Heart and Circulatory Physiology

Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea

Bradley G. Phillips, Masahiko Kato, Krzysztof Narkiewicz, Ian Choe, Virend K. Somers


Patients with obstructive sleep apnea (OSA) are frequently obese and are predisposed to weight gain. They also have heightened sympathetic drive. We reasoned that noradrenergic activation of β3-receptors on adipocytes would inhibit leptin production, predisposing to obesity in sleep apnea. We therefore tested the hypothesis that obesity and predisposition to weight gain in OSA are associated with low levels of plasma leptin. We prospectively studied 32 male patients (43 ± 2 yr) with OSA who were newly diagnosed and never treated and who were free of any other diseases. Control measurements were obtained from 32 similarly obese closely matched male subjects (38 ± 2 yr). Leptin levels were 13.7 ± 1.3 and 9.2 ± 1.2 ng/ml in patients with OSA and controls, respectively (P = 0.02). Weight gain over the year before diagnosis was 5.2 ± 1.7 and 0.5 ± 0.9 kg in sleep apnea patients and similarly obese control subjects, respectively (P = 0.04). Muscle sympathetic activity was 46 ± 4 and 30 ± 4 bursts/min in patients with OSA (n = 16) and control subjects (n = 18), respectively (P = 0.01). Plasma leptin levels are elevated in newly diagnosed otherwise healthy patients with untreated sleep apnea beyond the levels seen in similarly obese control subjects without sleep apnea. Higher leptin levels in OSA, independent of body fat content, suggest that OSA is associated with resistance to the weight-reducing effects of leptin.

  • obesity
  • heart rate
  • sympathetic nervous system

leptin, the protein product of the ob gene, elicits a decrease in appetite with loss of weight (5, 12). Adipocytes are the primary source of leptin (9). Despite the weight-reducing effects of leptin, obese patients have marked increases in leptin levels in proportion to body fat content (2). It is thought that obesity prevails in these subjects because of resistance to the effects of leptin (2).

Obesity is also strongly linked to obstructive sleep apnea (OSA) (19). Patients with sleep apnea have difficulty losing weight and, in fact, are predisposed to excessive weight gain, far more than is evident in similarly obese control subjects proven to be free of OSA (13).

The mechanism predisposing sleep apnea patients to weight gain is unknown. A recent analysis emphasizes that abnormalities in autonomic neural circuits should be considered as an important primary cause of central nervous system-mediated obesity (11). Adrenergic inhibition of leptin release, with consequent decreases in plasma leptin levels, may be implicated (10, 11). Isoproterenol infusions with adrenergic activation of adipocyte β3-receptors results in inhibition of adipocyte leptin production in humans (14). Treatment of sleep apnea lowers sympathetic nerve traffic (7, 21) and also reduces leptin levels (3). We reasoned that the high sympathetic drive in sleep apnea patients, evidenced by increased measurements of sympathetic nerve traffic, would act to similarly suppress adipocyte leptin production in sleep apnea patients. The consequent lower leptin would help explain obesity and the propensity to weight gain in patients with sleep apnea. We therefore tested the hypothesis that leptin levels are lower in patients with sleep apnea than in similarly obese patients proven to be free of OSA.



We prospectively studied 64 male subjects (40 ± 11 yr) who had no prior significant medical history and were not taking medications. OSA was evaluated in each subject by complete overnight polysomnographic study. Patients with an apnea-hypopnea index (total number of apneas + hypopneas averaged per hour of sleep) <10 were considered not to have significant sleep-disordered breathing and were classified as control subjects. The study night was the first occasion on which the subjects had undergone a polysomnographic study. Informed written consent was obtained from each subject. The studies were approved by the Institutional Human Use Committee.

Study protocol.

Complete polysomnographic recordings were obtained continuously during the study, as described previously (16). Hemodynamic and anthropometric data, weight history, and leptin levels were obtained in each subject. Blood pressure and heart rate were measured in duplicate with an automated sphygmomanometer (Dinamap, Critikon, Tampa, FL). Mean arterial pressure was calculated as the diastolic pressure plus one-third of the difference between the systolic and diastolic pressures. Percent body fat was measured by bioelectric impedance analysis (BIA-101S system, RJL Systems, Mt. Clemens, MI). Sympathetic nerve activity to muscle (MSNA) was recorded continuously by obtaining multiunit recordings of postganglionic sympathetic activity to muscle circulation, measured from a nerve fascicle in the peroneal nerve posterior to the fibular head, as described previously (20). MSNA recordings were obtained during 10 min of undisturbed supine rest while subjects were awake in carefully standardized conditions. Studies were conducted in the same room and ≥3 h after the last meal. All subjects were asked to void before the recordings. None of the subjects had apneas, hyponeas, or oxygen desaturations during the study. Sympathetic bursts were identified by careful inspection of the voltage neurogram, and sympathetic activity was expressed as bursts per minute. Blood was collected from the antecubital vein of the opposite arm from which blood pressure was measured. Blood samples were placed on ice until the plasma was separated at 2,800 rpm for 10 min and stored at −70°C until the day of analysis.

Leptin analysis.

Plasma leptin levels were measured using an RIA kit from Linco (St. Louis, MO). The assay range was 0.5–100 ng/ml. Inter- and intra-assay coefficients of variation in our laboratory were 7.0 and 5.1%, respectively.

Statistical analysis.

Values are means ± SE. Differences in hemodynamics, anthropometric measures, MSNA, and leptin levels between patients with OSA and controls were determined using an unpaired Student'st-test. Analysis of covariance was used to determine differences in leptin between patients with OSA and controls, adjusted for percent body fat. All statistical analyses were completed using SAS (SAS Institute, Cary, NC) and S-Plus (Statistical Sciences, Seattle, WA) computer software programs. Statistical significance was defined asP < 0.05.


Study subject characteristics are described in Table1. Patients with OSA (n = 32) and controls (n = 32) were matched for age, height, weight, percent body fat, and mean arterial pressure. Because of difficulties recruiting substantial numbers of otherwise healthy women with OSA, only male patients and controls were studied. Leptin levels were 13.7 ± 1.3 and 9.2 ± 1.2 ng/ml in patients with OSA and controls (P = 0.02), respectively (Fig. 1). Adjusted for percent body fat, leptin levels were still higher in patients with OSA than in controls (P = 0.03). Patients with OSA had a history of weight gain (5.2 ± 1.7 kg) over the year preceding the study compared with control subjects, in whom average weight increased by 0.5 ± 0.9 kg (P = 0.04; Fig. 1). Successful microneurographic studies were completed in 34 subjects. MSNA, measured in 16 OSA patients, was 46 ± 4 bursts/min compared with 30 ± 4 bursts/min in 18 control subjects (P = 0.01).

View this table:
Table 1.

Patient characteristics

Fig. 1.

Differences in plasma leptin levels (open bars) and change in body weight over the year before the study (hatched bars) in male patients with obstructive sleep (OSA, n = 32) and matched controls (n = 32) who are without sleep-disordered breathing. Values are means ± SE.


The important and novel finding of this study is that plasma leptin levels are elevated in OSA. Circulating plasma leptin levels were ∼50% higher in male patients with OSA than in matched controls. The difference in plasma leptin is therefore independent of percent body fat.

The reason for higher leptin levels in sleep apnea is unclear. Our original expectation was that leptin would be lower in patients with sleep apnea, secondary to elevated sympathetic nerve activity stimulating adipocyte β-receptors, which would elicit a decrease in leptin production (14, 16). MSNA was significantly higher in patients with OSA than in matched controls (P = 0.01). Despite this potential mechanism for decreasing leptin production, our data show that sleep apnea is associated with an increase in leptin levels. One possible explanation for higher leptin levels may be adipocyte β3-receptor downregulation as a result of OSA-induced sympathetic activation (8, 16) or because of other mechanisms (1, 18).

Consistent with an earlier study (13), we confirm that sleep apnea patients are also predisposed to weight gain, even though leptin levels are elevated. High leptin levels should reduce body fat (5, 12). Hyperleptinemia in the presence of obesity per se has been explained by “leptin resistance,” namely, inadequate signaling to decrease body fat for a given level of leptin (2). Leptin resistance may therefore predispose patients with sleep apnea to weight gain, even in a milieu of high leptin levels. This may explain the difficulty in weight management in this population, inasmuch as patients with sleep apnea may already be predisposed to weight gain secondary to reduced physical activity resulting from tiredness and daytime somnolence.

Leptin may also affect cardiovascular structure and function. Increases in leptin levels have been linked to elevations in blood pressure, heart rate, and sympathetic nerve activity (4,6, 15). There is growing evidence that the actions of leptin on the cardiovascular system remain intact, despite the inability of leptin to regulate body fat; central neural control of food intake and sympathetic outflow can be dissociated (11). Thus leptin resistance may be specific to metabolic effects of leptin, with preservation of cardiovascular and/or other effects. Animal studies demonstrate that leptin infusion results in sympathetic activation and tachycardia (4, 6,15). We have shown that leptin and sympathetic nerve activity are elevated in patients with OSA. Thus higher leptin levels in sleep apnea patients may contribute to the heightened sympathetic drive, even though there is resistance to the weight loss effects of leptin. Indeed, treatment of OSA with continuous positive airway pressure lowers sympathetic traffic (7, 21) and also lowers leptin levels (3). Our data suggest a potential mechanism for the treatment-induced reductions in leptin and sympathetic drive in OSA.

Our findings regarding sleep apnea-specific abnormalities in plasma leptin may have implications for understanding the disordered breathing during sleep in OSA. Tankersley et al. (17) demonstrated impaired ventilatory responses in leptin-deficient ob/obmice. Leptin resistance with respect to ventilatory control may be involved in abnormalities in breathing control mechanisms in patients with OSA.

The strengths of this study include closely matched demographics of the sleep apnea patients and similarly obese subjects who were proven to be free of sleep-disordered breathing. Neither patients nor controls were on medications, nor did they have any significant medical history. Our study is limited, in that our data were obtained only from men. Our findings cannot be extrapolated to female patients with sleep apnea. Furthermore, our measurements of plasma leptin may not directly reflect levels of leptin in cerebrospinal fluid.

In conclusion, we have demonstrated, first, that circulating plasma leptin levels are elevated in newly diagnosed male patients with untreated sleep apnea and, second, that there is a propensity to weight gain in sleep apnea patients, even in the setting of higher leptin levels. High leptin levels in obesity per se likely reflect resistance to metabolic effects of leptin. OSA may be accompanied by further resistance to metabolic effects of leptin, greater than the resistance evident in obesity alone.


V. K. Somers and B. G. Phillips are Sleep Academic Awardees of the National Institutes of Health. V. K. Somers is an Established Investigator of the American Heart Association. These studies were also supported by National Heart, Lung, and Blood Institute Grants HL-61560, HL-65176, and HL-14388 (to B. G. Phillips and V. K. Somers).


  • Address for reprint requests and other correspondence: V. K. Somers, Div. of Hypertension and Div. of Cardiovascular Diseases, Dept. of Internal Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (E-mail: somers.virend{at}mayo.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. §1734 solely to indicate this fact.


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