatory gene transcription. In parallel, oxidative stress activates the mitogen-activated protein kinase (MAPK) pathway. Activation of MAPKs, particularly p38α, p38γ, and JNK1, results in phosphorylation of GRα at sites such as Ser226, which interferes with nuclear translocation and reduces transcriptional repression (35). This mechanism further contributes to corticosteroid insensitivity.
Clinical studies have shown that patients with asthma and obesity exhibit higher systemic oxidative stress compared with non-obese patients (13, 24, 25, 38–40). Notably, in obese patients with asthma, oxidative stress levels correlate with acute exacerbation frequency, whereas no such association has been observed in non-obese patients (39). Moreover, elevated oxidative stress has been associated with reduced corticosteroid sensitivity in obese patients with asthma (13). Although direct evidence implicating obesity-induced PI3K or MAPK activation in corticosteroid insensitivity is not yet available, existing findings strongly suggest that these pathways play a contributory role.
4.2.2 Adenosine monophosphate–activated protein kinase–sirtuin 1 axis
Adenosine monophosphate-activated protein kinase (AMPK) is a ubiquitously expressed serine/threonine kinase in eukaryotes that functions as a key intracellular energy sensor (41). It has also been implicated in oxidative stress tolerance and longevity (42, 43). Sirtuin 1 (SIRT1) is a oxidized form of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that regulates diverse cellular processes, including metabolism, inflammation, and ageing. AMPK and SIRT1 interact bidirectionally. Activation of AMPK increases the intracellular NAD+/reduced form of nicotinamide adenine dinucleotide (NADH) ratio, thereby activating SIRT1 (44). Conversely, SIRT1 activates AMPK by deacetylating lysine residues on an upstream kinase in the AMPK pathway (45).
In obesity, AMPK activity is reduced in adipose tissue (46) due to enhanced inflammation and oxidative stress in hypertrophied adipose tissue. This phenomenon extends to multiple organ systems: studies comparing AMPK activity in PBMCs between obese and non-obese individuals demonstrated lower activity in the obese group (47, 48). Similar reductions in SIRT1 expression have been observed in adipose tissue and PBMCs of obese individuals due to enhanced inflammation and oxidative stress in hypertrophied adipose tissue (49–51). Importantly, dietary weight loss has been shown to restore SIRT1 levels (52), indicating that obesity modulates its expression.
Both AMPK and SIRT1 have been implicated in corticosteroid insensitivity. In patients with chronic obstructive pulmonary disease (COPD), reduced SIRT1 expression in immune cells correlates with diminished corticosteroid sensitivity (53). Furthermore, Mitani et al. reported that PBMCs from patients with COPD exhibited steroid insensitivity, which was reversed upon exposure to an AMPK activator (54), supporting a mechanistic link between AMPK and corticosteroid sensitivity. Collectively, these findings suggest that reduced AMPK and SIRT1 activity in patients with asthma and obesity may contribute to impaired corticosteroid responsiveness.
4.3 Potential roles of inflammatory cells and cytokines in corticosteroid insensitivity
4.3.1 Neutrophilic inflammation
In adults with late-onset obesity-related asthma, non–type 2 inflammation is frequently predominant. Sputum analyses have shown increased neutrophil counts in obese patients with asthma compared with non-obese patients (55, 56). Adipose tissue-derived adipocytokines, including IL-6, plasminogen activator inhibitor-1 (PAI-1), TNF-α, and leptin, can modulate airway epithelial and immune cell activation, thereby amplifying airway inflammation (57, 58). These mediators mainly drive non–type 2 inflammation, particularly neutrophilic inflammation. Since neutrophilic inflammation is widely recognised as poorly responsive to corticosteroids, this profile may be associated with corticosteroid insensitivity.
4.3.2 Interleukin-17
Interleukin-17 (IL-17) is a key mediator of neutrophilic inflammation. In severe asthma, IL-17 has been implicated in corticosteroid insensitivity (59). In obesity, Th17 cells are increased, leading to elevated circulating IL-17 levels (60). Consistently, obese patients with asthma have shown increased expression of NLRP3 in sputum cells, along with higher IL-1β and IL-17 levels (61, 62).
IL-17 may promote corticosteroid insensitivity through several mechanisms. First, IL-17–driven neutrophilic inflammation creates a steroid-unresponsive inflammatory milieu. Second, IL-17 has been reported to directly induce GRβ expression in airway epithelial cells, thereby conferring corticosteroid insensitivity (63).
4.3.3 Leptin
Leptin, an adipose-derived hormone that centrally regulates body weight, is elevated in peripheral blood in obesity due to reduced central leptin sensitivity. Peripheral leptin sensitivity, however, is preserved in tissues including immune cells (64). Consequently, elevated circulating leptin exerts multiple immunomodulatory effects in obese individuals. Leptin has been shown to activate the PI3K pathway (65). and enhance oxidative bursts in human monocytes (66). Although no clinical studies have directly demonstrated that obesity-related hyperleptinaemia induces corticosteroid insensitivity, both PI3K activation and oxidative stress are recognised contributors, suggesting that leptin may promote corticosteroid insensitivity through these mechanisms.
Leptin also has promoted Th17 cell activation (67, 68).leading to enhanced IL-17 signalling. Since IL-17 drives neutrophilic inflammation and induces GRβ expression in airway epithelial cells (64) leptin-mediated Th17/IL-17 activation may exacerbate corticosteroid insensitivity by combining inflammatory amplification with dysregulated GR expression.
5 Systemic modulators of corticosteroid resistance in obese asthma
5.1 Obstructive sleep apnoea syndrome
Obstructive sleep apnoea syndrome (OSAS) is characterised by recurrent upper airway obstruction during sleep, resulting in brief episodes of apnoea or hypopnoea. These events are accompanied by cycles of hypoxaemia and reoxygenation, persistent inspiratory effort against the occluded airway, and frequent sleep fragmentation. Obesity is a major risk factor for the development of OSAS. The prevalence of OSAS was reported to be markedly higher in obese individuals than in those of normal weight (69). Recent epidemiological data indicated that approximately 70% of obese adults (BMI ≥ 30 kg/m2) were diagnosed with OSAS (70). In OSAS, repetitive cycles of hypoxia and reoxygenation increase systemic oxidative stress (71, 72). This heightened oxidative stress is thought to contribute to corticosteroid insensitivity. Supporting this, ex vivo analyses of samples from patients with OSAS demonstrated associations between elevated oxidative stress, reduced HDAC2 expression, and corticosteroid resistance in patients with OSAS and asthma (73). Moreover, chronic intermittent hypoxia, a hallmark of OSAS, has been reported to activate the p38 MAPK signalling pathway, thereby promoting corticosteroid insensitivity (74). In addition, frequent sleep fragmentation disrupts the normal circadian rhythm of corticosterone, abolishing the typical early-morning peak and nocturnal trough, and significantly increasing circulating corticosterone levels (75). This alteration may downregulate GRs.
Taken together, these findings suggest that, in patients with OSAS, not only coexisting obesity but also OSAS-specific mechanisms promote corticosteroid resistance. Supporting this notion, an observational study reported a higher frequency of severe asthma exacerbations in patients with asthma and concomitant OSAS (76), likely reflecting the impact of these mechanisms.
5.2 Metabolic dysfunction–associated steatotic liver disease
Metabolic dysfunction–associated steatotic liver disease (MASLD), formerly referred to as non-alcoholic fatty liver disease (NAFLD), is characterised by excessive mitochondrial ROS production in hepatocytes, driven by lipid overload–induced β-oxidation and overactivation of the electron transport chain. This process is accompanied by insulin resistance and chronic inflammation (77). Systemic oxidative stress is also elevated in MASLD (77). Although no data are currently available on oxidative stress within the airways of patients with MASLD, systemic oxidative stress resulting from hepatocyte mitochondrial ROS overproduction may promote corticosteroid insensitivity.
5.3 Impaired antiviral immunity
Viral infections may contribute to reduced corticosteroid sensitivity. Respiratory syncytial virus (RSV), rhinovirus, and influenza virus infections have been shown to impair the anti-inflammatory effects of corticosteroids via induction of transforming growth factor-β (78). Another study demonstrated that rhinovirus type 16 activated NF-κB and c-Jun N-terminal kinase (JNK) signalling in airway epithelial cells, leading to corticosteroid insensitivity (79).
Obesity has been associated with altered immune responses to viral infections (80). For instance, influenza vaccine antibody titres declined significantly, and CD8+ T-cell responses were impaired in obese individuals compared with those of healthy weight (81). In a prospective study of 1,022 vaccinated adults, the risk of developing influenza was approximately twice as high in obese individuals as in non-obese individuals (82). Obesity-associated impairment of antiviral immunity may therefore increase susceptibility to recurrent viral infections, potentially contributing to corticosteroid insensitivity.
5.4 Vitamin D deficiency
Vitamin D has been implicated in the activity of various chronic diseases. In asthma, a study of 280 adults demonstrated that serum 25-hydroxyvitamin D concentrations were significantly related to both asthma severity and control (83). The prevalence of vitamin D deficiency was highest among patients with severe, poorly controlled asthma (83). Furthermore, a meta-analysis of clinical trials found that vitamin D supplementation reduced the incidence of asthma exacerbations (84). Regarding corticosteroid sensitivity, vitamin D concentrations have been directly associated with corticosteroid sensitivity, measured by dexamethasone-induced mitogen-activated protein kinase phosphatase 1 (MKP-1) inductions (85). Particularly in patients not using ICS, a dose-response relationship was observed, with MKP-1 induction increasing by 0.05-fold per 1 ng/mL rise in vitamin D levels (85).
Obesity has been linked to reduced serum vitamin D concentrations (86, 87) Additionally, obese individuals have shown poor responsiveness to vitamin D supplementation (86). Obesity-associated vitamin D insufficiency is likely due to reduced bioavailability from cutaneous and dietary sources as a result of sequestration in adipose tissue (86). Collectively, these findings suggest that obesity-related vitamin D deficiency may contribute to impaired corticosteroid sensitivity in obese patients with asthma.
5.5 Modification of corticosteroid pharmacokinetics
Altered corticosteroid pharmacokinetics have also been reported in obesity. In obese patients receiving oral prednisolone, reduced gastrointestinal absorption and increased systemic clearance of prednisolone were observed (88). When oral corticosteroid therapy is required, these pharmacokinetic changes may contribute to the apparent reduction in corticosteroid sensitivity.
6 Lifestyle factors contributing to corticosteroid resistance in obese asthma
6.1 Advanced glycation end products
Hyperglycaemia and obesity promote protein glycation, ultimately leading to the formation of advanced glycation end products (AGEs). AGEs possess both pro-inflammatory properties and the capacity to induce cell death (89, 90). A study demonstrated that human THP-1 macrophage-like cells stimulated with dietary AGEs exhibited reduced corticosteroid sensitivity compared with those stimulated with lipopolysaccharides. This finding suggests that AGE-induced inflammation contributes to corticosteroid insensitivity (91). It was further suggested that AGEs have increased intracellular ROS, which contributes to the development of corticosteroid insensitivity (91). Dietary patterns characteristic of obesity, such as high-fat and high-sugar intake, and obesity-related metabolic abnormalities, such as hyperglycaemia, and ageing are known to accelerate AGE accumulation. The increased AGE levels associated with obesity may therefore contribute to diminished corticosteroid responsiveness.
6.2 Physical inactivity
Several studies have demonstrated the beneficial effects of exercise on asthma control (92, 93). Adults with asthma who lacked regular exercise habits were enrolled in a controlled trial comparing supervised exercise (three sessions weekly) with standard care. Patients in the exercise group achieved a 24% reduction in maintenance inhaled corticosteroid dose regardless of baseline BMI, whilst the control group showed no reduction in ICS requirements (94). Experimental evidence has supported exercise-induced antioxidant responses; treadmill exercise in COPD models increased pulmonary Nrf2 expression, suggesting enhanced antioxidant pathway activation (95). A review of exercise effects on human PBMCs reported that appropriate exercise enhanced their antioxidant capacity (96).
Direct evidence linking exercise to improved corticosteroid sensitivity in human airways or immune cells remains limited. However, extensive research confirms exercise-mediated reductions in oxidative stress. This pathway likely underlies exercise-induced improvements in corticosteroid sensitivity. Physical inactivity, commonly observed in obese individuals, may therefore contribute to reduced corticosteroid responsiveness in this population.
7 Therapeutic perspectives to restore corticosteroid sensitivity in obese asthma
7.1 Lifestyle modification in obese individuals: weight reduction, dietary intervention, and exercise
Weight reduction is the most critical intervention in the treatment of obesity-related diseases, and obesity-related asthma is no exception. Numerous studies have demonstrated that weight loss leads to improved asthma control in obese asthma. Direct evidence also showed that weight reduction restored corticosteroid sensitivity: patients with obesity and asthma underwent bariatric surgery, and PBMCs were collected before and after surgery to assess corticosteroid sensitivity (97). A significant improvement in corticosteroid sensitivity in PBMCs was observed after surgery (97). This finding suggests that weight loss can restore obesity-related corticosteroid insensitivity. Therefore, weight reduction should be considered the primary therapeutic approach whenever feasible.
Dietary interventions not only contribute to weight reduction but may also directly improve corticosteroid sensitivity. Avoiding excessive carbohydrate intake can suppress the production of AGEs, thereby potentially preventing AGE-induced corticosteroid insensitivity (91). Exercise interventions have been reported to exert benefits beyond weight loss, directly improving asthma control. In patients with asthma, exercise was shown to reduce the required dose of ICS and to attenuate oxidative stress, irrespective of BMI (95, 96). Reduction in oxidative stress is expected to enhance corticosteroid sensitivity. Thus, exercise is recommended as an adjunctive therapy.
Patients with obesity-related asthma are also more likely to present with obesity-related comorbidities. These comorbidities contribute to both asthma severity and corticosteroid insensitivity, highlighting the importance of their appropriate management. In particular, the management of OSAS is of critical importance. Treatment of OSAS can reduce oxidative stress, potentially restoring corticosteroid sensitivity. Moreover, continuous positive airway pressure (CPAP) therapy for OSAS was shown to increase the GRα/GRβ ratio (98). GRα is essential for glucocorticoid action, whereas GRβ acts as a dominant-negative inhibitor of GRα-mediated transactivation. Thus, improvement in this ratio may also enhance corticosteroid sensitivity.
7.2 Pharmacological approaches
In the management of patients with asthma and obesity, standard asthma therapy, primarily ICS, should first be initiated in parallel with the non-pharmacological interventions described above. This approach achieves improved asthma control in a subset of patients. However, a substantial proportion of patients either fail to respond adequately to this treatment or are unable to achieve meaningful weight reduction. In such cases, treatment decisions should be guided by whether type 2 inflammation is present. When type 2 inflammatory features are identified, the use of biologic agents should be considered. Biologics have been reported to be effective in patients with obese asthma who meet established eligibility criteria (99–102). By contrast, pharmacological options for patients with a predominance of non–type 2 inflammation remain extremely limited, particularly those capable of restoring obesity-related corticosteroid insensitivity. The development of drugs specifically targeting this pathophysiology is therefore urgently needed.
7.2.1 Suppression of oxidative stress
In individuals with obesity, systemic oxidative stress derived from adipose tissue contributes to the progression of various obesity-related diseases. In an obese mouse model, pharmacological blockade of oxidative stress within adipose tissue suppressed ectopic fat accumulation and ameliorated MASLD (103). A similar mechanism may underlie improvements in airway inflammation and corticosteroid resistance in obesity-related asthma. However, the development of antioxidant drugs for airway diseases characterised by increased oxidative stress—irrespective of obesity status—remains far from clinical application.
Within this context, drug repositioning potentially offers a promising strategy. To et al. demonstrated that PBMCs from asthma patients with a high body fat percentage exhibited reduced corticosteroid sensitivity compared with those from patients with a normal body fat percentage (13). When cultured in the presence of metformin, these PBMCs showed restored corticosteroid sensitivity accompanied by a reduction in oxidative stress markers in the supernatant (13). This effect was not observed in PBMCs from patients with normal body fat percentage. This finding suggests that metformin restores corticosteroid sensitivity by suppressing oxidative stress (104–107). Given that metformin is already widely used for the treatment of diabetes and has a well-established safety profile, it may represent a promising candidate for repurposing as a therapeutic agent for obesity-related asthma.
7.2.2 Potential of phosphoinositide 3-kinase δ-specific inhibition
Oxidative stress plays a central role in the pathophysiology of obesity-associated asthma. In addition to directly suppressing oxidative stress, blocking downstream pathways through which oxidative stress impairs corticosteroid sensitivity represents a potential therapeutic strategy. Oxidative stress initially activates the PI3K–AKT pathway (32, 35), which in turn phosphorylates HDAC2, leading to reduced enzymatic activity and consequent impairment of corticosteroid sensitivity (36). Within this pathway, PI3Kδ has been identified as a key protein. In a smoke-induced inflammatory model, PI3Kδ inhibition restored corticosteroid function, providing evidence that the PI3Kδ pathway is pivotal in driving corticosteroid insensitivity (31). PI3Kδ-selective inhibitors are currently under development for other diseases, and their future application to obesity-associated asthma warrants consideration.
Among existing drugs, low-dose theophylline has attracted attention for its potential to restore corticosteroid sensitivity. Low-dose theophylline selectively inhibited oxidative stress–induced activation of PI3Kδ, thereby restoring HDAC2 activity and improving corticosteroid sensitivity (32, 108). This effect occurred at concentrations around 1 μM, which were too low to elicit phosphodiesterase inhibition or adenosine receptor antagonism. In humans, the optimal therapeutic range has been proposed to be at plasma concentrations below 5–10 mg/L (109), where neither bronchodilator nor adenosine antagonistic effects occur. Thus, low-dose theophylline may offer a promising and safe therapeutic option for improving corticosteroid sensitivity in obesity-associated asthma.
7.2.3 Potential of leptin antagonism
Hyperleptinaemia may contribute to reduced corticosteroid sensitivity (65–68). Consequently, controlling elevated leptin levels could potentially improve corticosteroid sensitivity. Research on the control of hyperleptinaemia has been conducted primarily in the context of therapies for obesity-related disorders. These studies focus on two main strategies: enhancing central leptin sensitivity and antagonising peripheral leptin activity (110). However, these approaches remain at an early investigational stage and are far from clinical application.
7.3 Metformin as a potential therapeutic agent
Metformin is widely used as an antidiabetic agent and is known to exert diverse pharmacological effects beyond glycaemic control (111). Several studies have suggested a potential benefit of metformin in asthma management. In a retrospective study of adolescents and young adults aged 12–21 years with asthma, those receiving metformin experienced fewer exacerbations compared with BMI-matched individuals not receiving the drug (112). Similarly, in patients with asthma and comorbid diabetes, metformin use was associated with a reduced risk of asthma exacerbations (113–115).
Although these clinical studies did not specifically evaluate the relationship between metformin and corticosteroid sensitivity, its known ability to activate AMPK and attenuate oxidative stress suggests a potential role in restoring obesity-associated reductions in corticosteroid sensitivity. Supporting this hypothesis, an ex vivo study demonstrated that metformin restored corticosteroid sensitivity (13). Clinical trials are warranted to investigate whether metformin can improve corticosteroid sensitivity in patients with obesity-related asthma.
7.4 Other considerations
Serum vitamin D levels are frequently reduced in individuals with obesity (86, 87). Vitamin D deficiency has also been linked to asthma exacerbations and reduced corticosteroid sensitivity. Therefore, in obese patients, it may be important to assess serum vitamin D levels and consider supplementation when appropriate.
Glucagon-like peptide-1 (GLP-1) receptor agonists, which are approved for the treatment of diabetes and obesity, exert pleiotropic effects across various organs beyond their metabolic actions (116). GLP-1 has been reported to modulate advanced glycation end product (AGE)–receptor for AGE (RAGE) interactions (117), thereby suppressing inflammation. Characteristic dietary patterns in obesity increase AGE accumulation, and excess AGEs have been implicated in impaired corticosteroid sensitivity through mechanisms involving oxidative stress. Consequently, GLP-1 receptor agonists may improve corticosteroid sensitivity by inhibiting AGE–RAGE interactions and blocking downstream AGE-related signalling pathways.
8 Conclusion and future directions
Obesity-associated asthma represents a complex clinical entity characterised by impaired corticosteroid sensitivity, increased risk of exacerbations, and poorer disease control. Among these features, reduced corticosteroid sensitivity plays a pivotal role in worsening the disease. Corticosteroid insensitivity leads to more frequent exacerbations, often necessitating systemic corticosteroid use. This treatment, in turn, promotes further weight gain and metabolic dysfunction, perpetuating a vicious cycle of poor asthma control and progressive obesity. Multiple obesity-related factors contribute to this pathophysiology. Increasing evidence implicates adipose tissue-derived adipocytokines, oxidative stress, dysregulated immune responses, and obesity-associated systemic comorbidities and lifestyle factors in the development of corticosteroid insensitivity (Figure 1).
Figure 1
Potential mechanisms underlying the association between obesity-related factors and steroid insensitivity in obese asthma. Adipose tissue hypertrophy in obesity is characterised by increased oxidative stress and the upregulation of pro-inflammatory cytokines. These changes induce attenuated AMPK and SIRT1 expression and activity, a reduced GRα/GRβ ratio, elevated Th17/IL-17 responses, increased leptin secretion, and enhanced systemic oxidative stress. These alterations interact to promote neutrophilic inflammation and to modify multiple intracellular signalling pathways, ultimately leading to the development of steroid insensitivity. In addition, obesity-related comorbidities, lifestyle factors, and other systemic conditions further exacerbate the establishment of steroid-insensitive asthma. AMPK, adenosine monophosphate-activated protein kinase; SIRT1, sirtuin 1; GR, glucocorticoid receptor; Th17, T helper 17; IL-17, interleukin-17; PI3K, phosphoinositide 3-kinase; MAPK, mitogen-activated protein kinase; HDAC2, histone deacetylase 2; OSAS, obstructive sleep apnoea syndrome; MASLD, metabolic dysfunction–associated steatotic liver disease; AGEs, advanced glycation end-products.
Therapeutic strategies must therefore extend beyond standard asthma pharmacotherapy. Lifestyle interventions, including weight loss, structured exercise, and dietary modification, are central to management and can improve both asthma control and corticosteroid responsiveness (Table 1). However, their effects are often limited, highlighting the urgent need for targeted pharmacological approaches. Potential avenues include agents that suppress oxidative stress or selective PI3Kδ inhibitors, although these remain distant from clinical application. Drug-repurposing candidates such as low-dose theophylline, metformin, and GLP-1 receptor agonists are of particular interest given their well-established safety profiles and mechanistic potential. These agents may represent promising options for translation into clinical practice through drug repurposing in the management of obesity-related asthma (Table 1).
Table 1
| Therapeutic approach | Primary mechanism(s) targeted | Effect on corticosteroid sensitivity | Evidence level | Clinical applicability |
|---|---|---|---|---|
| Lifestyle modifications | ||||
| Weight reduction (including bariatric surgery) |
|
Direct restoration of corticosteroid sensitivity in PBMCs demonstrated post-bariatric surgery (97) | Clinical evidence | First-line intervention; feasible when possible |
| Dietary intervention (carbohydrate restriction) |
|
Prevents AGE-induced corticosteroid insensitivity (91) | Mechanistic evidence | Adjunctive therapy; contributes to weight loss |
| Exercise |
|
Attenuates oxidative stress, reduces ICS dose requirement (94–96) | Clinical evidence | Recommended adjunctive therapy; benefits independent of weight loss |
| Comorbidity management | ||||
| Obstructive sleep apnoea syndrome |
|
Enhances corticosteroid sensitivity through improved GR signalling and reduced oxidative stress | Clinical evidence | Critical in obese asthma patients with OSAS |
| Standard therapy | ||||
| Inhaled corticosteroids |
|
Variable response; may be ineffective in obesity-related corticosteroid resistance | Standard practice | First-line pharmacotherapy with lifestyle interventions |
| Biologic agents |
|
Effective in obese asthma with type 2 inflammation (99–102) | Clinical evidence | For type 2 inflammation-predominant obese asthma |
| Targeting oxidative stress | ||||
| Metformin | Restores corticosteroid sensitivity in PBMCs from high body fat percentage patients (13) | Ex vivo evidence | Promising repurposing candidate; established safety profile; clinical trials warranted | |
| Restores corticosteroid sensitivity by activation of AMPK (54) | ||||
| Targeting PI3K-AKT-HDAC2 pathway | ||||
| PI3Kδ-specific inhibitors |
|
Restores corticosteroid function in smoke-induced inflammation model (31) | Preclinical evidence | Under development; future application warranted |
| Low-dose theophylline | Improves corticosteroid sensitivity at plasma concentrations <5–10 mg/L (109) | Mechanistic evidence | Promising and safe option; requires clinical validation in obese asthma | |
| Targeting leptin | ||||
| Leptin antagonism | Potential improvement in corticosteroid sensitivity | Early investigational | Far from clinical application | |
| Other considerations | ||||
| Vitamin D supplementation | May improve corticosteroid sensitivity and reduce exacerbations | Clinical evidence | Consider assessment and supplementation in obese patients | |
| GLP-1 receptor agonists |
|
May improve corticosteroid sensitivity through AGE pathway inhibition | Mechanistic hypothesis | Approved for diabetes/obesity; potential benefit in obese asthma |
Therapeutic options for restoring corticosteroid sensitivity in obese asthma.
AGE, advanced glycation end product; AMPK, adenosine monophosphate-activated protein kinase; GLP-1, Glucagon-like peptide-1; GR, glucocorticoid receptor; HDAC2, histone deacetylase 2; ICS, inhaled corticosteroids; OSAS, obstructive sleep apnoea syndrome; PBMCs, peripheral blood mononuclear cells; PI3 K, phosphoinositide 3-kinase; RAGE, receptor for AGE.
Future research should prioritise elucidating the causal pathways underlying corticosteroid insensitivity through mechanistic studies, thereby guiding the rational development of targeted therapies. Given the availability of several drug-repositioning candidates, early clinical investigations of these agents are strongly warranted to accelerate progress towards effective therapies for this challenging phenotype.
Statements
Author contributions
MT: Data curation, Validation, Conceptualization, Writing – review & editing, Investigation, Writing – original draft, Funding acquisition, Visualization. YT: Conceptualization, Writing – review & editing.
Funding
The author(s) declare financial support was received for the research and/or publication of this article. Financial support was provided by JSPS KAKENHI (Grant Number 20K08546).
Conflict of interest
YT has received lecture fees from Novartis Pharma, GlaxoSmithKline, AstraZeneca, and Sanofi. However, they are unrelated to the current study.
The remaining author declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that Generative AI was used in the creation of this manuscript. The authors acknowledge the use of ChatGPT (chat.openai.com) solely to assist with English language editing of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
AGE, advanced glycation end product; AMPK, adenosine monophosphate-activated protein kinase; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CPAP, continuous positive airway pressure; GLP-1, glucagon-like peptide-1; GR, glucocorticoid receptor; HDAC2, histone deacetylase 2; ICS, inhaled corticosteroids; IgE, immunoglobulin E; IL, interleukin; JNK, c-Jun N-terminal kinase; MASLD, metabolic dysfunction–associated steatotic liver disease; MAPK, mitogen-activated protein kinase; MKP-1, mitogen-activated protein kinase phosphatase 1; NAD+, oxidized form of nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; NAFLD, non-alcoholic fatty liver disease; OSAS, obstructive sleep apnoea syndrome; PAI-1, plasminogen activator inhibitor-1; PBMCs, peripheral blood mononuclear cells; PI3K, phosphoinositide 3-kinase; RAGE, receptor for AGE; ROS, reactive oxygen species; RSV, respiratory syncytial virus; SIRT1, sirtuin 1; TNF-α, tumour necrosis factor-alpha.
References
1.
Hasegawa K Tsugawa Y Lopez BL Smithline HA Sullivan AF Camargo CA Jr . Body mass index and risk of hospitalization among adults presenting with asthma exacerbation to the emergency department. Ann Am Thorac Soc. (2014) 11(9):1439–44. 10.1513/AnnalsATS.201406-270BC
2.
Luthe SK Hirayama A Goto T Faridi MK Camargo CA Jr Hasegawa K . Association between obesity and acute severity among patients hospitalized for asthma exacerbation. J Allergy Clin Immunol Pract. (2018) 6(6):1936–41.e4. 10.1016/j.jaip.2018.02.001
3.
Varraso R Siroux V Maccario J Pin I Kauffmann F . Asthma severity is associated with body mass index and early menarche in women. Am J Respir Crit Care Med. (2005) 171(4):334–9. 10.1164/rccm.200405-674OC
4.
To M Hitani A Kono Y Honda N Kano I Haruki K et al Obesity-associated severe asthma in an adult Japanese population. Respir Investig. (2018) 56(6):440–7. 10.1016/j.resinv.2018.07.003
5.
Belhassen M Marchal C Deygas F Jacoud F Van Ganse E . In patients with asthma, obesity status is associated with poor control and high exacerbation rates, which are reversed after bariatric surgery. Respir Med. (2025) 236:107917. 10.1016/j.rmed.2024.107917
6.
Holguin F Bleecker ER Busse WW Calhoun WJ Castro M Erzurum SC et al Obesity and asthma: an association modified by age of asthma onset. J Allergy Clin Immunol. (2011) 127(6):1486–93 e2. 10.1016/j.jaci.2011.03.036
7.
Dixon AE Poynter ME . Mechanisms of asthma in obesity. Pleiotropic aspects of obesity produce distinct asthma phenotypes. Am J Respir Cell Mol Biol. (2016) 54(5):601–8. 10.1165/rcmb.2016-0017PS
8.
Dixon AE Pratley RE Forgione PM Kaminsky DA Whittaker-Leclair LA Griffes LA et al Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J Allergy Clin Immunol. (2011) 128(3):508–15.e2. 10.1016/j.jaci.2011.06.009
9.
Bates JHT Poynter ME Frodella CM Peters U Dixon AE Suratt BT . Pathophysiology to phenotype in the asthma of obesity. Ann Am Thorac Soc. (2017) 14(Suppl 5):S395–8. 10.1513/AnnalsATS.201702-122AW
10.
Peters-Golden M Swern A Bird SS Hustad CM Grant E Edelman JM . Influence of body mass index on the response to asthma controller agents. Eur Respir J. (2006) 27(3):495–503. 10.1183/09031936.06.00077205
11.
Anderson WJ Lipworth BJ . Does body mass index influence responsiveness to inhaled corticosteroids in persistent asthma?. Ann Allergy Asthma Immunol. (2012) 108(4):237–42. 10.1016/j.anai.2011.12.006
12.
Boulet LP Franssen E . Influence of obesity on response to fluticasone with or without salmeterol in moderate asthma. Respir Med. (2007) 101(11):2240–7. 10.1016/j.rmed.2007.06.031
13.
To M Arimoto Y Honda N Furusho N Kinouchi T Takeshita Y et al Elevated oxidative stress and steroid insensitivity in patients with asthma and high body fat percentage. Ann Allergy Asthma Immunol. (2025) 134(6):664–70. 10.1016/j.anai.2025.03.009
14.
Gregor MF Hotamisligil GS . Thematic review series: adipocyte biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res. (2007) 48(9):1905–14. 10.1194/jlr.R700007-JLR200
15.
Pagliassotti MJ Kim PY Estrada AL Stewart CM Gentile CL . Endoplasmic reticulum stress in obesity and obesity-related disorders: an expanded view. Metab Clin Exp. (2016) 65(9):1238–46. 10.1016/j.metabol.2016.05.002
16.
Vigouroux C Caron-Debarle M Le Dour C Magré J Capeau J . Molecular mechanisms of human lipodystrophies: from adipocyte lipid droplet to oxidative stress and lipotoxicity. Int J Biochem Cell Biol. (2011) 43(6):862–76. 10.1016/j.biocel.2011.03.002
17.
Boden G Duan X Homko C Molina EJ Song W Perez O et al Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes. (2008) 57(9):2438–44. 10.2337/db08-0604
18.
Tripathi YB Pandey V . Obesity and endoplasmic reticulum (ER) stresses. Front Immunol. (2012) 3:240. 10.3389/fimmu.2012.00240
19.
Kawasaki N Asada R Saito A Kanemoto S Imaizumi K . Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Sci Rep. (2012) 2:799. 10.1038/srep00799
20.
Kanneganti TD Dixit VD . Immunological complications of obesity. Nat Immunol. (2012) 13(8):707–12. 10.1038/ni.2343
21.
Lumeng CN Bodzin JL Saltiel AR . Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. (2007) 117(1):175–84. 10.1172/JCI29881
22.
Kawai T Autieri MV Scalia R . Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol Cell Physiol. (2021) 320(3):C375–91. 10.1152/ajpcell.00379.2020
23.
Furukawa S Fujita T Shimabukuro M Iwaki M Yamada Y Nakajima Y et al Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. (2004) 114(12):1752–61. 10.1172/JCI21625
24.
Holguin F Fitzpatrick A . Obesity, asthma, and oxidative stress. J Appl Physiol. (2010) 108(3):754–9. 10.1152/japplphysiol.00702.2009
25.
Okauchi Y Kishida K Funahashi T Noguchi M Ogawa T Okita K et al Cross-sectional and longitudinal study of association between circulating thiobarbituric acid-reacting substance levels and clinicobiochemical parameters in 1,178 middle-aged Japanese men—the amagasaki visceral fat study. Nutr Metab (Lond). (2011) 8:82. 10.1186/1743-7075-8-82
26.
Fujita K Nishizawa H Funahashi T Shimomura I Shimabukuro M . Systemic oxidative stress is associated with visceral fat accumulation and the metabolic syndrome. Circ J. (2006) 70(11):1437–42. 10.1253/circj.70.1437
27.
Ito K Hanazawa T Tomita K Barnes PJ Adcock IM . Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene expression: role of tyrosine nitration. Biochem Biophys Res Commun. (2004) 315(1):240–5. 10.1016/j.bbrc.2004.01.046
28.
Bamberger CM Bamberger AM de Castro M Chrousos GP . Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest. (1995) 95(6):2435–41. 10.1172/JCI117943
29.
Boullu-Ciocca S Paulmyer-Lacroix O Fina F Ouafik L Alessi MC Oliver C et al Expression of the mRNAs coding for the glucocorticoid receptor isoforms in obesity. Obes Res. (2003) 11(8):925–9. 10.1038/oby.2003.127
30.
Sutherland ER Goleva E King TS Lehman E Stevens AD Jackson LP et al Cluster analysis of obesity and asthma phenotypes. PLoS One. (2012) 7(5):e36631. 10.1371/journal.pone.0036631
31.
Marwick JA Caramori G Stevenson CS Casolari P Jazrawi E Barnes PJ et al Inhibition of PI3Kδ restores glucocorticoid function in smoking-induced airway inflammation in mice. Am J Respir Crit Care Med. (2009) 179(7):542–8. 10.1164/rccm.200810-1570OC
32.
To Y Ito K Kizawa Y Failla M Ito M Kusama T et al Targeting phosphoinositide-3-kinase-δ with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. (2010) 182(7):897–904. 10.1164/rccm.200906-0937OC
33.
Rossios C To Y Osoata G Ito M Barnes PJ Ito K . Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3-kinase inhibition. Br J Pharmacol. (2012) 167(4):775–86. 10.1111/j.1476-5381.2012.01864.x
34.
Kim RY Horvat JC Pinkerton JW Starkey MR Essilfie AT Mayall JR et al MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase-mediated suppression of histone deacetylase 2. J Allergy Clin Immunol. (2017) 139(2):519–32. 10.1016/j.jaci.2016.04.038
35.
Barnes PJ . Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. (2013) 131(3):636–45. 10.1016/j.jaci.2012.12.1564
36.
Ito K Lim S Caramori G Chung KF Barnes PJ Adcock IM . Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J. (2001) 15(6):1110–2. 10.1096/fsb2fj000432fje
37.
Barnes PJ Adcock IM Ito K . Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J. (2005) 25(3):552–63. 10.1183/09031936.05.00117504
38.
To M Kono Y Ogura N Mikami S Honda N Hitani A et al Obesity-related systemic oxidative stress: an important factor of poor asthma control. Allergol Int. (2018) 67(1):147–9. 10.1016/j.alit.2017.06.002
39.
Freitas PD Silva AG Ferreira PG DAS A Salge JM Carvalho-Pinto RM et al Exercise improves physical activity and comorbidities in obese adults with asthma. Med Sci Sports Exerc. (2018) 50(7):1367–76. 10.1249/MSS.0000000000001574
40.
Woo SD Park HS Yang EM Ban GY Park HS . 8-iso-prostaglandin F2α as a biomarker of type 2-low airway inflammation and remodeling in adult asthma. Ann Allergy Asthma Immunol. (2024) 133:73–80. 10.1016/j.anai.2024.04.007
41.
Zong H Ren JM Young LH Pypaert M Mu J Birnbaum MJ et al AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A. (2002) 99(25):15983–7. 10.1073/pnas.252625599
42.
Burkewitz K Zhang Y Mair WB . AMPK at the nexus of energetics and aging. Cell Metab. (2014) 20(1):10–25. 10.1016/j.cmet.2014.03.002
43.
Joo MS Kim WD Lee KY Kim JH Koo JH Kim SG . AMPK facilitates nuclear accumulation of Nrf2 by phosphorylating at serine 550. Mol Cell Biol. (2016) 36(14):1931–42. 10.1128/MCB.00118-16
44.
Cantó C Gerhart-Hines Z Feige JN Lagouge M Noriega L Milne JC et al AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. (2009) 458(7241):1056–60. 10.1038/nature07813
45.
Lan F Cacicedo JM Ruderman N Ido Y . SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem. (2008) 283(41):27628–35. 10.1074/jbc.M805711200
46.
Luo T Nocon A Fry J Sherban A Rui X Jiang B et al AMPK activation by metformin suppresses abnormal extracellular matrix remodeling in adipose tissue and ameliorates insulin resistance in obesity. Diabetes. (2016) 65(8):2295–310. 10.2337/db15-1122
47.
Lei T Yu L Qin L Xu B Zhou L Cheng J et al Stress kinases, endoplasmic reticulum stress, and Alzheimer’s disease related markers in peripheral blood mononuclear cells from subjects with increased body weight. Sci Rep. (2016) 6:30890. 10.1038/srep30890
48.
García-Prieto CF Gil-Ortega M Vega-Martín E Ramiro-Cortijo D Martín-Ramos M Bordiú E et al Beneficial effect of bariatric surgery on abnormal MMP-9 and AMPK activities: potential markers of obesity-related CV risk. Front Physiol. (2019) 10:553. 10.3389/fphys.2019.00553
49.
Stefanowicz M Nikołajuk A Matulewicz N Karczewska-Kupczewska M . Adipose tissue, but not skeletal muscle, sirtuin 1 expression is decreased in obesity and related to insulin sensitivity. Endocrine. (2018) 60(2):263–71. 10.1007/s12020-018-1544-1
50.
Pedersen SB Ølholm J Paulsen SK Bennetzen MF Richelsen B . Low sirt1 expression, which is upregulated by fasting, in human adipose tissue from obese women. Int J Obes. (2008) 32(8):1250–5. 10.1038/ijo.2008.78
51.
Lee H Chu SH Park JY Park HK Im JA Lee JW . Visceral adiposity is associated with SIRT1 expression in peripheral blood mononuclear cells: a pilot study. Endocr J. (2013) 60(11):1269–73. 10.1507/endocrj.EJ13-0207
52.
Crujeiras AB Parra D Goyenechea E Martínez JA . Sirtuin gene expression in human mononuclear cells is modulated by caloric restriction. Eur J Clin Investig. (2008) 38(9):672–8. 10.1111/j.1365-2362.2008.01998.x
53.
Hodge G Tran HB Reynolds PN Jersmann H Hodge S . Lymphocyte senescence in COPD is associated with decreased sirtuin 1 expression in steroid resistant pro-inflammatory lymphocytes. Ther Adv Respir Dis. (2020) 14:1753466620905280. 10.1177/1753466620905280
54.
Mitani A Azam A Vuppusetty C Ito K Mercado N Barnes PJ . Quercetin restores corticosteroid sensitivity in cells from patients with chronic obstructive pulmonary disease. Exp Lung Res. (2017) 43(9–10):417–25. 10.1080/01902148.2017.1393707
55.
Telenga ED Tideman SW Kerstjens HA Hacken NH Timens W Postma DS et al Obesity in asthma: more neutrophilic inflammation as a possible explanation for a reduced treatment response. Allergy. (2012) 67(8):1060–8. 10.1111/j.1398-9995.2012.02855.x
56.
Scott HA Gibson PG Garg ML Wood LG . Airway inflammation is augmented by obesity and fatty acids in asthma. Eur Respir J. (2011) 38(3):594–602. 10.1183/09031936.00139810
57.
Suzukawa M Koketsu R Baba S Igarashi S Nagase H Yamaguchi M et al Leptin enhances ICAM-1 expression, induces migration and cytokine synthesis, and prolongs survival of human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. (2015) 309(8):L801–11. 10.1152/ajplung.00365.2014
58.
Peters MC McGrath KW Hawkins GA Hastie AT Levy BD Israel E et al Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med. (2016) 4(7):574–84. 10.1016/S2213-2600(16)30048-0
59.
Xie Y Abel PW Casale TB Tu Y . Th17 cells and corticosteroid insensitivity in severe asthma. J Allergy Clin Immunol. (2022) 149(2):467–79. 10.1016/j.jaci.2021.12.769
60.
Sumarac-Dumanovic M Stevanovic D Ljubic A Jorga J Simic M Stamenkovic-Pejkovic D et al Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women. Int J Obes. (2009) 33(1):151–6. 10.1038/ijo.2008.216
61.
Gutmann D Dressler M Eickmeier O Herrmann E Kirwil M Schubert R et al Proinflammatory pattern in the lower airways of non-asthmatic obese adolescents. Cytokine. (2024) 173:156452. 10.1016/j.cyto.2023.156452
62.
Wood LG Li Q Scott HA Rutting S Berthon BS Gibson PG et al Saturated fatty acids, obesity, and the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in asthmatic patients. J Allergy Clin Immunol. (2018) 143:305–15. 10.1016/j.jaci.2018.04.037
63.
Vazquez-Tello A Semlali A Chakir J Martin JG Leung DY Eidelman DH et al Induction of glucocorticoid receptor-β expression in epithelial cells of asthmatic airways by T-helper type 17 cytokines. Clin Exp Allergy. (2010) 40(9):1312–22. 10.1111/j.1365-2222.2010.03544.x
64.
Frasca D Ferracci F Diaz A Romero M Lechner S Blomberg BB . Obesity decreases B cell responses in young and elderly individuals. Obesity. (2016) 24(3):615–25. 10.1002/oby.21383
65.
Martín-Romero C Sánchez-Margalet V . Human leptin activates PI3K and MAPK pathways in human peripheral blood mononuclear cells: possible role of Sam68. Cell Immunol. (2001) 212(2):83–91. 10.1006/cimm.2001.1851
66.
Sánchez-Pozo C Rodriguez-Baño J Domínguez-Castellano A Muniain MA Goberna R Sánchez-Margalet V . Leptin stimulates the oxidative burst in control monocytes but attenuates the oxidative burst in monocytes from HIV-infected patients. Clin Exp Immunol. (2003) 134(3):464–9. 10.1111/j.1365-2249.2003.02321.x
67.
Yu Y Liu Y Shi FD Zou H Matarese G La Cava A . Cutting edge: leptin-induced RORγt expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus. J Immunol. (2013) 190(7):3054–8. 10.4049/jimmunol.1203275
68.
Reis BS Lee K Fanok MH Mascaraque C Amoury M Cohn LB et al Leptin receptor signaling in T cells is required for Th17 differentiation. J Immunol. (2015) 194(11):5253–60. 10.4049/jimmunol.1402996
69.
Julien JY Martin JG Ernst P Olivenstein R Hamid Q Lemiere C et al Prevalence of obstructive sleep apnea-hypopnea in severe versus moderate asthma. J Allergy Clin Immunol. (2009) 124(2):371–6. 10.1016/j.jaci.2009.05.016
70.
Esmaeili N Gell L Imler T Hajipour M Taranto-Montemurro L Messineo L et al The relationship between obesity and obstructive sleep apnea in four community-based cohorts: an individual participant data meta-analysis of 12,860 adults. EClinicalMedicine. (2025) 83:103221. 10.1016/j.eclinm.2025.103221
71.
Lavie L Vishnevsky A Lavie P . Evidence for lipid peroxidation in obstructive sleep apnea. Sleep. (2004) 27(1):123–8.
72.
Barceló A Miralles C Barbé F Vila M Pons S Agustí AG . Abnormal lipid peroxidation in patients with sleep apnoea. Eur Respir J. (2000) 16(4):644–7. 10.1034/j.1399-3003.2000.16d13.x
73.
Lo CY Wang CH Lin CY Lin TY Chang PJ Lo YL et al Corticosteroid insensitivity in asthma associated with obstructive sleep apnoea: role of oxidative stress and histone acetylation. Br J Pharmacol. (2025) 182(23):5790–802. 10.1111/bph.70157
74.
Liang L Gu X Shen HJ Shi YH Li Y Zhang J et al Chronic intermittent hypoxia reduces the effects of glucosteroid in asthma via activating the p38 MAPK signaling pathway. Front Physiol. (2021) 12:703281. 10.3389/fphys.2021.703281
75.
Dumaine JE Ashley NT . Acute sleep fragmentation induces tissue-specific changes in cytokine gene expression and increases serum corticosterone concentration. Am J Physiol Regul Integr Comp Physiol. (2015) 308(12):R1062–9. 10.1152/ajpregu.00049.2015
76.
Wang Y Liu K Hu K Yang J Li Z Nie M et al Impact of obstructive sleep apnea on severe asthma exacerbations. Sleep Med. (2016) 26:1–5. 10.1016/j.sleep.2016.06.013
77.
Hong T Chen Y Li X Lu Y . The role and mechanism of oxidative stress and nuclear receptors in the development of NAFLD. Oxid Med Cell Longevity. (2021) 2021:6889533. 10.1155/2021/6889533
78.
Xia YC Radwan A Keenan CR Langenbach SY Li M Radojicic D et al Glucocorticoid insensitivity in virally infected airway epithelial cells is dependent on transforming growth factor-β activity. PLoS Pathog. (2017) 13(1):e1006138. 10.1371/journal.ppat.1006138
79.
Papi A Contoli M Adcock IM Bellettato C Padovani A Casolari P et al Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor κB and c-Jun N-terminal kinase activation. J Allergy Clin Immunol. (2013) 132(5):1075–85.e6. 10.1016/j.jaci.2013.05.028
80.
Almond M Farne HA Jackson MM Jha A Katsoulis O Pitts O et al Obesity dysregulates the pulmonary antiviral immune response. Nat Commun. (2023) 14(1):6607. 10.1038/s41467-023-42432-x
81.
Sheridan PA Paich HA Handy J Karlsson EA Hudgens MG Sammon AB et al Obesity is associated with impaired immune response to influenza vaccination in humans. Int J Obes. (2012) 36(8):1072–7. 10.1038/ijo.2011.208
82.
Neidich SD Green WD Rebeles J Karlsson EA Schultz-Cherry S Noah TL et al Increased risk of influenza among vaccinated adults who are obese. Int J Obes. (2017) 41(9):1324–30. 10.1038/ijo.2017.131
83.
Korn S Hübner M Jung M Blettner M Buhl R . Severe and uncontrolled adult asthma is associated with vitamin D insufficiency and deficiency. Respir Res. (2013) 14(1):25. 10.1186/1465-9921-14-25
84.
Jolliffe DA Greenberg L Hooper RL Griffiths CJ Camargo CA Kerley J et al Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data. Lancet Respir Med. (2017) 5(11):881–90. 10.1016/S2213-2600(17)30306-5
85.
Sutherland ER Goleva E Jackson LP Stevens AD Leung DY . Vitamin D levels, lung function, and steroid response in adult asthma. Am J Respir Crit Care Med. (2010) 181(7):699–704. 10.1164/rccm.200911-1710OC
86.
Wortsman J Matsuoka LY Chen TC Lu Z Holick MF . Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. (2000) 72(3):690–3. 10.1093/ajcn/72.3.690
87.
Vimaleswaran KS Berry DJ Lu C Tikkanen E Pilz S Hiraki LT et al Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. (2013) 10(2):e1001383. 10.1371/journal.pmed.1001383
88.
Goleva E Covar R Martin RJ Leung DY . Corticosteroid pharmacokinetic abnormalities in overweight and obese corticosteroid resistant asthmatics. J Allergy Clin Immunol Pract. (2016) 4(2):357–60.e2. 10.1016/j.jaip.2015.11.013
89.
Zhou Z Tang Y Jin X Chen C Lu Y Liu L et al Metformin inhibits advanced glycation end products-induced inflammatory response in murine macrophages partly through AMPK activation and RAGE/NFκB pathway suppression. J Diabetes Res. (2016) 2016:4847812. 10.1155/2016/4847812
90.
Liu Z Ma Y Cui Q Xu J Tang Z Wang Y et al Toll-like receptor 4 plays a key role in advanced glycation end products-induced M1 macrophage polarization. Biochem Biophys Res Commun. (2020) 531(4):602–8. 10.1016/j.bbrc.2020.08.014
91.
van der Lugt T Weseler AR Vrolijk MF Opperhuizen A Bast A . Dietary advanced glycation endproducts decrease glucocorticoid sensitivity in vitro. Nutrients. (2020) 12(2):441. 10.3390/nu12020441
92.
Hansen ESH Pitzner-Fabricius A Toennesen LL Rasmusen HK Hostrup M Hellsten Y et al Effect of aerobic exercise training on asthma in adults: a systematic review and meta-analysis. Eur Respir J. (2020) 56(1):2000146. 10.1183/13993003.00146-2020
93.
Valkenborghs SR Wood LG Callister R Upham JW Grainge CL Anderson S et al Effects of moderate- versus vigorous-intensity exercise training on asthma outcomes in adults. J Allergy Clin Immunol Pract. (2024) 12(10):2744–53.e8. 10.1016/j.jaip.2024.06.015
94.
Pitzner-Fabricius A Dall CH Henriksen M Hansen ESH Toennesen LL Hostrup M et al Effect of high-intensity interval training on inhaled corticosteroid dose in asthma patients: a randomized controlled trial. J Allergy Clin Immunol Pract. (2023) 11(7):2133–43.e8. 10.1016/j.jaip.2023.04.013
95.
Kubo H Asai K Kojima K Sugitani A Kyomoto Y Okamoto A et al Exercise ameliorates emphysema of cigarette smoke-induced COPD in mice through the exercise-irisin-Nrf2 axis. Int J Chron Obstruct Pulmon Dis. (2019) 14:2507–16. 10.2147/COPD.S226623
96.
Da Rosa PC Bertomeu JB Royes LFF Osiecki R . The physical exercise-induced oxidative/inflammatory response in peripheral blood mononuclear cells: signaling cellular energetic stress situations. Life Sci. (2023) 321:121440. 10.1016/j.lfs.2023.121440
97.
Bantulà M Tubita V Roca-Ferrer J Mullol J Valero A Bobolea I et al Weight loss and vitamin D improve hyporesponsiveness to corticosteroids in obese asthma. J Investig Allergol Clin Immunol. (2023) 33(6):464–73. 10.18176/jiaci.0861
98.
Mahboub B Kharaba Z Ramakrishnan RK Askari S Salameh NS Alhariri LI et al Continuous positive airway pressure therapy suppresses inflammatory cytokines and improves glucocorticoid responsiveness in patients with obstructive sleep apnea and asthma: a case-control study. Ann Thorac Med. (2022) 17(3):166–72. 10.4103/atm.atm_37_22
99.
Gibson PG Prazma CM Chupp GL Bradford ES Forshag M Mallett SA et al Mepolizumab improves clinical outcomes in patients with severe asthma and comorbid conditions. Respir Res. (2021) 22(1):171. 10.1186/s12931-021-01746-4
100.
Geng B Dixon AE Ko J Janampally P Haselkorn T Holweg CTJ et al Impact of body mass index on omalizumab response in adults with moderate-to-severe allergic asthma. Ann Allergy Asthma Immunol. (2022) 128(5):553–60. 10.1016/j.anai.2022.01.025
101.
Busse WW Paggiaro P Muñoz X Casale TB Castro M Canonica GW et al Impact of baseline patient characteristics on dupilumab efficacy in type 2 asthma. Eur Respir J. (2021) 58(4):2004605. 10.1183/13993003.04605-2020
102.
Menzies-Gow A Corren J Bourdin A Chupp G Israel E Wechsler ME et al Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med. (2021) 384(19):1800–9. 10.1056/NEJMoa2034975
103.
Okuno Y Fukuhara A Hashimoto E Kobayashi H Kobayashi S Otsuki M et al Oxidative stress inhibits healthy adipose expansion through suppression of SREBF1-mediated lipogenic pathway. Diabetes. (2018) 67(6):1113–27. 10.2337/db17-1032
104.
Rena G Hardie DG Pearson ER . The mechanisms of action of metformin. Diabetologia. (2017) 60(9):1577–85. 10.1007/s00125-017-4342-z
105.
Sova H Puistola U Morin-Papunen L Karihtala P . Metformin decreases serum 8-hydroxy-2'-deoxyguanosine levels in polycystic ovary syndrome. Fertil Steril. (2013) 99(2):593–8. 10.1016/j.fertnstert.2012.10.013
106.
Esteghamati A Eskandari D Mirmiranpour H Noshad S Mousavizadeh M Hedayati M et al Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial. Clin Nutr. (2013) 32(2):179–85. 10.1016/j.clnu.2012.08.006
107.
Polverino F Wu TD Rojas-Quintero J Wang X Mayo J Tomchaney M et al Metformin: experimental and clinical evidence for a potential role in emphysema treatment. Am J Respir Crit Care Med. (2021) 204(6):651–66. 10.1164/rccm.202012-4510OC
108.
Cosio BG Tsaprouni L Ito K Jazrawi E Adcock IM Barnes PJ . Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. (2004) 200(5):689–95. 10.1084/jem.20040416
109.
Barnes PJ . Theophylline. Pharmaceuticals. (2010) 3(3):725–47. 10.3390/ph3030725
110.
Ozcan L Ergin AS Lu A Chung J Sarkar S Nie D et al Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. (2009) 9(1):35–51. 10.1016/j.cmet.2008.12.004
111.
Bharath LP Nikolajczyk BS . The intersection of metformin and inflammation. Am J Physiol Cell Physiol. (2021) 320(5):C873–c9. 10.1152/ajpcell.00604.2020
112.
Ararat E Landes RD Forno E Tas E Perry TT . Metformin use is associated with decreased asthma exacerbations in adolescents and young adults. Pediatr Pulmonol. (2023) 59:48–54. 10.1002/ppul.26704
113.
Uppal P Mohammed SA Rajashekar S Giri Ravindran S Kakarla M Ausaja Gambo M et al Type 2 diabetes Mellitus and asthma: pathomechanisms of their association and clinical implications. Cureus. (2023) 15(3):e36047. 10.7759/cureus.36047
114.
Wu TD Fawzy A Akenroye A Keet C Hansel NN McCormack MC . Metformin use and risk of asthma exacerbation among asthma patients with glycemic dysfunction. J Allergy Clin Immunol Pract. (2021) 9(11):4014–20.e4. 10.1016/j.jaip.2021.07.007
115.
Calixto MC Lintomen L André DM Leiria LO Ferreira D Lellis-Santos C et al Metformin attenuates the exacerbation of the allergic eosinophilic inflammation in high fat-diet-induced obesity in mice. PLoS One. (2013) 8(10):e76786. 10.1371/journal.pone.0076786
116.
Muskiet MHA Tonneijck L Smits MM van Baar MJB Kramer MHH Hoorn EJ et al GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol. (2017) 13(10):605–28. 10.1038/nrneph.2017.123
117.
Nguyen DV Linderholm A Haczku A Kenyon N . Obesity-related, metabolic asthma: a new role for glucagon-like peptide 1 agonists. Lancet Respir Med. (2017) 5(3):162–4. 10.1016/S2213-2600(17)30051-6
Summary
Keywords
adult asthma, drug-repositioning, obesity, oxidative stress, steroid insensitivity
Citation
To M and To Y (2025) Corticosteroid insensitivity in obese asthma: potential mechanisms and therapeutic perspectives. Front. Allergy 6:1719900. doi: 10.3389/falgy.2025.1719900
Received
07 October 2025
Revised
06 November 2025
Accepted
11 November 2025
Published
25 November 2025
Volume
6 - 2025
Edited by
Akira Yamasaki, Tottori University, Japan
Reviewed by
Koichiro Takahashi, Saga University, Japan
Tomoya Harada, Tottori University Hospital, Japan
Updates
Copyright
© 2025 To and To.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Masako To m-to@dokkyomed.ac.jp; ytou-alg@umin.ac.jp
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.