Background: Leptin is a protein hormone produced by fat cells of mammals. It acts within the hypothalamus via a specific receptor to reduce appetite and increase energy expenditure. Plasma leptin levels correlate closely with total body fat mass operating via a central feedback mechanism. In human obesity serum leptin levels are up to four times higher than in lean subjects, indicating a failure of the feedback loop and central leptin resistance. In leptin deficient obese mice (ob/ob mice) leptin infusion reverses hypoventilation. It was hypothesised that a relative deficiency in CNS leptin, indicated by high circulating leptin levels, may be implicated in the pathogenesis of obesity hypoventilation syndrome (OHS). Methods: Fasting morning leptin levels were measured in obese and non-obese patients with and without daytime hypercapnia (n=56). Sleep studies, anthropometric data, spirometric parameters, and awake arterial blood gas tensions were measured in each patient. Results: In the whole group serum leptin levels correlated closely with % body fat (r=0.77). Obese hypercapnic patients (mean (SD) % body fat 43.8 (6.0)%) had higher fasting serum leptin levels than eucapnic patients (mean % body fat 40.8 (6.2)%), with mean (SD) leptin levels of 39.1 (17.9) and 21.4 (11.4) ng/ml, respectively (p<0.005). Serum leptin (odds ratio (OR) 1.12, 95% CI 1.03 to 1.22) was a better predictor than % body fat (OR 0.92, 95% CI 0.76 to 1.1) for the presence of hypercapnia. Conclusions: Hyperleptinaemia is associated with hypercapnic respiratory failure in obesity. Treatment with leptin or its analogues may have a role in OHS provided central leptin resistance can be overcome. INTRODUCTIONObesity is rapidly increasing in prevalence with a major impact on ill health and health costs.1 Sleep disordered breathing, usually manifest by obstructive sleep apnoea (OSA), is common in obesity. However, some patients with obesity and OSA develop daytime hypercapnia (obesity hypoventilation syndrome, OHS). 2Leptin is a protein hormone produced by mammalian adipocytes. It acts within the hypothalamus via a specific receptor to reduce appetite and increase energy expenditure. 3Serum levels correlate positively with total body fat mass. In obesity there may be a failure of central feedback mechanisms leading to leptin resistance.3 There is evidence, for example, that obese humans have a relative deficiency of CNS leptin compared with lean controls. 4 Recent data have shown, however, that leptin replacement reverses the hypoventilation that occurs in the leptin deficient mouse model of obesity. 5We further characterised this relationship by measuring leptin levels and arterial blood gas tensions in patients with various degrees of obesity and sleep disordered breathing, including patients with awake hypercapnia. METHODSConsecutive patients undergoing diagnostic sleep studies at Royal Prince Alfred Hospital between July and December 1999 were studied. Anthropometric measurements, spirometric tests, and arterial blood gas sampling were performed ...

The quantitative measurement of regional aerosol deposition in human lungs using two-dimensional (2D) gamma scintigraphy has proven to be useful in therapeutic and diagnostic aerosol studies. The penetration index (PI) has been defined as the ratio of activity in a peripheral lung zone to a central lung zone, but the ability to discriminate between aerosol deposition in the large airways and lung parenchyma is reduced by the fact that the latter overlies the former in the central zone. To overcome this, we used a three-dimensional (3D) technique. Seven healthy subjects inhaled isotonic saline aerosols containing 99mTc-DTPA on two occasions. The droplets had a mass median aerodynamic diameter (MMAD) of either 2.6 or 5.5 microns (with geometric standard deviations [sigma g] of 1.4 and 1.7, respectively). Transmission tomography was performed on each subject to delineate lung boundaries in 2D and 3D. After inhalation, anterior (A) and posterior (P) images were collected and a tomographic study performed. Mid-lung slices were taken from coronal (CC) and transverse (TC) sections. PI was calculated on the 2D images (AP and P) and the 3D slices (CC and TC) using exactly defined regions. The PI values were smaller for the large droplet aerosol (5.5 microns) in all subjects and methods. The relative differences in PI between large and small (2.6 microns) droplet studies (d values) were greater and less variable for the 3D methods (TC, 56.5 +/- 11.4% and CC, 52.4 +/- 12.3%) compared to the 2D methods (P, 25.4 +/- 17.1% and AP, 38.3 +/- 15%; p less than 0.005). We found the 3D methods to be more sensitive for discriminating between aerosol deposition in large and small airways than were the conventional 2D methods.

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Background: Leptin is a protein produced by adipose tissue that circulates to the brain and interacts with receptors in the hypothalamus to inhibit eating. In obese humans, serum leptin is up to four times higher than in lean subjects, indicating that human obesity is associated with a central resistance to the weight-lowering effects of leptin. Although the leptin-deficient mouse (ob/ob) develops obesity hypoventilation syndrome (OHS), in humans with OHS, serum leptin is a better predictor of awake hypercapnia in obesity than the body mass index (BMI). This suggests that central leptin resistance may promote the development of OHS in humans. We speculated that the reversal of OHS by regular non-invasive ventilation (NIV) therapy decreases leptin levels. Objectives: The aim of this study was to investigate whether ventilatory treatment of OHS would alter circulating leptin concentrations. Method: We measured fasting serum leptin levels, BMI, spirometry and arterial blood gases in 14 obese hypercapnic subjects undergoing a diagnostic sleep study. Results: The average age of the subjects was (mean ± SE) 62 ± 13 years, BMI 40.9 ± 2.2 kg/m², PaCO₂ 6.7 ± 0.2 kPa, PaO₂ 8.9 ± 0.4 kPa and total respiratory disturbance index 44 ± 35 events/hour. Subjects were clinically reviewed after a median of 2.3 years (range 1.6–3) with repeat investigations. Nine patients were regular NIV users and 5 were non-users. NIV users had a significant reduction in serum leptin levels (p = 0.001), without a change in BMI. In these patients, there was a trend towards an improved daytime hypercapnia and hypoxemia, while in the 5 non-users, no changes in serum leptin, BMI or arterial blood gases occurred. Conclusion: Regular NIV use reduces serum leptin in OHS. Leptin may be a modulator of respiratory drive in patients with OHS.