Download Fat Accumulation, Leptin, and Hypercapnia in Obstructive Sleep

Fat Accumulation, Leptin, and
Hypercapnia in Obstructive Sleep
Apnea-Hypopnea Syndrome*
Ryuhi Shimura, MD; Koichiro Tatsumi, MD, FCCP; Akira Nakamura, MD;
Yasunori Kasahara, MD, FCCP; Nobuhiro Tanabe, MD, FCCP;
Yuichi Takiguchi, MD, FCCP; and Takayuki Kuriyama, MD, FCCP
Background: Obesity and visceral fat accumulation (VFA) are risk factors for the development of
obstructive sleep apnea-hypopnea syndrome (OSAHS), and a subgroup of OSAHS patients
acquire hypoventilation. Circulating leptin, an adipocyte-derived signaling factor, increases in
accordance with body mass index (BMI); under experimental conditions, leptin selectively
decreases visceral adiposity and it is also a respiratory stimulant.
Objective: To investigate whether the location of body fat deposits, ie, the distribution of VFA and
subcutaneous fat accumulation (SFA), contributes to hypoventilation and whether circulating
levels of leptin are involved in the pathogenesis of hypoventilation, which is often observed in
OSAHS.
Methods: We assessed VFA and SFA by abdominal CT scan, and measured lung function and
circulating levels of leptin in 106 eucapnic and 79 hypercapnic male patients with OSAHS.
Results: In the whole study group, circulating leptin levels correlated with BMI (r ⴝ 0.56), VFA
(r ⴝ 0.24), and SFA (r ⴝ 0.47), but not with PO2 or sleep mean arterial oxygen saturation (SaO2).
BMI, percentage of predicted vital capacity, FEV1/FVC ratio, apnea-hypopnea index, sleep mean
SaO2, VFA, and SFA were not significantly different between two groups. Circulating leptin levels
were higher in the hypercapnic group than in the eucapnic group. Logistic regression analysis
indicated that serum leptin was the only predictor for the presence of hypercapnia (␤ ⴝ 0.21,
p < 0.01).
Conclusions: These results suggest that the location of body fat deposits may not contribute to the
pathogenesis of hypoventilation, and circulating leptin may fail to maintain alveolar ventilation in
hypercapnic patients with OSAHS.
(CHEST 2005; 127:543–549)
Key words: hypoventilation syndrome; obesity; respiratory depression; subcutaneous fat; visceral fat
Abbreviations: AHI ⫽ apnea-hypopnea index; BMI ⫽ body mass index; CSF ⫽ cerebrospinal fluid; OSAHS ⫽ obstructive
sleep apnea-hypopnea syndrome; Sao2 ⫽ oxygen saturation; SFA ⫽ subcutaneous fat accumulation; VC ⫽ vital capacity;
VFA ⫽ visceral fat accumulation
was first described as an adipose-derived
L eptin
hormone, which induces a complex response
including control of body weight and energy expenditure after interaction with specific receptors lo*From the Department of Respirology, Graduate School of
Medicine, Chiba University, Chiba, Japan.
This study was supported by a Grant-in-Aid for Scientific Research (C)(14570541) from the Ministry of Education, Science,
Sports and Culture, and grants to Respiratory Failure Research
Group from the Ministry of Health, Labour and Welfare, Japan.
Manuscript received February 26, 2004; revision accepted September 2, 2004.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: Koichiro Tatsumi, MD, FCCP, Department
of Respirology, Graduate School of Medicine, Chiba University,
1– 8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan; e-mail: tatsumi@
faculty.chiba-u.jp
www.chestjournal.org
cated in the CNS and in peripheral tissues.1 Leptin
receptors are found in the hypothalamus, particularly
in the arcuate nucleus, where leptin is thought to
exert its primary feedback signaling.2 Circulating
levels of leptin reflect the amount of energy stored in
adipose tissue and are reported to correlate with the
body mass index (BMI) in humans.3,4
Control of body weight is clinically important in
patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) because obesity, male gender, and
increasing age are recognized to be risk factors for
OSAHS. Among these risk factors, obesity plays a
major role, because approximately 70% of patients
with this disorder are obese and obesity is the only
reversible risk factor of importance.5 Among those
with OSAHS, some individuals present an increase
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543
in resting Paco2, leading to obesity hypoventilation
syndrome.6 Obesity itself is thought to affect the
respiratory control system. The mechanical load
imposed by obesity, especially visceral fat accumulation (VFA), on the respiratory system may explain
the development of hypoventilation, although the
majority of obese people breathe normally.6 Alternatively, central defects of the respiratory control
system may contribute to respiratory depression;
however, the precise mechanisms have been undefined.7
Leptin may be a modulator of the respiratory
control system. The absence of leptin in the C57BL/
6J-Lepob mouse is associated with marked obesity,
elevated Paco2, and a reduced hypercapnic ventilatory response.8 Conversely, leptin replacement in
these mutant mice stimulated ventilation and hypercapnic ventilatory response across all sleep/wake
states. The effects of leptin deficiency on respiratory
depression, and the effects of leptin administration
on respiratory control, were more pronounced during sleep than wakefulness in mice, although the
precise mechanism by which leptin influences respiratory control has been undefined.9,10 However,
whether endogenous leptin plays a role in the respiratory control system in healthy humans and/or
patients with OSAHS remains unclear. In addition,
whether leptin affects visceral adiposity has not been
determined in OSAHS, although it has been reported that leptin selectively decreases visceral adiposity in rats.11
The purpose of the present study was to examine
whether the location of body fat deposits, ie, the
distribution of VFA and subcutaneous fat accumulation (SFA), contributes to hypoventilation, and
whether circulating levels of leptin are involved in
the pathogenesis of hypoventilation, which is often
observed in OSAHS. We hypothesized that reduced
levels of leptin may explain the increase of Paco2
when BMI is similar in eucapnic and hypercapnic
OSAHS patients.
Materials and Methods
The study population consisted of 185 male patients with
OSAHS who were examined using polysomnography from April
2001 to December 2003. All patients were free from respiratory
infection, heart failure, and other respiratory problems, including
COPD, at the time of polysomnography. They were asked to
complete a questionnaire on sleep symptoms, medical history,
and medications. OSAHS was established on the basis of clinical
and polysomnographic criteria. The average number of episodes
of apnea and hypopnea per hour of sleep (the apnea-hypopnea
index [AHI]) was calculated as the summary measurement of
sleep-disordered breathing. In addition to clinical symptoms, an
AHI of ⬎ 5 was also used as a selection criterion.
A male population with clinical symptoms of sleep apnea
(n ⫽ 520) was first divided into two groups according to AHI
(AHI ⱖ 5 [n ⫽ 426] and AHI ⬍ 5 [n ⫽ 94]). Next, patients with
AHI ⱖ 5 were subclassified into two groups according to Paco2
level (Paco2 ⬎ 45 mm Hg [n ⫽ 79] and Paco2 ⱕ 45 mm Hg
[n ⫽ 327]). Hypercapnic OSAHS patients (Paco2 ⬎ 45 mm Hg)
were more obese and had a higher AHI and a lower arterial
oxygen saturation (Sao2) during sleep compared with eucapnic
OSAHS patients. Then, eucapnic OSAHS patients (Paco2 ⱕ 45
mm Hg) were further subclassified into two subgroups according
to AHI (AHI ⬎ 60 [n ⫽ 45] and AHI ⱕ 60 [n ⫽ 302]). In
addition, to compare hypercapnic and eucapnic patients matched
for BMI and age, and to match the number of patients, those with
an AHI ⱕ 60 were further subclassified into two groups according to BMI (BMI ⬎ 30 [n ⫽ 61] and BMI ⱕ 30 [n ⫽ 241]).
Finally, a subgroup with an AHI ⬎ 60 (n ⫽ 45) and a subgroup
with an AHI ⱕ 60 and a BMI ⬎ 30 (n ⫽ 61) were selected for the
eucapnic group (Fig 1).
Pulmonary function tests were performed to determine vital
capacity (VC) and FEV1 using a standard spirometer (Fudac-60;
Fukuda Denshi; Tokyo, Japan). Arterial blood gas samples during
room air breathing were drawn with the patient in the supine
position and measured in a blood gas analyzer (Model 1312;
Instrumental Laboratory; Milano, Italy).
Overnight polysomnography (Compumedics; Melbourne, Australia) was performed between 9 pm and 6 am. Polysomnography
consisted of continuous polygraphic recording from surface leads
for EEG, electro-oculography, electromyography, ECG, thermistors for nasal and oral airflow, thoracic and abdominal
impedance belts for respiratory effort, pulse oximetry for oxyhemoglobin level, tracheal microphone for snoring, and sensor for
the position during sleep. Polysomnographic records were staged
manually according to standard criteria.12 Respiratory events
were scored according to American Academy of Sleep Medicine
criteria13: apnea was defined as complete cessation of airflow
lasting ⱖ 10 s, and hypopnea was defined as either a ⱖ 50%
reduction in airflow for ⱖ 10 s or a ⬍ 50% but discernible
reduction in airflow accompanied either by a decrease in oxyhemoglobin saturation of ⬎ 3% or arousal. Severity of OSAHS was
determined based on the AHI and mean and lowest Sao2.
At 7 am on the morning after the sleep study, venous blood was
obtained in the fasting state to measure leptin. Serum levels of
leptin were determined by radioimmunoassay (Linco Research;
St. Louis, MO) with intraassay and interassay coefficients of
variation of 2.8 to 3.8% (n ⫽ 10) and 0.4 to 4.6% (n ⫽ 10),
respectively.14
Areas of SFA and VFA were measured by CT in a single
cross-sectional scan at the level of the umbilicus.15 The area of
VFA was divided by that of SFA to calculate the VFA/SFA ratio.
The study protocol was approved by the Research Ethics Committee of Chiba University School of Medicine, and all patients
gave their informed consent prior to the study.
Statistical Analysis
The results are expressed as mean ⫾ SEM. Age, BMI, pulmonary function parameters, and sleep parameters were compared
between hypercapnic and eucapnic patients using the MannWhitney U test. Since data were not normally distributed, we
used Spearman rank correlation coefficient to examine the
association of two parameters. Analysis of covariance was used to
compare the influence of BMI, VFA, and SFA on circulating
leptin levels between hypercapnic and eucapnic patients. Logistic
regression analysis was performed with Paco2 as the dependent
variable and leptin, BMI, VFA, SFA, mean Sao2 during sleep,
percentage of predicted VC, and percentage of predicted FEV1
as explanatory variables; p ⬍ 0.05 was considered statistically
significant.
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Clinical Investigations
Fat Accumulation, Leptin, and
Hypercapnia in Obstructive Sleep
Apnea-Hypopnea Syndrome*
Ryuhi Shimura, MD; Koichiro Tatsumi, MD, FCCP; Akira Nakamura, MD;
Yasunori Kasahara, MD, FCCP; Nobuhiro Tanabe, MD, FCCP;
Yuichi Takiguchi, MD, FCCP; and Takayuki Kuriyama, MD, FCCP
Background: Obesity and visceral fat accumulation (VFA) are risk factors for the development of
obstructive sleep apnea-hypopnea syndrome (OSAHS), and a subgroup of OSAHS patients
acquire hypoventilation. Circulating leptin, an adipocyte-derived signaling factor, increases in
accordance with body mass index (BMI); under experimental conditions, leptin selectively
decreases visceral adiposity and it is also a respiratory stimulant.
Objective: To investigate whether the location of body fat deposits, ie, the distribution of VFA and
subcutaneous fat accumulation (SFA), contributes to hypoventilation and whether circulating
levels of leptin are involved in the pathogenesis of hypoventilation, which is often observed in
OSAHS.
Methods: We assessed VFA and SFA by abdominal CT scan, and measured lung function and
circulating levels of leptin in 106 eucapnic and 79 hypercapnic male patients with OSAHS.
Results: In the whole study group, circulating leptin levels correlated with BMI (r ⴝ 0.56), VFA
(r ⴝ 0.24), and SFA (r ⴝ 0.47), but not with PO2 or sleep mean arterial oxygen saturation (SaO2).
BMI, percentage of predicted vital capacity, FEV1/FVC ratio, apnea-hypopnea index, sleep mean
SaO2, VFA, and SFA were not significantly different between two groups. Circulating leptin levels
were higher in the hypercapnic group than in the eucapnic group. Logistic regression analysis
indicated that serum leptin was the only predictor for the presence of hypercapnia (␤ ⴝ 0.21,
p < 0.01).
Conclusions: These results suggest that the location of body fat deposits may not contribute to the
pathogenesis of hypoventilation, and circulating leptin may fail to maintain alveolar ventilation in
hypercapnic patients with OSAHS.
(CHEST 2005; 127:543–549)
Key words: hypoventilation syndrome; obesity; respiratory depression; subcutaneous fat; visceral fat
Abbreviations: AHI ⫽ apnea-hypopnea index; BMI ⫽ body mass index; CSF ⫽ cerebrospinal fluid; OSAHS ⫽ obstructive
sleep apnea-hypopnea syndrome; Sao2 ⫽ oxygen saturation; SFA ⫽ subcutaneous fat accumulation; VC ⫽ vital capacity;
VFA ⫽ visceral fat accumulation
was first described as an adipose-derived
L eptin
hormone, which induces a complex response
including control of body weight and energy expenditure after interaction with specific receptors lo*From the Department of Respirology, Graduate School of
Medicine, Chiba University, Chiba, Japan.
This study was supported by a Grant-in-Aid for Scientific Research (C)(14570541) from the Ministry of Education, Science,
Sports and Culture, and grants to Respiratory Failure Research
Group from the Ministry of Health, Labour and Welfare, Japan.
Manuscript received February 26, 2004; revision accepted September 2, 2004.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: Koichiro Tatsumi, MD, FCCP, Department
of Respirology, Graduate School of Medicine, Chiba University,
1– 8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan; e-mail: tatsumi@
faculty.chiba-u.jp
www.chestjournal.org
cated in the CNS and in peripheral tissues.1 Leptin
receptors are found in the hypothalamus, particularly
in the arcuate nucleus, where leptin is thought to
exert its primary feedback signaling.2 Circulating
levels of leptin reflect the amount of energy stored in
adipose tissue and are reported to correlate with the
body mass index (BMI) in humans.3,4
Control of body weight is clinically important in
patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) because obesity, male gender, and
increasing age are recognized to be risk factors for
OSAHS. Among these risk factors, obesity plays a
major role, because approximately 70% of patients
with this disorder are obese and obesity is the only
reversible risk factor of importance.5 Among those
with OSAHS, some individuals present an increase
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543
Figure 2. Serum leptin levels vs percentage of BMI in patients with OSAHS. Each closed circle
represents a hypercapnic patient, and each open circle represents a eucapnic patient. The dashed and
solid regression lines describe the relationship between serum leptin levels and BMI in hypercapnic
and eucapnic patients, respectively. Hypercapnic patients had higher leptin levels relative to BMI
compared with eucapnic patients (p ⬍ 0.05).
hypercapnia (␤ ⫽ 0.209, p ⬍ 0.01), while BMI, VFA,
SFA, mean Sao2 during sleep, percentage of predicted
VC, and FEV1/FVC ratio were not predictors.
Discussion
In the present study, we found that circulating
levels of leptin were higher in hypercapnic patients
with OSAHS than in eucapnic patients with OSAHS,
although BMI, percentage of predicted VC, FEV1/
FVC ratio, AHI, sleep mean Sao2, VFA, and SFA
were not significantly different between two groups.
The levels of leptin relative to BMI, VFA, and SFA
were higher in hypercapnic patients compared with
those in eucapnic patients. Logistic regression analysis indicated that serum leptin was the only predic-
Figure 3. Serum leptin levels vs VFA in patients with OSAHS. Each closed circle represents a
hypercapnic patient, and each open circle represents a eucapnic patient. The dashed and solid
regression lines describe the relationship between serum leptin levels and VFA in hypercapnic and
eucapnic patients, respectively. Circulating leptin levels relative to VFA were higher in hypercapnic
patients compared with those in eucapnic patients (p ⬍ 0.05).
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Clinical Investigations
Figure 4. Serum leptin levels vs SFA in patients with OSAHS. Each closed circle represents a
hypercapnic patient, and each open circle represents a eucapnic patient. The dashed and solid
regression lines describe the relationship between serum leptin levels and SFA in hypercapnic and
eucapnic patients, respectively. Hypercapnic patients had higher leptin levels relative to SFA compared
with eucapnic patients (p ⬍ 0.05).
tor for the presence of hypercapnia (␤ ⫽ 0.21,
p ⬍ 0.01). These results suggest that leptin did not
prevent hypoventilation in OSAHS, although leptin
is a respiratory stimulant in mice.
Phipps et al16 reported that hyperleptinemia was
associated with hypercapnic respiratory failure in 40
men and 16 women: eucapnia (n ⫽ 44) and hypercapnia (n ⫽ 12). Obesity is the major factor regulating circulating leptin, which is also influenced by
gender and age.17,18 We confirmed the results of
Phipps et al16 in a larger sample (n ⫽ 185) of only
men to avoid any gender effect on circulating levels
of leptin. In addition, circulating levels of leptin were
compared in hypercapnic and eucapnic patients with
OSAHS matched for BMI and age. Moreover,
whether the location of body fat deposits, ie, the
distribution of VFA and SFA, contributes to hypoventilation was examined. VFA correlated weakly
with levels of circulating leptin, compared with the
relation between SFA and serum leptin, suggesting
that the amount of visceral adiposity may not play a
major role in the levels of circulating leptin.
Circulating leptin concentrations were higher in
obese subjects than in normal-weight subjects, although several factors other than the amount of body
fat may contribute to the elevation of circulating
leptin concentrations.4,19,20 The mechanism of the
increase in circulating leptin involves the induction
of the ob gene.17 Circulating leptin concentrations
seem to be regulated by changes in body fat at the
level of ob gene expression.18 If leptin acts as it
www.chestjournal.org
should, when adipocytes send the signal to the brain
about the amount of adipose tissue, appetite will
decrease and energy expenditure will increase, resulting in weight loss. Considering the fact that
circulating leptin levels are elevated in most overweight individuals, obesity may be associated with
leptin resistance.21–23 In the present study, circulating leptin concentrations increased in parallel with
BMI, although this relationship was not as constant
as observed in inbred mice.3,4
Obese C57BL/6J-Lepob mice, which lack circulating leptin, exhibit respiratory depression and elevated Paco2. Three days of leptin infusion restores
ventilation, particularly during rapid eye movement
sleep, in these obese mutant mice. Thus, leptin can
prevent respiratory depression in obesity, while deficiency or reduced leptin levels may induce hypoventilation in some obese subjects.9 Based on the
findings of this mutant mice study, obese humans
may acquire hypoventilation when circulating leptin
levels are proportionately low. Therefore, we hypothesized that the reduced levels of leptin may
explain the presence of hypoventilation in OSAHS.
Alternatively, OSAHS patients may exhibit elevated Paco2 when leptin levels in the CNS are
relatively low, despite circulating leptin levels being
high; ie, decreased central/circulating leptin ratio.24,25 Obesity was suggested to be caused or
related to the saturation of the leptin transport
system from the periphery to the CNS.26 Moreover,
decreased sensitivity to leptin of the leptin-effector
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547
system in the CNS may also explain the presence of
hypoventilation. This is analogous to what is observed in leptin-resistant mice, which bear a mutation in the leptin receptor gene (db/db mice).27
Then, hypoventilation in OSAHS could be explained
by two opposing hypotheses, insufficient brain leptin
levels or impairment of the leptin transport system to
the brain, and depressed sensitivity to leptin in the
CNS. In our study, hypercapnic patients had higher
leptin levels than eucapnic patients when compared
relative to BMI; this may suggest that hypoventilation in OSAHS is partly due to depressed sensitivity
to leptin in the CNS. However, human obesity is a
complex disorder, and the pathophysiology of leptin
is not as simple as it seems to be in rodent models of
obesity. In addition, other mechanisms apart from fat
mass could contribute to the increased leptin levels
in OSAHS subjects.19,20,28
In this study, hypercapnic patients were found to
have higher leptin levels than eucapnic patients
when compared relative to VFA and SFA. The linear
regression line between leptin levels and VFA and
SFA was shifted upward in hypercapnic patients
compared with that in eucapnic patients (Fig 2, 3). It
has been reported that leptin selectively decreases
visceral adiposity in rats.11 Whether leptin affects
visceral adiposity was not clarified in this study.
However, visceral adiposity was similar in hypercapnic and eucapnic patients, despite circulating leptin
levels being higher in hypercapnic patients.
The relation between cerebrospinal fluid (CSF)
leptin and circulating leptin is best described by a
logarithmic function.24 The lower capacity of leptin
transport from blood to brain in obese individuals
may be one of the mechanisms for leptin resistance.24 The higher levels of circulating leptin observed in hypercapnic patients in the present study
may suggest a higher degree of resistance to leptin in
these patients compared to eucapnic patients. However, leptin gene defects are rare in human obesity,29
and there are no known functional or structural
abnormalities of the brain leptin receptor in humans.
We acknowledge one important limitation to our
study: we did not obtain CSF samples from our
patients to measure the levels of leptin. In addition,
whether the ratio of CSF to blood leptin was modified or not under hypercapnia was unclear. Ideally,
we should have performed the study in all subjects
with and without hypercapnia matched for BMI.
However, it was difficult to match hypercapnic subjects with eucapnic subjects with respect to BMI and
sleep parameters, if all subjects were included in this
study. Thus, in order to match hypercapnic and
eucapnic patients for BMI, a subgroup with an AHI
⬎ 60 (n ⫽ 45) and a subgroup with an AHI ⱕ 60 and
a BMI ⬎ 30 (n ⫽ 61) were selected for the eucapnic
group. The average BMI was 33.0 ⫾ 0.4 in the
present study, which was lower compared with a
Western study dealing with OSAHS. East Asian
subjects are more likely to acquire OSAS at a lower
BMI than Western subjects.30
In summary, the increased concentration of circulating leptin relative to BMI, VFA, and SFA was
associated with hypercapnia in OSAHS patients. The
central mechanisms of leptin regulating breathing
may shed light regarding the pathogenesis of obesity
hypoventilation syndrome.
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