Systemic complications related to obesity
Although the relationship between obesity and pulmonary dysfunction is becoming increasingly
clear, there is still much controversy regarding whether it occurs in other populations.
Complex diseases such as asthma, obstructive sleep apnea (OSA), and chronic obstructive
pulmonary disease (COPD) are multifactorial diseases that involve interactions among
environmental, genetic, and behavioral factors 7]. Obesity is associated with various diseases and is an important cardiovascular risk
factor. Overweight status promotes metabolic and structural changes that increase
susceptibility to various diseases, including cardiovascular diseases, metabolic disorders,
renal and biliary diseases, and certain types of cancer 7].
Obese individuals exhibit a persistent proinflammatory state that leads to insulin
resistance, endothelial dysfunction, systemic arterial hypertension (SAH), and dyslipidemia.
These factors culminate in type 2 diabetes mellitus (T2DM) and promote atherogenesis,
which in turn increases the risk of coronary heart disease, stroke, and heart failure
8], 9].
Several studies have shown a direct correlation between obesity and OSA. However,
the exact pathophysiology of OSA in obese patients remains poorly understood 10]. The mechanisms involved include an increase in neck circumference as well as the
direct action of adipose tissue on the airways via a decrease in the luminal diameter
of the airway and an increase in the probability of airway collapse 11], 12].
Asthma is also correlated with obesity. Obese individuals with asthma are more likely
to have difficult-to-control complications and diseases, and individuals with a higher
body mass index (BMI) have a greater risk of developing asthma. The mechanisms involved
in this association include increased bronchial hyperresponsiveness (BHR), functional
respiratory decline with decreased respiratory volume and flow, chronic systemic inflammation
triggered by increased levels of inflammatory cytokines and chemokines, and factors
derived from adipocytes, including leptin, adiponectin, and plasminogen activator
inhibitor 13], 14]. Several other factors also appear to contribute to the increased risk of asthma
in obese individuals, including changes in respiratory function, low exercise tolerance,
and predisposition to gastroesophageal reflux 15], 16].
A possible relationship between obesity and COPD has been discussed. An epidemiological
study of 650,000 patients revealed that the prevalence of obesity was significantly
higher in patients with COPD than in those without COPD (24.6 and 17.1 %, respectively,
p??0.0001) 17]. Because pro-inflammatory mediators are present in both obese individuals and in
individuals with COPD, these mediators may be the connection between these two conditions
18].
More than one-fifth of the population of the United States and approximately 60 %
of obese individuals have metabolic syndrome 19]. In this context, an association between metabolic syndrome and pulmonary disease
has been widely debated in recent years 20], 21]. Metabolic syndrome has been identified as an independent risk factor for worsening
respiratory symptoms, impairment of lung function, asthma, and pulmonary hypertension.
Several possible mechanisms have been proposed to explain these associations, including
exposure to high insulin levels during fetal maturation (which induces alterations
in airway smooth muscle), the effects of abdominal adiposity, deregulation of adipokine
metabolism, and inflammation induced by fat in the lungs 22].
In the gastrointestinal tract, obesity is associated with gastroesophageal reflux
disease, cholelithiasis, and liver steatosis. In the osteoarticular system, obesity
is correlated with an increased prevalence of osteoarthritis, and in the reproductive
system, obesity is correlated with female infertility, polycystic ovary syndrome,
and erectile dysfunction 23].
Obesity is also associated with cancers of the breast, cervix, colon, endometrium,
esophagus, kidney, liver, ovaries, prostate, and rectum. Furthermore, obese women
have a higher prevalence of depression, menorrhagia, amenorrhea, and urinary incontinence.
During pregnancy, obesity is associated with a higher risk of maternal complications;
obese patients also have a higher incidence of adverse fetal outcomes 23].
Biochemical and molecular changes
Obesity is associated with a state of chronic systemic inflammation that is driven
predominantly by the action of substances released by adipose tissue. Chronic inflammation
is caused by activation of the innate immune system, which promotes a pro-inflammatory
state and oxidative stress (OS) and a consequent systemic acute-phase response 5]. Systemic inflammation may play a crucial role in the pathogenesis of various obesity-related
complications, including metabolic syndrome, T2DM, cardiac disease, liver dysfunction,
and cancer.
Adipose tissue is an endocrine and energy storage organ composed of adipocytes, fibroblasts,
endothelial cells, and immune cells. These cells secrete hormones and cytokines (adipokines)
that exert endocrine, paracrine, and autocrine functions. Under physiological and
pathological conditions, adipokines induce the production of reactive oxygen species
(ROS), which trigger OS; this, in turn, leads to increased production of other adipokines.
During this process, immune cells produce free oxygen radicals that promote a systemic
proinflammatory state 24].
Excess adipose tissue is associated with the production of various proinflammatory
cytokines, including tumor necrosis factor-? (TNF-?), interleukin-1-? (IL-1?), and
interleukin-6 (IL-6) 25]. TNF-? plays a critical role in the inflammatory response of the immune system as
well as in the apoptosis of adipose cells, lipid metabolism, hepatic lipogenesis,
and the induction of OS. Increased levels of TNF-? promote a response via the release
of IL-6, another proinflammatory molecule, and the reduction of levels of anti-inflammatory
cytokines such as adiponectin. TNF-? also increases the interaction of electrons with
oxygen, generating superoxide anions. TNF-? levels are elevated in obese individuals
and decrease with weight loss 26].
IL-1? is a pyrogenic cytokine that is released primarily by monocytes in response
to tissue damage or infection. It has recently been proposed that IL-1? is also associated
with the proinflammatory response in obesity via the increased production of other
cytokines, including IL-6 27]. IL-6 is secreted by adipocytes, endothelial cells, pancreatic cells, macrophages,
and monocytes and participates in the regulation of energy homeostasis and inflammation.
IL-6 influences the transition from acute to chronic inflammation by stimulating the
synthesis of pro-inflammatory cytokines and the down-regulation of anti-inflammatory
targets 28]. Visceral adipose tissue secretes two or three times more IL-6 than subcutaneous
adipose tissue via the production of other pro-inflammatory molecules 29]. In humans, high levels of IL-6 are associated with glucose intolerance, T2DM, SAH,
and especially obesity. This cytokine may also suppress the activity of lipoprotein
lipase and modulate central appetite control at the hypothalamic level 30].
Obese individuals are also more susceptible to oxidative damage. The accumulation
of adipose tissue, particularly visceral adipose tissue, induces the synthesis of
proinflammatory cytokines, including TNF-?, IL-1, and IL-6. These cytokines promote
the generation of reactive oxygen and nitrogen species by macrophages and monocytes,
which may lead to increased OS 25]. ROS induce the release of pro-inflammatory cytokines and the expression of adhesion
molecules, including connective tissue growth factor, insulin-like growth factor I,
platelet-derived growth factor, and vascular cell adhesion molecule I, all of which
trigger OS and appear to accelerate aging and cell death, with numerous systemic consequences
29], 31].
Another mechanism involved in the increased susceptibility of obese individuals to
oxidative damage is the depletion of enzymes that are active in antioxidant pathways,
including superoxide dismutase (SOD), glutathione peroxidase, and catalase. Antioxidant
pathways associated with vitamins A, C, and E and beta-carotene also seem to be depleted
32]. Compared with normal-weight individuals, SOD activity is significantly decreased
in obese subjects 33]. Oxidative damage leads to the increased production of free radicals, OS, mitochondrial
DNA damage, and depletion of adenosine triphosphate, culminating in damage to cellular
structures. The cellular damage caused by this lipotoxic state is a direct consequence
of the cascade of proinflammatory cytokines released by adipose tissues 34].
Adipose tissue is a source of several bioactive adipokines, including leptin, adiponectin,
visfatin, resistin, apelin, and type I plasminogen activation inhibitor (PAI-I). These
adipokines are directly associated with physiological and pathological processes involving
OS 5].
Leptin is a hormone that is secreted by adipocytes in amounts that are directly proportional
to adipose tissue mass and triglyceride levels. The function of leptin is primarily
anorexigenic; it binds to proteins, circulates in the plasma, reaches the central
nervous system, and promotes satiety. However, it has been postulated that obesity
is associated with increased levels of leptin and that a decrease in leptin’s anorexigenic
effect via resistance mechanisms occurs in obese patients 25]. The mechanism by which leptin promotes OS has not been determined. However, one
hypothesis is that hexamethylene bis-acetamide inducible-1 (Hexim1) is involved in
maintaining whole-body energy balance 35]. These hormones may act by inducing the synthesis of cytokines such as TNF-?, interleukin-2
(IL-2), and interferon-? and can exert their functions in various cell types, including
T cells, monocytes, neutrophils, and endothelial cells 36]. Studies have also shown that leptin increases serum levels of C-reactive protein
(CRP), confirming its pro-inflammatory effect 36].
In contrast to leptin, adiponectin, which is secreted by differentiated adipocytes,
has anti-inflammatory and anti-atherogenic effects. It inhibits the adhesion of monocytes
to endothelial cells, the transformation of macrophages into foam cells, and the activation
of endothelial cells 37]. Adiponectin also decreases TNF-? and CRP levels and increases the release of nitric
oxide (NO) from endothelial cells. A deficiency in this hormone results in decreased
levels of NO and reduced leukocyte adhesion, leading to chronic vascular inflammation
38]. It has also been observed that TNF-? and IL-6 are potent inhibitors of the synthesis
of adiponectin and other adipokines, including visfatin. Exposure of adipocytes to
high levels of ROS also suppresses the production of adiponectin. These mechanisms
explain why low levels of adiponectin are found in obese individuals 39].
Visfatin, a recently discovered adipokine, has been positively correlated with the
accumulation of adipose tissue. In addition, the level of this hormone decreases with
weight loss 40]. Visfatin has pro-oxidant and pro-inflammatory activity and is elevated in obese
individuals compared with normal-weight individuals 41]. It stimulates leukocytes and the production of pro-inflammatory cytokines (IL-1,
IL-6, and TNF-?) and promotes the generation of ROS 41].
Resistin, a compound present at low levels in adipocytes and at high levels in circulating
monocytes, was initially described as an adipokine that is involved in the regulation
of appetite, energy balance, and insulin resistance. However, other studies have shown
that resistin is associated with an increase in the incidence of cardiovascular disease
in obese individuals. The mechanisms involved are directly related to OS and involve
the activation of endothelial cells and the upregulation of adhesion molecules and
pro-inflammatory cytokines in vascular walls 42].
In summary, the dysfunction of adipose tissue can induce systemic OS and lead to abnormal
production of adipokines, which contributes to the development of obesity-related
disorders. Furthermore, the level of oxidative damage biomarkers is increased in obese
individuals and is directly correlated with BMI, percentage of body fat, and levels
of triglycerides and low-density lipoproteins 43]. The accumulation of fat, particularly abdominal visceral fat, impairs antioxidant
mechanisms 44]. All these events lead to a chronic and persistent proinflammatory state that results
in systemic pathologies.
Obesity and lung function
Obesity affects the respiratory system by several mechanisms, including direct mechanical
changes due to fat deposition on the chest wall, abdomen, and upper airway as well
as systemic inflammation 45]. It increases the work of breathing and, therefore, increases neural respiratory
drive, in addition to causing respiratory sleep disorders and eventually hypercapnic
respiratory failure 46]. In this context, tests of pulmonary function may be useful in evaluating whether
a physiological change can be explained by the well-known effects of obesity on the
respiratory system. Moreover, the detection of changes in the respiratory system resulting
from obesity may be important because several of these changes can be reversed by
weight loss or by surgical treatment of obesity (Fig. 1).
Fig. 1. Pulmonary function abnormalities resulting from obesity
In normal respiration, the diaphragm contracts, pushing the abdominal contents down
and forward. At the same time, the contraction of the external intercostal muscles
pulls the ribs upward and forward 47]. In obese individuals, this mechanism is impaired because the excess body fat that
lines the chest and occupies the abdomen limits the action of the respiratory muscles.
These structural changes in the thoracic-abdominal area restrict diaphragmatic mobility
and rib movement, which promotes changes in the dynamics of the respiratory system
and reduces its compliance, leading to mechanical impairment of the respiratory muscles
48]. Reduction in lung compliance can also result from increased pulmonary blood volume,
closure of dependent airways with the formation of small areas of atelectasis, or
increased alveolar surface tension due to a reduction in FRC 45], 49]. In addition, changes in the neural control of breathing and increases in thoracic
blood volume due to fat deposition in the chest also promote changes in pulmonary
function parameters 50]. Of note, Rasslan et al. 51] observed that adipose tissue is an endocrine and paracrine organ that produces many
cytokines and bioactive mediators, resulting in a pro-inflammatory state that may
be associated with pulmonary hypoplasia, atopy, BHR, and increased risk of asthma
in obese individuals.
Lung volume
Evaluation of static lung volume primarily indicates a reduction in the expiratory
reserve volume (ERV), functional residual capacity (FRC), and total lung capacity
(TLC). Reductions in FRC and ERV are detectable even at a modest increase in weight.
This results from a shift in the balance of inflationary and deflationary pressures
on the lung due to the mass load of adipose tissue around the rib cage and abdomen
49]. Elevated intra-abdominal pressure can be transmitted to the chest. This dramatically
reduces the FRC and ERV and requires patients to breathe in a less efficient part
of their pressure-volume curve, which in turn increases the work of breathing 46].
Jones and Nzekwu 52] reported that decreases in ERV, FRC, and TLC seem to exhibit an exponential correlation
with increased BMI and are directly correlated with the mechanical effects produced
by fat deposition in the chest and abdomen. According to this study, obesity decreases
respiratory system compliance and creates mechanical restraints on the muscles responsible
for breathing. In addition, Mafort et al. 53] used spirometry and whole body plethysmography to evaluate 30 patients who were overweight
or obese and showed that the primary change in lung volume in these patients was reduced
ERV. According to these authors, deposition of fat in the thoracic-abdominal region
is one of the main causes of the observed reduction in ERV. It is noteworthy that
marked reductions in ERV may lead to abnormalities in ventilation distribution, with
closure of airways in the dependent zones of the lung and inequalities in the ventilation-perfusion
ratio 49].
Airway function
Despite an association with increased BMI, airway function as measured by spirometry
is little affected by obesity except in morbidly obese individuals 45]. However, the use of spirometry to evaluate lung function in morbidly obese subjects
revealed a proportional reduction in forced vital capacity (FVC) and forced expiratory
volume in one second (FEV
1
), suggesting the occurrence of restrictive lung disease 54], 55]. The reduction in FEV
1
and FVC appears to be directly associated with the degree of obesity in morbidly obese
subjects with more severe restrictions. However, obesity has little direct effect
on airway caliber. The FEV
1
/FVC ratio is generally well preserved or elevated even in morbidly obese individuals,
indicating that FEV
1
and FVC are affected at the same rate 56]. A reduction in expiratory flows in an obese individual is unlikely to indicate bronchial
obstruction unless the flow measurements have been normalized for the reduction in
FVC 49].
Whole-body plethysmography, impulse oscillometry, or the forced oscillation technique
(FOT) can also be used to assess the mechanical properties of the airways in obese
individuals, more precisely through the measurement of airway resistance (Raw) 57]. Given that Raw is highly dependent on lung volume and hence is affected by any reduction
in the FRC, Raw is increased in obese individuals. In contrast, specific airway resistance,
which is corrected for lung volume, is within the normal range in such individuals.
However, some studies have suggested that the increase in Raw is not completely explained
by reduced lung volume because differences between obese individuals and non-obese
individuals may persist after correction of Raw for lung volume 57], 58]. The cause of the increase in Raw is unknown; one possibility is that the structure
of the airway may be remodelled by exposure to proinflammatory adipokines or by lipid
deposition 49].
Respiratory muscle strength
The function of the respiratory muscles may be impaired with increasing obesity, possibly
due to the load imposed on the diaphragm. The observed dysfunction of the respiratory
muscles can be partially explained by the increased resistance imposed by the presence
of excess fatty tissue on the chest and abdomen, which causes mechanical disadvantage
to these muscles 59].
Respiratory muscle strength can be assessed by measuring maximal inspiratory pressure
(MIP) and maximal expiratory pressure (MEP). In obese individuals, both MIP and MEP
may be reduced. The impairment of respiratory muscles is multifactorial; although
some studies indicate that the diaphragm exhibits higher electromyographic activity
in obese individuals than in normal-weight individuals, ineffective muscle contraction
and premature fatigue also occur 50], 60], 61], indicating that the reduction in MIP and MEP may be due to distension of the diaphragmatic
muscles, increased respiratory effort, and ineffective muscle biomechanics caused
by fat deposition in the thoracic and abdominal regions. Moreover, when in the supine
position, the weight of the abdomen in obese individuals causes the diaphragm to ascend
into the chest, resulting in the closure of small airways at the base of the lung
and thereby generating an intrinsic positive end-expiratory pressure that results
in increased ventilatory work and consequent muscle impairment 60], 61].
Ventilation distribution and gas exchange
Most obese individuals present an arterial partial pressure of oxygen (PaO
2
) within the normal range. However, among morbidly obese subjects, the alveolar-arterial
oxygen gradient [P(A-a)O
2
] is slightly widened because of the presence of areas of atelectasis and maldistribution
of ventilation, which can cause a major ventilation-perfusion imbalance. In these
individuals, the lower parts of the lungs are relatively poorly ventilated and perfused,
possibly due to the closure of small airways, whereas the upper regions of the lungs
exhibit enhanced ventilation 45], 62].
When assessing the carbon monoxide lung diffusion capacity (DLco), it should be noted
that lung tissue perfusion is a determining factor because most perfused areas have
higher concentrations of red blood cells and consequently higher diffusion of this
gas than non-perfused areas. This factor is important when evaluating the diffusion
of gases in obese individuals. Fat deposition in the thoracic region leads to higher
vascularization in this area. This explains, at least in part, the increase in the
DLco observed in the obese population 63]. In a recent study, the authors observed elevated DLco in 23.3 % of obese individuals,
and elevated DLco was most frequent in individuals with the highest accumulation of
fat in the thoracic region (r s
?=?0.42; p??0.01) 64].
Relationships between obesity, asthma, and bronchial hyperresponsiveness
Obesity has been associated with a higher incidence, prevalence, and severity of asthma
and with altered pulmonary function, poor treatment response, and high morbidity 15], 65]–68]. The incidence of asthma is 1.47 times higher in obese individuals than in non-obese
individuals, and a three-unit increase in BMI is associated with a 35 % increase in
the risk of asthma 69], 70]. Decreases in FRC and tidal volume in addition to sedentary lifestyle and limited
ability to perform+ physical activities among obese individuals may worsen asthma
symptoms 15], 71], 72]. In a cohort study of more than 25,000 children and adults with asthma, Schatz et
al. 73] showed that a higher BMI was associated with worsened asthma control and an increased
risk of asthma exacerbations.
The inflammatory changes described in obese individuals have been cited as factors
that might affect the clinical manifestations of asthma in these individuals. The
inflammatory condition of an obese individual, which includes higher expression levels
of leptin, adiponectin, TNF-?, transforming growth factor-? (TGF-?), CRP, and eotaxin,
determines how these inflammatory mechanisms overlap with those involved in asthma
and may exacerbate the influence of these cytokines on the contractility of the muscles
of the airways 68], 74].
By reducing functional lung volume, obesity can change airway diameter due to the
interdependence of the airway and the adjacent pulmonary parenchyma; these effects
favor the development of BHR even in non-asthmatic individuals. BHR has the potential
to enhance the effects of obesity on airway closure and hence on the distribution
of ventilation 49]. Torchio et al. 68] evaluated 41 healthy subjects through the methacholine challenge test measured in
a body plethysmograph and FOT and demonstrated that BHR was significantly associated
with obesity. These authors also observed that in obese men, but not in obese women,
BHR was associated with a decrease in lung volume. However, it remains unclear whether
conditions associated with BHR, such as obesity, are a risk factor for asthma. Studies
have provided conflicting results. Confounding factors include the different mechanisms
involved in obesity and asthma, self-reported diagnosis of asthma, gender differences,
the absence of synergistic effects of obesity and asthma on lung function, and the
use of different methods to measure lung function 75]–77].
Although the association between asthma and obesity remained uncertain until recently,
the existence of different asthma phenotypes is now well recognized. More recently,
Bates 78] highlighted two phenotypes of asthma in obese individuals: an early-onset allergic
(EOA) form that is complicated by obesity and a late-onset non-allergic (LONA) form
that occurs only in the setting of obesity. Whereas obese LONA asthmatics have more
compliant airways, obese EOA asthmatics display considerable inflammatory thickening
of the airways. Thus, these two phenotypes appear to be quite distinct pathological
conditions in obese individuals with asthma.
Patterns of body fat distribution and pulmonary function
Accumulation of fat in the thoracic and abdominal regions is likely to directly affect
the downward movement of the diaphragm and chest wall properties 49]. The pattern of body fat distribution seems to be relevant to the changes in lung
function observed in overweight and obese individuals. Changes in chest wall compliance
are more affected by the amount of fat in both the chest and upper abdomen than by
the amount of fat only in the chest, suggesting that respiratory system mechanics
may differ in obese individuals with the same BMI but with different patterns of body
fat distribution 45]. The pattern of body fat distribution can be assessed using several strategies, including
anthropometric methods, electrical bioimpedance, and dual-energy X-ray absorptiometry
(DXA) 79]–81]. Bioelectrical impedance analysis (BIA) has been widely used due to its high speed
of information processing and because it is a non-invasive, convenient, and relatively
inexpensive method that estimates the distribution of fluids in the intra- and extracellular
spaces in addition to the body components 82]. DXA is a noninvasive method and is considered the gold standard for body composition
assessment. It uses low-dose x-rays and permits the assessment of both total body
fat and fat in various body compartments, including the thoracic, android, and gynoid
regions 64], 83].
Obesity is associated with reduced respiratory system compliance, which itself is
exponentially correlated with BMI, waist circumference, and waist-hip ratio 45]. Nevertheless, lung volumes are only slightly associated with BMI, whereas DXA-derived
variables present highly significant correlations with FRC and ERV in both men and
women 49]. The android pattern of body fat deposition appears to negatively influence lung
volume and lung capacity by generating increased resistance to diaphragmatic contraction
and impairing respiratory mechanics. This would also explain the greater loss in FEV
1
and FVC in obese men than in women with a corresponding BMI because the gynoid pattern
prevails in women 84], 85]. In a recent study, Mafort et al. found a significant correlation between TLC and
waist circumference (r s
?=??0.34; p?=?0.03). These results reinforce the idea that abdominal fat plays a role in the
development of restrictive lung disease and its deleterious effect on mechanical ventilation
64].
Dyspnea on exertion in obese individuals
Dyspnea on exertion is a common complaint of obese adults. However, the mechanism
responsible for this symptom is not well defined yet 86]. Almost 40 % of obese individuals complain of dyspnea on exertion, an incidence that
is higher than that in general population 87]. Obesity has clear potential to directly affect respiration during exercise because
there is an increase in oxygen consumption (VO
2
) and carbon dioxide production (VCO
2
) due to stiffening of the respiratory system with the increase in mechanical work
needed to sustain exercise. Thus, even a slight increase in minute ventilation (V
E
) relative to resting levels can result in a considerable increase in the ratio between
VO
2
and respiratory work in obese adults. This ratio increases considerably in conditions
in which higher levels of V
E
are required, as during exercise, and this may result in dyspnea on exertion 87]–89].
Cardiopulmonary exercise testing (CPX) can provide valuable information on the performance
of the cardiac and respiratory systems in obese individuals with dyspnea on exertion.
Using CPX, Bernhardt et al. 87] compared obese men with dyspnea grade ?2 with those with dyspnea grade ?4 assessed
by the Borg scale. In that study, the authors found no association between the level
of perception of dyspnea and VO
2
and concluded that differences in the intensity of exercise, ventilatory demand, cardiovascular
fitness, or quality of the respiratory sensation do not seem to play an important
role in the development of dyspnea on exertion in these individuals. Also using CPX,
Hothi et al. 90] evaluated VO
2max
/kg in 152 obese individuals and 173 non-obese individuals with severe heart failure
(HF). They found that VO
2max
/kg is not a reliable indicator of cardiac fitness in all patients. Instead, they
found that despite having lower VO
2max
/kg, obese patients with HF are capable of generating higher cardiac power than nonobese
patients with HF. These results argue against the widespread use of VO
2max
/kg as a cardiac conditioning indicator for all HF patients.
Interestingly, Carpio et al. 91] evaluated the performance of obese patients with asthma and obese patients with misdiagnosed
asthma (the presence of asthma-like symptoms) compared with obese control subjects
during CPX. These authors observed that the level of dyspnea and the Borg-VO
2
slope during CPX were higher in obese patients with asthma and in patients with misdiagnosed
asthma than in obese control subjects. These authors concluded that the presence of
asthma-like symptoms in obese individuals can be attributed to an increased perception
of dyspnea, which, during exercise, is mainly associated with systemic inflammation
and excessive ventilation for metabolic demands.
Relationships between obesity, obesity hypoventilation syndrome, and obstructive sleep
apnea
Obesity is the most common known risk factor for the development of OSA 92]. The prevalence of OSA associated with high rates of morbidity and mortality increases
with age; the peak incidence occurs at approximately age 55, and the condition is
more prevalent in males than in females by a ratio of 2:1 93]. OSA is a systemic disease that causes an increase in TNF-?, IL-6, insulin resistance,
and glucose intolerance; these inflammatory cytokines have also been implicated in
the immunological mechanisms of obesity 94]. Central obesity and increased neck circumference are predisposing factors for OSA
95], 96]. The resulting reduction or interruption of airflow, which occurs despite inspiratory
effort, causes poor alveolar ventilation and oxyhemoglobin desaturation and, in cases
of prolonged events, a progressive increase in the arterial partial pressure of carbon
dioxide 97].
There is a strong association between OSA and metabolic syndrome as a whole or with
its individual components 20]. The prevalence of metabolic syndrome in patients with OSA is 60 %, significantly
higher than in general population 98]. This association is partially explained by the fact that patients with OSA are more
likely to have high visceral adiposity as well as abnormal glucose metabolism 20], 99]. There is ample evidence suggesting that OSA may exacerbate or induce the majority
of the components of metabolic syndrome. Some of these effects can be improved with
the use of continuous positive airway pressure. However, the modest and inconsistent
benefits obtained with this technique suggest that factors other than intermittent
hypoxia or the apnea-hypopnea index may play an important role 20].
Some obese individuals develop obesity hypoventilation syndrome (OHS), which is defined
by the triad of obesity, daytime hypoventilation, and sleep-disordered breathing and
represents hypoventilation that occurs in the absence of a neuromuscular, mechanical,
or metabolic cause 100]. The prevalence of OHS is estimated to be 8.5 % in patients with OSA and 19-31 %
in obese subjects 101], 102]. OHS is more prevalent in women than in men, and postmenopausal women with OSA have
a higher prevalence of OHS. This has been attributed to hormonal influences, particularly
to the role of progesterone as a respiratory stimulant prior to menopause 103], 104]. Compared with eucapnic obese patients, patients with OHS have severe upper airway
obstruction, restrictive pulmonary damage, decreased central respiratory drive, increased
incidence of pulmonary hypertension, and increased mortality 100]. Among the possible mechanisms involved in the pathogenesis of OHS, some studies
have reported damage to respiratory mechanics caused by obesity, leptin resistance
leading to central hypoventilation, respiratory sleep disorders, and impaired compensatory
responses to acute hypercapnia 97], 100], 102]. With respect to pulmonary function, patients with OHS present a reduction in chest
wall compliance of approximately 2.5-fold compared to patients with eucapnic obesity,
as well as increased pulmonary resistance that is likely secondary to the reduction
in FRC 100].
Impact of treatment of obesity and weight loss on lung function
As previously reported, obesity causes a number of changes in pulmonary function parameters.
It is also known that weight loss improves these parameters, supporting the hypothesis
that respiratory changes caused by obesity are a direct result of excess weight 45].
Several studies have shown that ERV, one of the parameters that is most significantly
altered in obese individuals, increases after weight loss, adopting a calorie-restricted
diet, or bariatric surgery 105], 106]. Hakala et al. 107] found a considerable increase in the ERV of patients whose BMI decreased from 45
to 39 kg/m
2
after adopting a calorie-restricted diet. Babb et al. showed that even modest reductions
in weight, i.e., a decrease in BMI from 35 to 33 kg/m
2
, induce an increase in end-expiratory lung volume during submaximal exercise 108]. Weight loss also causes changes in other parameters, including FRC, TLC, and gas
exchange, resulting in increased blood oxygenation 107]. Respiratory muscle strength and dyspnea also improve after weight loss 109], 110].
In a recent publication, Mafort et al. 64] showed that obese and overweight patients exhibited a significant reduction in BMI
after six months of intragastric balloon therapy; the median BMI value decreased from
39.1 kg/m
2
at the beginning of the evaluation to 34.5 kg/m
2
at the end of the evaluation (p?=?0.0001). The reduction in BMI was accompanied by statistically significant reductions
in TLC (p?=?0.0001), FRC (p?=?0.0001), residual volume (p?=?0.0005), and ERV (p?=?0.0001).
In obese patients with asthma, both surgical and nonsurgical weight loss are associated
with improvement in symptoms, decreased use of medication, increased effectiveness
of drug therapy, and a reduction in risk of exacerbation and hospital admission rate
111]. Improvements in lung function, including FEV
1
, FVC, and Raw, after weight loss in obese patients with asthma have also been reported
in several studies 66], 112]–114]. In a randomized study of obese adult patients with severe uncontrolled asthma, Dias-Júnior
et al. 114] showed that following a weight loss program for a period of 6 months was associated
with improvement in asthma control and lung function.
A decrease in BHR to methacholine after weight loss in obese individuals with asthma
was reported by Al-Alwan et al. 112] and by van Huisstede et al. 115]. In a prospective controlled study of obese individuals with asthma, Pakhale et al.
66] observed a significant improvement in BHR to methacholine compared to controls (p?=?0.009) after 3 months of a behavioral weight loss program. Boulet et al. 67] evaluated severely obese patients with asthma before and after bariatric surgery
and observed reduced BHR, increased lung volume, and noticeably decreased asthma symptoms
and medication required to control asthma 12 months after surgery. This study also
showed that reduction in BMI and improved BHR were correlated with a reduction in
CRP.