This study suggests that higher serum leptin concentrations are associated with current asthma in adults and that the relationship may be stronger in women than in men. This study also demonstrates three interesting facets of this relationship. Firstly, the association between concentrations of leptin and current asthma appeared stronger in premenopausal than in postmenopausal women. Secondly, adjusting for the two commonly used anthropometric measures of obesity (BMI and triceps skinfold thickness) yielded different results. BMI may confound the association between leptin and asthma, making the association appear larger than may be actually true. On the other hand, adjusting for triceps skinfold thickness does not explain the association of leptin with asthma either, which persists and becomes greater after adjusting for skinfold thickness. The reason for this difference is unclear. Finally, while BMI itself was associated with current asthma in women, this association was not much affected by adjustment for serum leptin concentrations. This suggests that the effect of BMI on asthma is not mediated by the leptin pathway alone and probably involves other mechanistic pathways.
The effect of leptin on lung development and physiology is poorly understood, even though leptin receptors are present in high concentrations in acini of fetal and adult animal lungs.41
Leptin is believed to play a role in the intrauterine, neonatal, and postnatal development of murine lung.42
In addition, some data suggest that leptin concentrations are increased acutely during inflammation30,33
and, in turn, promote inflammation.43,44,45
Support for this comes from experiments showing a prompt dose dependent increase in serum leptin levels and leptin mRNA expression in the adipose tissue of mice following the administration of pro‐inflammatory cytokines such as tumour necrosis factor α (TNF‐α) and interleukin (IL)‐1,30
as well as demonstration of increased serum TNF‐α, IL‐6 and IL‐12 levels and increased phagocytosis by macrophages on exogenous administration of leptin.45
In wild type mice, administration of exogenous leptin augments ozone induced airway inflammation.43
In humans, enhanced concentrations of leptin are related to soluble TNF receptor (sTNF‐R) 55, a marker of pro‐inflammatory status in patients with chronic obstructive pulmonary disease.31
Guler et al35
found that the median serum leptin concentrations of children (especially boys) were significantly higher in those with asthma than in healthy controls (3.53 v
2.26 ng/ml, p
0.01) even though there was no difference in BMI levels. In a study involving children born with very low birth weight who subsequently became overweight, Mai et al46
showed that current asthmatics had median leptin concentrations twice as high as children without current asthma (30.8 v
14.3 ng/ml, p
0.14), but this was not the case in non‐overweight children. Taken together, prior studies suggest that leptin may potentially play an important role in the pathophysiology of asthma.
Serum leptin concentrations are also related to obesity.26,29,47
For equivalent BMI, leptin concentrations are higher in women than in men.28,29
In addition, obesity is associated with increased concentrations of acute phase proteins, suggesting a pro‐inflammatory state.48,49,50
In recent years obesity has been identified as a risk factor for asthma.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18
A prospective study suggested that an increase in weight leads to incident cases of asthma, independent of physical activity.5
It is believed by some that a decrease in physical activity, particularly among the obese, may also play a role in the increased prevalence and severity of asthma.51,52
While the causal pathway remains unknown, the explanations advanced for the association between obesity and asthma include mechanical effects such as lack of tidal stretch leading to latching of airway smooth muscle, immunological effects of pro‐inflammatory cytokines, genetic, hormonal and environmental effects such as change in dietary factors and increased exposure to indoor allergens.53,54
Some investigators have noted that the association between obesity and asthma may be stronger in women than in men, suggesting that reproductive hormones might be involved in the causal pathway.4,5,7,8,19,20,21,22,23,24,25
In addition, Castro‐Rodriguez et al7
found this association to be stronger in girls whose puberty started before the age of 11 years than in girls whose puberty started later. Barr et al55
showed that exogenous hormone replacement therapy in adult postmenopausal women was associated with an increased relative risk for asthma, with a positive dose‐response between the daily dose of conjugated oestrogens and the risk of asthma. Similarly, administration of exogenous reproductive hormones to women has also been noted to increase serum leptin concentrations further.32
These observations have led some to conclude that leptin may be important in explaining the link between obesity and asthma, particularly in women.
Our study does not support the assertion that leptin plays a dominant role in the association between obesity and asthma in women, but it does support the conclusion that leptin itself may play a part in asthma in women. This would be consistent with data obtained from previous animal and human studies.31,35,43,46
Further relationships between asthma, leptin, and female reproductive hormones cannot be adequately addressed in this study because of the cross sectional design and inadequate sample size.
The study has some additional limitations. The definition of asthma was a self‐reported doctor diagnosis of asthma, and this may result in some misclassification bias. Serum reproductive hormone concentrations were not measured nor were the leptin concentrations measured in relation to the day of the menstrual cycle in premenopausal women. Finally, in order to confirm definitively that leptin has a different effect on asthma status in various groups, a statistically significant interaction is required. It is not sufficient to observe a statistically significant relationship in one group and not in the other.56
This exploratory analysis lacks the power to detect a statistically significant interaction and further work in larger cohorts is warranted.
In summary, using nationally representative data, this study has shown that higher serum leptin concentrations are associated with current asthma in women and that this association may be stronger in premenopausal women. In addition, while BMI is also associated with current asthma in women, this study does not confirm that leptin contributes significantly to this association. Future studies will need to confirm and expand on these observations to improve our understanding of the pathogenesis of asthma.