The Relationship between the Circadian Rhythm of Circulating Leptin and the Very Low-Frequency Component of Heart Rate Variability |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
ABSTRACT |
|---|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Cachexic patients with chronic obstructive pulmonary disease (COPD) show abnormalities of the autonomic nervous system (ANS), neuroendocrine function, and energy expenditure. Leptin has been implicated in the regulation of ANS, neuroendocine function, and thermogenesis in humans. We assessed the physiologic significance of the circadian rhythm of circulating leptin using power spectrum analysis of heart rate variability (HRV) in nine cachexic male patients with COPD, eight noncachexic patients with COPD, and seven healthy control subjects. A diurnal pattern of 24-h leptin levels was present in both the control subjects (analysis of variance [ANOVA]; F = 7.80, p < 0.0001) and noncachexic COPD patients (F = 9.29, p < 0.0001), but was strikingly absent in the cachexic COPD patients (F = 2.09, p = NS). Analysis of HRV demonstrated that the diurnal rhythm of 24-h very low frequency (VLF; 0.003 to 0.04 Hz) showed significantly identical fluctuations with those of 24-h leptin levels, in all of the three groups (r = 0.388, p < 0.0001). Because VLF has been considered to reflect neuroendocrine and thermoregulatory influences, these data may suggest that the loss of circadian rhythm of circulating leptin has clinical importance in the pathophysiologic features in cachexic patients with COPD.
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Unexplained weight loss, commonly observed in patients with chronic obstructive pulmonary disease (COPD), is clinically important because it is an independent risk factor of mortality in these patients (1). Cachexia is a pathologic state characterized by weight loss together with anorexia, weakness, anemia, and asthenia (4). At the metabolic level, cachexia is associated with loss of skeletal muscle protein along with a depletion of body lipid stores (4). Cachexic patients with COPD show abnormalities of the autonomic nervous system (ANS), neuroendocrine function, and energy expenditure. However, its pathophysiologic mechanisms are poorly understood (5).
Leptin is a 16-kilodalton adipocyte-derived hormone that circulates in the systemic blood in the free and bound form (11). Circulating levels of leptin reflect the amount of energy stored in adipose tissue (15, 16). Leptin acts either directly, or by binding to specific receptors in the hypothalamus, to decrease food intake, influence glucose and lipid metabolism, alter neuroendocrine function, and increase thermoregulatory energy expenditure by altering sympathetic and parasympathetic nervous system activities (11). It has been demonstrated that circulating leptin levels show significant ultradian and circadian variation with a distinct nocturnal peak, although the mechanisms regulating leptin production in the adipose tissue and its potential physiologic significance remain unknown (17).
Power spectrum analysis (PSA) of heart rate variability (HRV) is a reliable method, which can be used as an index of cardiac autonomic balance (23, 24). PSA of HRV is a noninvasive technique, based on electrocardiogram (ECG) sampling of RR interval variation, thus providing a dynamic assessment of sympathetic and parasympathetic components of the ANS (23, 24). Although further studies will be required to improve physiologic understanding of each HRV component, they have been considered to mirror thermoregulation and neuroendocrine regulation as well as sympathetic and parasympathetic modulations of cardiac ANS (25). Physiologic interpretation of these components of HRV is similar to the physiologic properties of leptin (11).
We have previously reported that circulating leptin is regulated physiologically even in the presence of cachexia in patients with COPD (28). Because our previous studies evaluated the level of circulating leptin during its morning nadir after an overnight fast, its diurnal variation and related pathophysiologic significance in patients with COPD have not been clarified.
Against these backgrounds, we investigated the questions of: (1) whether the circadian rhythm of circulating leptin is preserved in cachexic patients with COPD, and (2) whether the diurnal pattern of circulating leptin is reflected in the fluctuations of HRV, in order to demonstrate its pathophysiologic significance. Elucidating these questions may provide novel insights into the pathophysiology of cachexia in patients with COPD.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Study Population
Seventeen patients with COPD (all male) were diagnosed by the criteria from the American Thoracic Society (29). The present patients with COPD have been clinically stable for at least 3 mo and were absent of clinical signs of exacerbation, such as infection or heart failure. Patients who were associated with conditions known to affect serum leptin levels, such as the use of corticosteroids, renal or liver insufficiency, metabolic diseases, and smoking, were strictly excluded (30- 33). None of the patients was receiving nutritional support therapy.
Seven age-matched healthy males were also studied as control subjects. These control subjects had no medical illnesses, had normal physical examinations, laboratory data, and no history of endocrine, renal, liver, or other metabolic disorders. All were nonsmokers. None of the control subjects was taking any medications.
In order to arrange the appropriate conditions for HRV analysis,
we confirmed that all the patients with COPD and control subjects
were in sinus rhythm, normotensive, not diabetics, and without known
coronary artery disease. At the time of this study, none of the patients
with COPD was taking medications that are known to affect HRV,
such as anticholinergic agents or 
-receptor agonists (23).
All subjects were admitted to our hospital for this research. Informed consent was obtained from all subjects in this study.
Pulmonary Function Test
FVC and FEV1 were measured with standard spirometric techniques (CHESTAC-25 part II EX; Chest Corp., Tokyo, Japan). Reference values were those proposed by Quanjer and associates (34). Arterial blood gas was analyzed with the subject breathing room air in the sitting position (280 Blood Gas System; Ciba Corning Diagnostics Corp., Medfield, MA).
Experimental Protocol
After an overnight fast, all subjects had anthropometric measurements and were tested for body composition using bioelectrical impedance analysis with an instrument and software from the Omron Corporation (HBF-301; Tokyo, Japan) (28). Because of the wide spectrum of nutritional status in the patients with COPD, the present patients with COPD were divided into two groups according to their percent body fat (%fat). One is relatively cachexic patients with COPD (cachexic patients with COPD; n = 9, %fat < 20%), the other is relatively noncachexic patients with COPD (noncachexic patients with COPD; n = 8, %fat > 20%). We took %fat as a standard to assess nutritional status rather than body mass index (BMI), because BMI is a less accurate and reliable measurement for body composition assessment compared with %fat (35, 36). Twenty percent (%fat) as a cutoff index is based on the reference values (37).
First blood sample for serum leptin measurement was withdrawn from each subject at 9:00 A.M., and thereafter samples were withdrawn at 11:30 A.M., 2:00 P.M., 5:30 P.M., 8:00 P.M., midnight, 3:00 A.M., and 6:00 A.M. Meals were provided at 7:30 A.M., noon, and 6:00 P.M. Each subject received an isocaloric diet (approximately 30 kcal/kg/d) with 65%, 20%, and 15% of energy from carbohydrate, fat, and protein, respectively. All subjects slept from 10:00 P.M. until 6:00 A.M. the following day. All subjects underwent 24-h Holter ECG monitoring from 9:00 A.M. until 9:00 A.M. the following day, in parallel with the blood sampling.
Determination of Serum Leptin Levels
Serum leptin levels were determined in duplicate by high-sensitivity radioimmunoassay (Linco Res, Inc., St. Louis, MO) (28).
Heart Rate Variability
All subjects underwent 24-h Holter monitoring with two-channel recorder and Holter system (model SM-50 and DMW-9000H, respectively; Fukuda Denshi Corp., Tokyo, Japan). Subjects with less than 22-h recordings or normal sinus beats less than 80% of total beats were excluded. At this point, two cachexic patients with COPD and one noncachexic patients with COPD in the present study were excluded. The frequency histogram of all RR intervals was displayed on a screen and strips in both tails of RR distribution were visually checked: premature beats and artifacts, whose RR intervals were differing by more than 20% from the previous intervals, were carefully eliminated, both automatically and manually. Then the ECG data were digitalized with a sampling frequency of 125 Hz and transferred to a personal computer for the calculation of HRV parameters for entire 24-h periods.
Time domain analyses of HRV are derived from statistical calculations performed on the set of normal-to-normal (N-N) interbeat intervals: the average heart rate (HR) in beats per minute, the average interbeat interval of N-Ns in milliseconds (NN), the standard deviation of N-Ns (SDNN) in milliseconds, the square root of the mean of the squared differences between adjacent N-Ns (rMSSD) in milliseconds, and the proportion of successive N-N differences > 50 ms (%NN50) in percent, were calculated.
Frequency domain analysis of HRV was performed on the sequence of N-N intervals of the entire 24-h segment. The data were processed by the maximal entropy method by use of the software CHIRAM (Suwa Trust, Tokyo, Japan). RR interval data containing irregular beats were analyzed using the complement method: irregularly time-sampled signals were complemented and regularly resampled with the previous and following signals for spectral analysis (38). A spectral plot for 1 h was the average of the spectra computed over 5-min periods. Spectral measurements were plotted hourly and then averaged for 24 h. The resulting power spectrum was separated into an ultra-low frequency (ULF; < 0.003 Hz), a very low frequency (VLF; 0.003 to 0.04 Hz), a low frequency (LF; 0.04 to 0.15 Hz), and a high frequency (HF; 0.15 to 0.40 Hz). A total frequency (TF; < 0.40 Hz) and the ratio of LF to HF power (LF/HF) were also determined.
Statistical Analysis
A Mann-Whitney U test for nonparametric data was used to analyze the difference between the two groups. The relations between variables were evaluated by Spearman's rank correlations. To demonstrate diurnal variations, a single-factor analysis of variance (ANOVA) test was used with post hoc correction (Fisher's protected test). Repeated measures ANOVA test was also used to assess the differences between the groups with respect to diurnal variations of serum leptin and HRV components. Correlations between the diurnal rhythm of serum leptin and other rhythms were performed using Pearson's correlation coefficient between the values at the same time (17, 21). Results were expressed as mean ± SD. Significance was determined at the 5% level. Statistical analysis was performed using the Statview Statistical Package (Statview, Inc., Berkeley, CA).
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Characteristics and Serum Leptin Levels of the Study Population
Clinical characteristics and serum leptin levels of the cachexic patients with COPD (n = 9, %fat < 20%), noncachexic patients with COPD (n = 8, %fat > 20%), and healthy control subjects (n = 7) are summarized in Table 1. The cachexic patients with COPD had significantly lower BMI and %fat compared with the control subjects. The present patients with COPD were associated with airflow limitation, decreased PaO2, and increased PaCO2. Impairment of lung function and hypoxemia tended to be more severe in cachexic patients with COPD than in noncachexic patients with COPD. We confirmed that the 24-h average serum leptin levels (log transformed) correlated well with both BMI (r = 0.701, p < 0.001, Figure 1A) and %fat (r = 0.644, p < 0.01, Figure 1B) in all of the three groups.
|
|
Circadian Rhythm of Circulating Leptin of the Study Population
We measured serum leptin levels eight points in a day (9:00 A.M., 11:30 A.M., 2:00 P.M., 5:30 P.M., 8:00 P.M., midnight, 3:00 A.M., and 6:00 A.M.) from each subject. Figures 2A, 2B, and 2C demonstrate 24-h profiles of circulating leptin levels in the seven control subjects, eight noncachexic patients with COPD, and nine cachexic patients with COPD, respectively. We observed significant diurnal variations in the control subjects (ANOVA; F = 7.80, p < 0.0001) and noncachexic patients with COPD (F = 9.29, p < 0.0001). Overall, the nadir leptin levels were observed at 9:00 A.M. after overnight fasting, rising gradually to zenith levels at midnight, declining thereafter toward fasting values in both groups. The zenith leptin levels were 60.7% and 70.0% higher than the nadir levels in the control subjects and noncachexic patients with COPD, respectively. On the contrary, this diurnal variation of circulating leptin was strikingly absent in the cachexic patients with COPD (F = 2.09, p = not significant [NS]). The zenith leptin levels (5:30 P.M.) were only 21.4% higher than the nadir levels (9:00 A.M.) in cachexic patients with COPD.
|
Time and Frequency Domain Analysis of HRV
Time and frequency domain analysis of HRV are summarized in Table 2. Time domain analysis of HRV demonstrated significantly increased HR (85.3 ± 10.2 versus 67.5 ± 9.2 beats/ min; p < 0.01) in cachexic patients with COPD compared with healthy control subjects. Frequency domain analysis of HRV revealed that TF levels in cachexic patients with COPD were significantly reduced compared with healthy control subjects (2,861 ± 1,143 versus 5,449 ± 2,311 ms2; p < 0.05). Within TF, VLF, and ULF levels were significantly lower in cachexic patients with COPD than in healthy control subjects.
|
Circadian Rhythm of HRV Components of the Study Population
VLF component of HRV showed significant circadian rhythm in all of the three groups. Figures 3A, 3B, and 3C demonstrate 24-h profiles of VLF levels (absolute value) in the seven control subjects, seven noncachexic patients with COPD, and seven cachexic patients with COPD, respectively. We observed significant diurnal variations in the control subjects (F = 1.61, p < 0.05), noncachexic patients with COPD (F = 2.41, p < 0.001), and cachexic patients with COPD (F = 2.76; p < 0.001). In all of the three groups, i.e., control subjects (zenith: 5:00 A.M. and nadir: 8:00 P.M.), noncachexic patients with COPD (zenith: 4:00 A.M. and nadir: 6:00 P.M.), and cachexic patients with COPD (zenith: 4:00 A.M. and nadir: 8:00 A.M.), we observed increased VLF levels between midnight and early morning hours compared with lower VLF levels observed in the afternoon. The zenith VLF levels were 200%, 324%, and 247% higher compared with nadir VLF levels in control subjects, noncachexic patients with COPD, and cachexic patients with COPD, respectively.
|
Relationship between Circadian Rhythm of Serum Leptin and VLF
Similar diurnal fluctuations were observed between serum leptin levels and VLF values in control subjects, noncachexic patients with COPD, and cachexic patients with COPD, respectively. In fact, repeated measures ANOVA test revealed that circadian rhythm of serum leptin in cachexic patients with COPD is significantly different from those in other groups (F = 13.56, p < 0.001). Similar results were obtained with respect to circadian rhythm of VLF values, although the difference did not reach statistical significance (F = 3.28, p = 0.06). To demonstrate this, we analyzed the relationship between both values at the same time in all of the three groups. As shown in Figure 4, there is a significant positive correlation between these values (r = 0.388, p < 0.0001).
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
In the present study, both 24-h profiles of circulating leptin levels and HRV were investigated simultaneously in cachexic patients with COPD, noncachexic patients with COPD, and control subjects. We demonstrated that circadian rhythm of circulating leptin is absent in cachexic patients with COPD. In addition, VLF component of HRV showed similar diurnal rhythm with circulating leptin levels in all of the study groups. Because VLF has been considered to reflect neuroendocrine and thermoregulatory influences to the heart, these data may suggest that loss of circadian rhythm of circulating leptin has clinical importance in the pathophysiologic features in cachexic patients with COPD.
PSA of HRV derived from 24-h Holter ECG monitoring is one of the noninvasive means of assessing the activity of the ANS (23, 24). In particular, frequency domain analysis of HRV is known to represent the activity of the sympathetic and parasympathetic nervous system separately: that is, LF power represents the activity of both the sympathetic and parasympathetic nervous system, and HF power represents the activity of the parasympathetic nervous system alone. Consequently, LF/HF is widely used for the evaluation of sympathetic nervous tone (23, 24). In the present study, we could not find any correlation between the diurnal rhythm of serum leptin levels and LF/HF values in the study population, although the direct sympathoexcitatory effects of leptin have been reported in animal studies (39). There seem to be several possible reasons. One reason is that the sympathetic nervous system in humans may be primarily influenced by other neurohormones, such as catecholamines or the renin-angiotensin system (23, 24). Moreover, physiologic mechanisms of heart period modulations responsible for LF and HF power components can not be considered stationary during the 24-h period (23, 24). The other reason may involve several pitfalls in our experimental protocol. Because all the subjects in the present study were admitted to our hospital, they were sometimes lying in bed and taking naps in the daytime, which tends to influence LF/HF values. In addition, slight pain accompanied with each blood sampling can easily promote the secretion of catecholamines for a short time. These factors might have confounding effects on determining LF/HF values in our study populations.
Although physiologic interpretation of the VLF and ULF components of HRV is still controversial, the VLF component has been considered to mirror neuroendocrine and thermoregulatory influences to the heart (25). They account for up to 95% of TF (in contrast, the HF and LF components account for only the remaining 5% of TF) and are stable for the experimental conditions mentioned previously (23). We found time lag in the zenith of VLF values compared with those of serum leptin levels for approximately 4 to 5 h in control subjects and noncachexic patients with COPD. This time lag is not inexplicable, because it has been shown that it takes at least 3 h from leptin infusion to achieve maximal effect of stimulating the thermogenic sympathetic nerve activity (39). Taken together, the positive correlation between the circadian rhythm of circulating leptin levels and VLF values demonstrated in the present study may suggest that circulating leptin, at least in part, plays a determinant role in the VLF values of HRV.
Spectral analysis of HRV in survivors of acute myocardial infarction suggests that the VLF and ULF components carry the highest predictive value of mortality (40). In the present study, cachexic patients with COPD showed not only more severe impairment of lung function and hypoxemia, but also significantly reduced VLF and ULF values, compared with noncachexic patients with COPD. These data may support the fact that cachexia observed in patients with COPD is an independent risk factor of mortality per se (1).
The finding that the circadian rhythm of circulating leptin
is abolished in patients with severe illness is not novel. It has
previously been reported that there is no nocturnal rise in circulating leptin levels in patients with critical illness (41). In
patients with acute sepsis, leptin levels were found elevated, whereas the circadian rhythm was abolished (42, 43). There also seems to be a relationship between inflammatory cytokines, such as tumor necrosis factor-
(TNF-) or interleukin-1 (IL-1), and leptin in inflammatory status (31, 32). Because
there is a relation between metabolic derangements and increased levels of inflammatory mediators in patients with
COPD (44), the changes in circulating leptin may indeed be a
relevant finding in cachexic patients with COPD. However,
this possibility seems to be unlikely, because we previously
demonstrated that there is no relationship between circulating
leptin levels and the activated TNF- system in patients with
COPD (28).
Loss of circadian rhythm of circulating leptin in cachexic patients with COPD might have some clinical significance for the following reasons. First, absence of nocturnal peak of circulating leptin may be a compensatory mechanism for lower body fat content in cachexic patients with COPD, preserving body fat content by the inhibition of the thermogenic energy expenditure during the nighttime. Second, we found that the HRV was decreased at all frequencies in cachexic patients with COPD. These changes indicate a shift of sympathovagal balance toward a sympathetic predominance and reduced vagal tone (23). These abnormalities of ANS in cachexic patients with COPD might be caused by various kinds of stress in these patients, such as chronic hypoxemia or pulmonary hypertension (44). The activated sympathetic nervous system is closely linked with the increased circulating catecholamines, which are one of the major suppressors of leptin expression (11). Third, leptin affects several neuroendocrine mechanisms and regulates multiple hypothalamic-pituitary axes (11). Also, it has been reported that there are abnormalities of hypothalamic-pituitary function in hypoxemic patients with COPD (7, 8). It can be speculated that the blunted diurnal variation in serum leptin observed in cachexic patients with COPD may result in an alteration of the afferent signal from the adipose tissue to the central nervous system, including hypothalamic- pituitary axes. Fourth, recent study has indicated that leptin acts through central neural pathways to stimulate ventilatory control mechanisms, thus preventing respiratory depression in obesity (45). Absence of nocturnal rise of circulating leptin in cachexic, but not in noncachexic patients with COPD, may imply that cachexic patients with COPD are more likely to fall into respiratory depression during the nighttime. Additionally, it has also been suggested that leptin itself is important for the immune defense (46). It is therefore of interest that we found an increased impairment of lung function in the patients with COPD who presented with an abrogation of normal circadian leptin release.
In summary, we demonstrated that diurnal variations in circulating leptin levels in cachexic patients with COPD are absent, but are present in control subjects and noncachexic patients with COPD. We also showed that the VLF component of HRV varies in a similar way to circulating leptin levels. We conclude that variations in circulating leptin levels are linked to the activity of the ANS, and that the loss of circadian variation in leptin levels may have pathophysiologic significance for cachexic patients with COPD.
| |
Footnotes |
|---|
Correspondence and requests for reprints should be addressed to Noriaki Takabatake, M.D., First Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2, Iida-Nishi, Yamagata 990-9585, Japan.
(Received in original form April 18, 2000 and in revised form August 21, 2000).
Acknowledgments: The authors thank Arjuna J. Celaya for his help with English, and the Cosmic Corporation (Tokyo, Japan) for technical assistance.
Supported in part by grants from the Ministry of Education, Science, Sports and Culture, Japan (10307016 and 11557044).
| |
References |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1. Schols AMWJ, Soeters PB, Mostert R, Saris WHM, Wouters EFM. Energy balance in chronic obstructive pulmonary disease. Am Rev Respir Dis 1991; 143: 1248-1252 [Medline].
2. Schols AMWJ, Soeters PB, Dingemans AMC, Mostert R, Frantzen PJ, Wouters EFM. Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. Am Rev Respir Dis 1993; 147: 1151-1156 [Medline].
3. Wilson DO, Rogers RM, Wright E, Anthonisen NR. Body weight in chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 139: 1435-1438 [Medline].
4. Argiles JM, Lopez-Soriano J, Busquets S, Lopez-Soriano FJ. Journey from cachexia to obesity by TNF. FASEB J 1997; 11: 743-751 [Abstract].
5. Stewart AG, Waterhouse JC, Howard P. Cardiovascular autonomic nerve function in patients with hypoxaemic chronic obstructive pulmonary disease. Eur Respir J 1991; 4: 1207-1214 [Abstract].
6. Stewart AG, Marsh F, Waterhouse JC, Howard P. Autonomic nerve dysfunction in COPD as assessed by the acetylcholine sweat-spot test. Eur Respir J 1994; 7: 1090-1095 [Abstract].
7. Semple Pd'A, Beastall GH, Watson WS, Hume R. Serum testosterone depression associated with hypoxia in respiratory failure. Clin Sci 1980; 58: 105-106 [Medline].
8. Semple PD, Beastall GH, Watson WS, Hume R. Hypothalamic-pituitary dysfunction in respiratory hypoxia. Thorax 1981; 36: 605-609 [Abstract].
9.
Schols AMWJ,
Fredrix EWHM,
Soeters PB,
Westerterp KR,
Wouters EFM.
Resting energy expenditure in patients with chronic obstructive
pulmonary disease.
Am J Clin Nutr
1991;
54:
983-987
10. Schols AMWJ, Buurman WA, Brekel AJS, Dentener MA, Wouters EFM. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax 1996; 51: 819-824 [Abstract].
11. Auwerx J, Staels B. Leptin. Lancet 1998; 351: 737-742 [Medline].
12.
Flier JS.
Leptin expression and action: new experimental paradigms.
Proc Natl Acad Sci USA
1997;
94:
4242-4245
13.
Mantzoros CS.
The role of leptin in human obesity and disease: a review
of current evidence.
Ann Intern Med
1999;
130:
671-680
14. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763-770 [Medline].
15. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Med 1995; 1: 1155-1161 [Medline].
16.
Considine RV,
Sinha MK,
Heiman ML,
Kriauciunas A,
Stephens TW,
Nyce MR,
Ohannesian JP,
Marco CC,
McKee LJ,
Bauer TL,
Caro JF.
Serum immunoreactive-leptin concentrations in normal-weight and
obese humans.
N Engl J Med
1996;
334:
292-295
17. Licinio J, Mantzoros C, Negrao AB, Cizza G, Wong ML, Bongiorno PB, Chrousos GP, Karp B, Allen C, Flier JS, Gold PW. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nature Med 1997; 3: 575-579 [Medline].
18.
Licinio J,
Negrao AB,
Mantzoros C,
Kaklamani V,
Wong ML,
Bongiorno PB,
Mulla A,
Cearnal L,
Veldhuis JD,
Flier JS,
Mccann SM,
Gold PW.
Synchronicity of frequently sampled, 24-h concentrations of
circulating leptin, luteinizing hormone, and estradiol in healthy women.
Proc Natl Acad Sci USA
1998;
95:
2541-2546
19. Sinha MK, Ohannesian JP, Heiman ML, Kriauciunas A, Stephens TW, Magosin S, Marco C, Caro JF. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J Clin Invest 1996; 97: 1344-1347 [Medline].
20. Sinha MK, Sturis J, Ohannesian J, Magosin S, Stephens T, Heiman ML, Polonsky KS, Caro JF. Ultradian oscillations of leptin secretion in humans. Biochem Biophys Res Commun 1996; 228: 733-738 [Medline].
21. Schoeller DA, Cella LK, Sinha MK, Caro JF. Entrainment of the diurnal rhythm of plasma leptin to meal timing. J Clin Invest 1997; 100: 1882-1887 [Medline].
22.
Simon C,
Gronfier C,
Schlienger JL,
Brandenberger G.
Circadian and
ultradian variations of leptin in normal man under continuous enteral
nutrition: relationship to sleep and body temperature.
J Clin Endocrinol Metab
1998;
83:
1893-1899
23. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation 1996;93:1043-1065.
24.
Paolisso G,
Manzella D,
Ferrara N,
Gambardella A,
Abete P,
Tagliamonte MR,
de Lucia D,
Furgi G,
Picone C,
Gentile S,
Rengo F,
Varricchio M.
Glucose ingestion affects cardiac ANS in healthy subjects with different amounts of body fat.
Am J Physiol
1997;
273:
E471-E478
25. Fleisher LA, Frank SM, Sessler DI, Cheng C, Matsukawa T, Vannier CA. Thermoregulation and heart rate variability. Clin Sci 1996; 90: 97-103 [Medline].
26. Thayer JF, Nabors-Oberg R, Sollers JJ III.. Thermoregulation and cardiac variability: a time-frequency analysis. Biomed Sci Instrum 1997; 34: 252-256 [Medline].
27. Taylor JA, Carr DL, Myers CW, Eckberg DL. Mechanisms underlying very-low-frequency RR-interval oscillations in humans. Circulation 1998; 98: 547-555 [Medline].
28.
Takabatake N,
Nakamura H,
Abe S,
Hino T,
Saito H,
Yuki H,
Kato S,
Tomoike H.
Circulating leptin in patients with chronic obstructive
pulmonary disease.
Am J Respir Crit Care Med
1999;
159:
1215-1219
29. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987;136:225-243.
30.
De Vos P,
Saladin R,
Auwerx J,
Staels B.
Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake.
J Biol Chem
1995;
270:
15958-15961
31.
Sarraf P,
Frederick RC,
Turner EM,
Ma G,
Jaskowiak NT,
Rivet DJ III,,
Flier JS,
Lowell BB,
Fraker DL,
Alexander HR.
Multiple cytokines
and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia.
J Exp Med
1997;
185:
171-175
32. Grunfeld C, Zhao C, Fuller J, Pollock A, Moser A, Friedman J, Feingold KR. Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters: a role for leptin in the anorexia of infection. J Clin Invest 1996; 97: 2152-2157 [Medline].
33. Nyström F, Ekman B, Österlund M, Lindström T, Öhman KP, Arnqvist HJ. Serum leptin concentrations in a normal population and in GH deficiency: negative correlation with testosterone in men and effects of GH treatment. Clin Endocrinol 1997; 47: 191-198 [Medline].
34. Quanjer PH. editor. Standardized lung function testing. Bull Eur Physiopathol Respir 1983; 19: 7-44 [Medline].
35. Curtin F, Morabia A, Pichard C, Slosman DO. Body mass index compared to dual-energy X-ray absorptiometry: evidence for a spectrum bias. J Clin Epidemiol 1997; 50: 837-843 [Medline].
36.
Smalley KJ,
Knerr AN,
Kendrick ZV,
Colliver JA,
Owen OE.
Reassessment of body mass indices.
Am J Clin Nutr
1990;
52:
405-408
37. Kunii M, Suzuki Y, Ishii H. Measurement of body composition by bioelectrical impedance method in Japanese. Jpn J Phys Fitness Sports Med 1987; 36: 586 .
38. Ohtomo N, Terachi S, Tanaka Y, Tokiwano K, Kaneko N. New method of time series analysis and its application to Wolf's sunspot number data. Jpn J Appl Phys 1994; 33: 2821-2831 .
39. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 1997; 100: 270-278 [Medline].
40. Bigger JT Jr,, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation 1992; 85: 164-171 [Medline].
41. Bornstein SR. Is leptin a stress related peptide? Nature Med 1997; 3: 937 [Medline].
42.
Bornstein SR,
Licinio J,
Tauchnitz R,
Engelmann L,
Negrao AB,
Gold P,
Chrousos GP.
Plasma leptin levels are increased in survivors of
acute sepsis: associated loss of diurnal rhythm in cortisol and leptin secretion.
J Clin Endocrinol Metab
1998;
83:
280-283
43. Torpy DJ, Bornstein SR, Chrousos GP. Leptin and interleukin-6 in sepsis. Horm Metab Res 1998; 30: 726-729 [Medline].
44.
Takabatake N,
Nakamura H,
Abe S,
Inoue S,
Hino T,
Saito H,
Yuki H,
Kato S,
Tomoike H.
The relationship between chronic hypoxemia and
the activation of the TNF- system in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med
2000;
161:
1179-1184
45.
O'Donnell CP,
Schaub CD,
Haines AS,
Berkowitz DE,
Tankersley CG,
Schwartz AR,
Smith PL.
Leptin prevents respiratory depression in
obesity.
Am J Respir Crit Care Med
1999;
159:
1477-1484
46. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998; 394: 897-901 [Medline].
This article has been cited by other articles:
 |
|
 |
|
  P. D. Wagner Possible mechanisms underlying the development of cachexia in COPD Eur. Respir. J., March 1, 2008; 31(3): 492 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Takabatake, Y. Shibata, S. Abe, T. Wada, J.-i. Machiya, A. Igarashi, Y. Tokairin, G. Ji, H. Sato, M. Sata, et al. A Single Nucleotide Polymorphism in the CCL1 Gene Predicts Acute Exacerbations in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 15, 2006; 174(8): 875 - 885. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhong, K.-M. Jan, K. H. Ju, and K. H. Chon Quantifying cardiac sympathetic and parasympathetic nervous activities using principal dynamic modes analysis of heart rate variability Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1475 - H1483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Broekhuizen, R. F Grimble, W M. Howell, D. J Shale, E. C Creutzberg, E. F Wouters, and A. M Schols Pulmonary cachexia, systemic inflammatory profile, and the interleukin 1{beta} -511 single nucleotide polymorphism Am. J. Clinical Nutrition, November 1, 2005; 82(5): 1059 - 1064. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. N. Agusti Systemic Effects of Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2005; 2(4): 367 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Andreas, S. D. Anker, P. D. Scanlon, and V. K. Somers Neurohumoral Activation as a Link to Systemic Manifestations of Chronic Lung Disease Chest, November 1, 2005; 128(5): 3618 - 3624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Takabatake, M. Sata, S. Inoue, Y. Shibata, S. Abe, T. Wada, J.-i. Machiya, G. Ji, T. Matsuura, Y. Takeishi, et al. A Novel Polymorphism in Secretory Phospholipase A2-IID Is Associated with Body Weight Loss in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., November 1, 2005; 172(9): 1097 - 1104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. F. M. Wouters Local and Systemic Inflammation in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 26 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Itoh, N. Nagaya, M. Yoshikawa, A. Fukuoka, H. Takenaka, Y. Shimizu, Y. Haruta, H. Oya, M. Yamagishi, H. Hosoda, et al. Elevated Plasma Ghrelin Level in Underweight Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 15, 2004; 170(8): 879 - 882. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Arao, N. Takabatake, M. Sata, S. Abe, Y. Shibata, T. Honma, K. Takahashi, A. Okada, Y. Takeishi, and I. Kubota In Vivo Evidence of Endothelial Injury in Chronic Obstructive Pulmonary Disease by Lung Scintigraphic Assessment of 123I-Metaiodobenzylguanidine J. Nucl. Med., November 1, 2003; 44(11): 1747 - 1754. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D D Sin and S F P Man Impaired lung function and serum leptin in men and women with normal body weight: a population based study Thorax, August 1, 2003; 58(8): 695 - 698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.G.N. Agusti, A. Noguera, J. Sauleda, E. Sala, J. Pons, and X. Busquets Systemic effects of chronic obstructive pulmonary disease Eur. Respir. J., February 1, 2003; 21(2): 347 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. TOBIN Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 642 - 662. [Full Text] [PDF]
|
|
|
|
|
|
A. L. Goldberger Heartbeats, Hormones, and Health . Is Variability the Spice of Life? Am. J. Respir. Crit. Care Med., May 1, 2001; 163(6): 1289 - 1290. [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Proc. Am. Thorac. Soc. | Am. J. Respir. Cell Mol. Biol. |