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J Appl Physiol 96: 991-998, 2004. First published October 24, 2003; doi:10.1152/japplphysiol.00926.2003
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Impact of interrupted leptin pathways on ventilatory control

Vsevolod Y. Polotsky,1 Marc C. Smaldone,1 Matthew T. Scharf,1 Jianguo Li,1 Clarke G. Tankersley,2 Philip L. Smith,1 Alan R. Schwartz,1 and Christopher P. O'Donnell1

1Department of Medicine, Division of Pulmonary and Critical Care Medicine, Bloomberg School of Public Health, and 2Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland 21224

Submitted 29 August 2003 ; accepted in final form 22 October 2003


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Leptin deficiency in ob/ob mice produces marked depression of the hypercapnic ventilatory response, particularly during sleep. We now extend our previous findings to determine whether 1) leptin deficiency affects the hypoxic ventilatory response and 2) blockade of the downstream excitatory actions of leptin on melanocortin 4 receptors or inhibitory actions on neuropeptide Y (NPY) pathways has an impact on hypercapnic and hypoxic sensitivity. We have found that leptin-deficient ob/ob mice have the same hypoxic ventilatory response as weight-matched wild-type obese mice. There were no differences in the hypoxic sensitivity between agouti yellow mice and weight-matched controls, or NPY-deficient mice and wild-type littermates. Agouti yellow mice, with blocked melanocortin pathways, exhibited a significant depression of the hypercapnic sensitivity compared with weight-matched wild-type controls during non-rapid eye movement sleep (5.8 ± 0.7 vs. 8.9 ± 0.7 ml·min-1·%CO2-1, P < 0.01), but not during wakefulness. NPY-deficient transgenic mice exhibited a small increase in the hypercapnic ventilatory response compared with wild-type littermates, but this was only present during wakefulness. We conclude that interruption of leptin pathways does not affect hypoxic sensitivity during sleep and wakefulness but that melanocortin 4 blockade is associated with depressed hypercapnic sensitivity in non-rapid eye movement sleep.

sleep; obesity hypoventilation; melanocortin receptor; neuropeptide Y

OBESITY HAS REACHED EPIDEMIC PROPORTIONS in the US, and the prevalence of obesity continues to rise (25, 26, 28). Numerous pathophysiological outcomes are associated with obesity, including respiratory depression (2, 5). Impaired activity of the upper airway respiratory muscles during sleep leads to obstructive sleep apnea (OSA) in >50% of obese individuals (body mass index >30 kg/m2) (38), whereas severe obesity (body mass index >40 kg/m2) can cause depression of the respiratory pump muscles during wakefulness, resulting in CO2 retention and the syndrome of obesity hypoventilation (OHS) (2, 5, 39). Although the mechanical loads of obesity on the upper airway and respiratory pump muscles have been implicated in the pathogenesis of OSA and OHS, not all obese people develop respiratory depression. It is likely that impairment of respiratory neural control mechanisms is also a major contributor to the development of OSA and OHS (2, 5, 39, 49).

We previously reported that leptin, a satiety-producing hormone secreted by adipocytes (10, 48), provides a common link between obesity and respiratory depression (30, 31, 47). Our initial study demonstrated that complete impairment of leptin signaling in genetically obese ob/ob mice significantly reduced the ventilatory response to hypercapnia during wakefulness (47). In later studies, we extended our initial observations to show that the ob/ob mouse modeled human OHS by exhibiting CO2 retention and depressed hypercapnic ventilatory responsiveness (HCVR), particularly during sleep (30, 37). Subsequent clinical studies have shown that both OSA and OHS are associated with the most common form of impaired leptin signaling in humans, namely leptin resistance (18, 35). Taken together, the animal and human studies suggest that both leptin deficiency and leptin resistance may lead to depressed hypercapnic sensitivity, especially during sleep. It is currently unknown whether the ob/ob mouse also exhibits a depressed hypoxic ventilatory response (HVR) during wakefulness and sleep, although our initial observations during wakefulness suggest that the respiratory depression associated with the leptin-deficient state may be specific to the hypercapnic response (47).

The central effects of leptin on satiety and metabolism are mediated predominantly in the arcuate nucleus of the hypothalamus (10, 42). No study to date has determined whether the effects of leptin on respiratory control are mediated through the same neural pathways in the hypothalamus that control appetite or whether leptin can act directly on chemosensory inputs in the ventrolateral medulla (both hypercapnic and hypoxic) or carotid body (predominantly hypoxic). The anorexigenic effects of leptin occur primarily through activation of melanocortin 4 (MC4) receptors (15, 19, 27, 29) and inhibition of neuropeptide Y (NPY) (8, 45) in the hypothalamus. Putatively, MC4 and NPY pathways could impact on respiratory control via neural connections between the hypothalamus and respiratory control centers in the medulla (11, 14, 34, 46).Thus impairment of MC4 pathways or activation of NPY pathways in the hypothalamus could contribute to the respiratory depression associated with impaired leptin signaling.

The purpose of the present study was to determine the effects of disrupted MC4 and NPY pathways on HCVR and HVR, and to examine whether leptin deficiency, which depresses central hypercapnic responsiveness, can also cause depression of HVR. Our approach was to simultaneously assess respiration and polysomnography to determine the HCVR and HVR in a series of transgenic and knockout mice during both wakefulness and sleep. Our overall hypothesis was that leptin deficiency causes depression of the HCVR, but not the HVR, by acting through hypothalamic pathways known to regulate appetite and metabolism. Specifically, we hypothesized that 1) leptin-deficient C57Bl/6J-Lepob mice would not exhibit a depressed HVR compared with weight-matched wildtype mice and 2) MC4 receptor blockade in mice with an agouti yellow mutation (Ay) would simulate inhibition of leptin pathways and decrease the HCVR, but not the HVR, whereas the absence of NPY in NPY-/- mice would simulate activation of leptin pathways and increase the HCVR but not the HVR.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Animals. Twelve mutant obese C57BL/6J-Lepob male mice, 22 C57BL/6J male mice, 7 mutant Ay male mice from Jackson Laboratory (Bar Harbor, ME), 9 NPY-deficient transgenic male mice (NPY-/-), and 9 littermates (NPY+/+), kindly provided by Dr. Richard D. Palmiter (University of Washington, Seattle, WA), were used in the study. The study was approved by the Johns Hopkins University Animal Use and Care Committee and complied with the American Physiological Society guidelines. For all surgical procedures, anesthesia was induced and maintained by using 1-2% isoflurane administered through a face mask. At the completion of experiments, animals were euthanized with pentobarbital (60 mg ip).

Surgical procedures, polysomnography, and respiratory control analysis. Mice were instrumented with chronically implanted polysomnographic electrodes for determination of sleep/wake state, as previously described (30). During data collection periods, the animals were placed in a whole body barometric plethysmography chamber to measure ventilation. The chamber (823 ml) was customized to allow the animal free movement while electroencephalogram (EEG) and electromyogram (EMG) electrodes were exited through a sealed port. The plethysmograph was referenced to a second chamber and flushed with compressed, humidified air (80% relative humidity) at ~600 ml/min. To measure ventilation, the ports through which the gases enter and exit the chamber were closed to produce a constant chamber volume. Once the chamber was at constant volume, tidal volume (VT) and breathing frequency (f) were measured from changes in pressure (Statham Gould PM15E differential pressure transducer, Hato Ray, Puerto Rico) due to inspiratory and expiratory temperature fluctuations. The body temperature was assumed to be constant at 37°C. Calibration injections of 10, 20, and 30 µl of room air were made with the animal inside the constant-volume chamber. Minute ventilation (E) is reported as the product of f and VT.

Sleep/wake state was assessed from EEG and EMG recordings as previously described (30, 36, 37). Wakefulness was characterized by low-amplitude, high-frequency (~10-20 Hz) EEG waves and high levels of EMG activity compared with sleep states. Non-rapid eye movement (NREM) sleep was characterized by high-amplitude, low-frequency (~2-5 Hz) EEG waves and an EMG activity considerably less than during wakefulness. Rapid eye movement (REM) sleep was characterized by low-amplitude, mixed-frequency (~5-10 Hz) EEG waves, although the predominant pattern was a fixed amplitude theta frequency consistent with hippocampal theta rhythm. During REM sleep, the EMG activity was either equal to or less than that seen during NREM sleep but was always less than that seen during wakefulness.

Ventilation was measured during wakefulness and NREM and REM sleep in response to a range of hypercapnic gases (0, 3, 5, and 8% CO2 in 40% O2 to ensure no hypoxic stimulus) and hypoxic gases (15% O2 and 10% O2 in 3% CO2 to eliminate hypoxia-induced hypocapnia). Least squares linear regression analysis was used to calculate HCVR (slope of the relationship between E and inspired CO2) and HVR (slope of the relationship between E and inspired O2) during wakefulness and NREM sleep. Data for the HVR are not presented during REM sleep due to the absence of sustained periods of REM sleep during hypoxic exposure.

Experimental groups. Comparisons of ventilatory control parameters were made between mice in three separate series of experiments: 1) wild-type lean C57BL/6J mice of ~30 g of weight maintained on a regular ad libitum chow diet (WT30), wild-type C57BL/6J mice maintained on a high-fat diet (49% fat; 5.8 kcal/g) for ~16 wk to develop diet-induced obesity with ~40 g of weight (WT40), C57BL/6J-Lepob mice of ~40 g of weight maintained on a regular ad libitum chow diet (OB40), and C57BL/6J-Lepob mice of ~60 g of weight maintained on a regular ad libitum chow diet (OB60); 2) NPY-/- and NPY+/+ mice maintained on a regular ad libitum chow diet; and 3) Ay and weight-matched wild-type C57BL/6J mice maintained on a high-fat diet (Ay control).

Plasma leptin determination. Arterial blood (1-1.2 ml) was obtained from direct cardiac puncture under isoflurane anesthesia. Serum leptin levels were measured with a mouse leptin radioimmunoassay kit from Linco Research (St. Charles, MO).

Statistical analyses. Data were analyzed by using Crunch 4 (Crunch Software; Oakland, CA), and results for E, HCVR, and HVR are shown as means ± SE. Statistical significance between groups was derived within each sleep/wake state by using ANOVA with Newman-Keuls post hoc analyses where appropriate.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
E and HVR in leptin-deficient mice. In the OB40 group, baseline E had a trend to be lower than in weight-matched obese wild-type mice (WT40 group) during wakefulness (P = 0.06) and was significantly lower during NREM sleep (37.5 ± 2.7 vs. 55.8 ± 3.1 ml/min, P < 0.05; Fig. 1) and REM sleep (36.4 ± 3.6 vs. 61.2 ± 3.8 ml/min, P < 0.05; Fig. 1). This difference in baseline E between the OB40 and WT40 strain was entirely due to a significantly lower VT in the leptindeficient mice (see Table 2). The OB60 mice had significantly higher levels of E at baseline than OB40 mice due to larger VT across all sleep/wake stages (Fig. 2, see Table 2). However, when E was corrected per body weight, there was no difference between the two groups. Similarly, in C57BL/6J mice, E and VT were higher in the WT40 mice than in the WT30 mice (Fig. 1, see Table 2), and the difference was no longer present when E was corrected per body weight. There was no statistically significant difference in the HVR or hypoxia-induced changes in VT and f during either wakefulness or NREM sleep between all four groups of mice, regardless of the presence or absence of leptin deficiency and obesity (Fig. 1, see Table 2).



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  		Fig. 1. Minute ventilation (E; A) at decreasing levels of inspired O2 (FIO2) and the hypoxic ventilatory response (HVR; B) across sleep/wake states are compared between wild-type lean C57BL/6J mice of ~30 g of weight (WT30), wild-type C57BL/6J mice maintained on a high-fat diet of ~40 g of weight (WT40), C57BL/6J-Lepob mice of ~40 g of weight (OB40), and C57BL/6J-Lepob mice of ~60 g of weight (OB60). Values are means ± SE. REM, rapid eye movement; NREM, non-rapid eye movement; {Delta}, change. Significance between strains was derived within each sleep/wake state by using 1-way between-subject ANOVA. *P < 0.05 for differences between WT30 and WT40 mice; {dagger}P < 0.05 for differences between OB40 and WT40 mice; {ddagger}P < 0.05 for differences between OB40 and OB60 mice.

 

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  		Table 2. Effect of hypoxic challenge on VT and f in the presence and absence of leptin

 


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  		Fig. 2. E (A) at decreasing levels of FIO2 and the HVR (B) across sleep/wake states are compared between NPY-/- and NPY+/+ mice. Values are means ± SE. Significance between strains was tested within each sleep/wake state by using 1-way between-subject ANOVA.

 

HVR and HCVR in NPY-deficient mice. Body weight (Table 1) and serum leptin levels (2.1 ± 0.1 vs. 2.6 ± 0.2 ng/ml) were similar between NPY-/- and NPY+/+ mice. There was no significant difference in either baseline respiratory frequency, VT, E, or the HVR between the two strains across all sleep/wake states (Fig. 2, Table 3). During hypercapnic challenge in wakefulness, the NPY-/- animals exhibited an elevated HCVR (P < 0.05) compared with wild-type littermates due to a trend to a larger increase in VT (Fig. 3, Table 3). There was no difference in the HCVR between the two groups of mice in NREM and REM sleep.


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  		Table 1. Age and body weight of Ay, NPY-/-, C57BL/6J-Lepob, and C57BL/6J wild-type mice

 

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  		Table 3. Effect of hypoxic and hypercapnic challenge on VT and f in Ay and NPY-/- mice

 


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  		Fig. 3. E (A) at increasing levels of inspired CO2 and the hypercapnic ventilatory response (HCVR) (B) across sleep/wake states are compared between NPY-/- and NPY+/+ mice. Values are means ± SE. Significance between strains was tested within each sleep/wake state by using 1-way between-subject ANOVA.

 

HVR and HCVR in Ay mice. The elevated body weight in both Ay and control mice was associated with high leptin levels that tended to be greater in Ay (29.0 ± 4.9 ng/ml) than in control mice (21.2 ± 1.3 ng/ml) but did not reach statistical significance (P = 0.13). Baseline E was significantly lower in Ay mice compared with control mice across all sleep/wake stages (Figs. 4 and 5). Low levels of E in Ay mice could be attributed to both smaller VT and f than in control animals (Table 3). The HVR was identical in both strains (Fig. 4). During NREM sleep, Ay mice exhibited a significant depression of the HCVR compared with control mice (Fig. 5), which was entirely due to smaller increases in VT (Table 3). During wakefulness and REM sleep, the HCVR was similar between strains (Fig. 5).



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  		Fig. 4. E (A) at decreasing levels of FIO2 and the HVR (B) across sleep/wake states are compared between agouti yellow (Ay) and weight-matched C57BL/6J mice with diet-induced obesity (control). Values are means ± SE. Significance between strains was derived within each sleep/wake state by using 1-way between-subject ANOVA. *P < 0.05 for differences between Ay and control mice.

 


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  		Fig. 5. E (A) at increasing levels of inspired CO2 and the HCVR (B) across sleep/wake states are compared between Ay and weight-matched C57BL/6J mice with diet-induced obesity (control). Values are means ± SE. Significance between strains was derived within each sleep/wake state by using 1-way between-subject ANOVA. *P < 0.05 for differences between Ay and control mice.

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
The purpose of the present study was to explore the effects of leptin deficiency and interruption of leptin signaling pathways (MC4 and NPY) on respiratory control during wakefulness and sleep. Several new findings resulted from the study. First, baseline E is decreased in both leptin-deficient mice and Ay mice with disrupted MC4 pathways but not in NPY-/- mice. This reduction in baseline E in leptin-deficient and Ay mice is likely due to the reduced basal metabolic rate reported in these strains (4, 8, 21, 44). Second, the HCVR, which is depressed by leptin deficiency (30, 31, 47) and restored by leptin replacement in ob/ob mice during sleep (30), is also depressed by the MC4 blockade in Ay mice during NREM sleep. There was no comparable effect of NPY deficiency on the HCVR during sleep, but NPY-/- mice did exhibit an increase in the HCVR during wakefulness. These data suggest that, at least in part, the effect of leptin on hypercapnic ventilatory sensitivity during sleep is mediated through MC4 pathways. Third, the HVR is not affected by leptin deficiency, MC4 blockade, or NPY deficiency, suggesting that 1) the effect of leptin on ventilatory control is specific for CO2-sensing neurons located in medulla and 2) leptin deficiency does not impact on the sensing of hypoxia either centrally by the medullary receptors or peripherally by the carotid bodies. In the discussion that follows, we explore the relationship and putative pathways linking leptin to ventilatory control and discuss the clinical implications of our work.

Baseline E. We confirmed our previous observations that leptin deficiency is associated with a decrease in baseline E that is more pronounced during sleep than wakefulness (30, 47). The reduction in baseline E is likely due to the centrally mediated reduction in metabolic rate present in the leptin-deficient mice (4, 8). The metabolic effects of leptin are centrally mediated (16, 24, 42) and involve both MC4 and NPY pathways (8, 15, 19, 27, 29, 45). Intracerebroventricular administration of NPY or MC4 blockade with agouti-related peptide (AGRP) has been shown to decrease oxygen consumption in rats (17, 44). Our data, showing a decrease in baseline E in Ay mice compared with weight-matched controls, are consistent with a decrease in metabolic rate due to MC4 blockade by overexpressed AGRP. In contrast, NPY-deficient mice did not display any increase in baseline E as would be predicted by the decrease in oxygen consumption that accompanies intracerebroventricular administration of NPY in rats (17), as described in the RESULTS (Figs. 2 and 3). Most likely, NPY-deficient mice maintain a normal metabolic rate through compensatory inhibition of the MC4 pathway (22). Thus the decrease in baseline E in ob/ob and Ay mice and the unchanged baseline E in NPY-/- mice are consistent with the known metabolic profiles in each of these strains.

Respiratory control during sleep and wakefulness in Ay and NPY-/- mice. The 35% decrease in HCVR during NREM sleep in Ay mice is a significant and physiologically relevant finding. During NREM sleep, the tidal ventilatory recordings from barometric plethysmography are remarkably stable, free from any nonrespiratory movement artifacts, and independent of waking cortical influences on respiratory control centers. The data from the Ay mice are consistent with our previous observation in ob/ob mice that leptin replacement selectively reverses HCVR depression during NREM and REM sleep but not during wakefulness (30). Furthermore, the depression of the HCVR in Ay mice was due to smaller increases in VT than in the background strain, consistent with leptin replacement specifically modulating VT responses to hypercapnia in ob/ob mice during NREM sleep. The depression of the HCVR during NREM sleep in Ay mice compared with wild-type mice was not seen during REM sleep. However, given that wild-type mice did not have any detectable HCVR during REM sleep, it was impossible for the Ay mice to exhibit a relative reduction in HCVR during REM. Thus the decrease in HCVR evident in Ay mice supports an important role for MC4 receptor pathways in mediating the effects of leptin on respiratory control during NREM sleep.

In contrast to Ay mice, the only alteration in HCVR that occurred in NPY-/- mice was manifested during wakefulness. The physiological relevance of such an alteration in the HCVR during wakefulness, but not sleep, is difficult to interpret. One possible interpretation of our data is that hypercapnia exacerbated the previously described enhanced anxiety of the NPY-/- mice relative to their littermates (33). In contrast, cortical anxiety would not be present during sleep, and ventilatory responses to hypercapnia would be comparable between NPY-deficient mice and wild-type mice. Thus the impact of NPY pathways in mediating the effects of leptin on ventilatory control is likely less significant than for MC4 pathways, particularly with respect to abnormalities in respiratory control associated with sleep.

Central leptin signaling pathways and respiratory control. We have previously reported that leptin deficiency leads to marked suppression of the HCVR (30, 31, 47). Moreover, leptin replacement caused large increases in baseline E and significantly increased the HCVR during NREM and REM sleep, independent of weight, metabolism, and food intake (30). Our data now demonstrate that the effect of leptin deficiency on respiratory control is specific to hypercapnia and does not extend to hypoxic sensitivity, implying that leptin deficiency does not impact on either peripheral or central chemoreceptors sensing hypoxia.

The site of central action of leptin on respiratory control is unknown. The present study represents a first attempt to localize the pathways that mediate the central actions of leptin. Our data indicate that MC4 pathways may contribute to the depression of hypercapnic sensitivity that occurs during sleep in leptin-deficient mice. Given that 1) the anorexogenic effects of leptin are primarily dependent on hypothalamic pathways (10, 13, 42, 48) and 2) hypothalamic neural projections can influence central hypercapnic ventilatory responsiveness (40, 41), it is attractive to propose that the effects of leptin on respiratory control are also dependent on hypothalamic pathways. However, the blockade of MC4 receptors by AGRP in Ay mice is not limited to hypothalamic regions. Indeed, MC4 receptors and Y1 receptors for NPY are widely distributed in respiratory-related centers (e.g., the nucleus of the solitary tract) (11, 34). Thus impairment of MC4 or NPY pathways could impact on hypercapnic responsiveness at the level of the hypothalamus, the medulla, or potentially other respiratory-sensitive areas in the central nervous system.

Leptin receptors are also abundant in the nucleus of the solitary tract and other centers in the medulla involved in respiratory responses to CO2 and pH (23, 43). Given that the respiratory effects of MC4 receptor blockade and NPY defi-ciency are not as marked as effects seen in leptin-deficient mice (30), it is possible that leptin may act directly through leptin receptors on respiratory neurons in the medulla, in addition to acting through hypothalamic pathways. Nevertheless, the present study clearly supports a role for MC4 pathways to stimulate respiratory responses to hypercapnia in an analogous manner to hypothalamic control of appetite.

In conclusion, human obesity is most commonly associated with elevated leptin levels, a condition described as leptin resistance (7, 20). Two possibilities have been proposed to account for resistance of obese humans to the biological effects of elevated leptin levels. The first possibility is that leptin, derived in adipocytes, has limited access to the hypothalamus due to a saturable leptin receptor mechanism at the blood-brain barrier (1, 6, 12). A second possibility is that leptin levels in the cental nervous system are appropriate, but either hypothalamic leptin receptors or their downstream signaling pathways are impaired in human obesity. Recent studies have suggested that severe obesity is associated with impairment in the MC4 arm of the leptin pathway (3, 9). Furthermore, there is emerging evidence that the melanocortin pathway is linked to OSA. Palmer et al. (32) demonstrated that OSA patients have an increased incidence of polymorphisms in the proopiomelanocortin gene, the precursor of {alpha}-melanocyte-stimulating hormone, which is the ligand for MC4 receptors. Thus studies in humans indicate that the melanocortin pathway has clinical relevance for both obesity and OSA in a manner analogous to the agouti mouse, which is also characterized by obesity and respiratory depression during sleep. Taking the clinical observations in combination with our present data, a defect in the MC4 pathway may account for the presence of leptin resistance and the respiratory depression of OSA and OHS.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
The authors gratefully acknowledge Dr. Richard D. Palmiter (University of Washington, Seattle, WA) for providing NPY-deficient transgenic mice and Raisa Gelman for technical assistance with a radioimmune assay.

GRANTS

This work was supported by National Heart, Lung, and Blood Institute Grants HL-68715, HL-63767, and HL-66324.


   FOOTNOTES
 

Address for reprint requests and other correspondence: V. Y. Polotsky, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (E-mail: vpolots1{at}jhmi.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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