REGULATION OF LEPTIN PRODUCTION

Leptin production is regulated by several factors.^17,18 Insulin and glucocorticoids act directly on adipocytes to increase leptin production, and chronic hyperinsulinaemia and increased cortisol turnover may underlie the increase in leptin expression observed in obesity. Similarly, the observed increase in serum leptin levels 4–7 hours after meals is probably related to increased circulating insulin in concert with the permissive effects of cortisol. Fasting results in decreased serum leptin levels—probably through falling insulin levels and the ability of catecholamines to decrease leptin expression (isoproterenol and β₃ adrenergic receptor agonists reduce leptin production by adipocytes). Women have been noted to have higher serum leptin levels than men, and this could relate to a difference in body fat composition between the sexes or the permissive effects of oestrogen and progesterone on leptin production. Under conditions of constant enteral feeding, circulating leptin levels are higher at night than during the day; in addition to a small circadian influence, sleep is associated with an increase in plasma leptin levels in normal subjects.¹⁹

EFFECTS OF LEPTIN ON RESPIRATION

Apart from its anti-obesity effects, leptin exerts important physiological effects on the control of respiration.²⁰ Ob/ob mice, which lack the gene responsible for production of leptin, demonstrate hypoventilation in addition to marked obesity (Paco₂ on average 1.5 kPa higher than wild type mice during wakefulness).²¹ Furthermore, these animals have an impaired hypercapnic ventilatory response (HCVR) during both wakefulness and sleep. During REM sleep the HCVR is absent in ob/ob mice. This impairment of the HCVR in ob/ob mice relative to wild type mice cannot be attributed to the mechanical effects of obesity as it precedes the development of the latter.²⁰ Furthermore, leptin replacement studies in ob/ob mice have shown improvements in baseline minute ventilation and HCVR during wakefulness and sleep under experimental conditions which prevented a concomitant weight change in the animal.^21,22

ROLE OF LEPTIN IN OSA

The high prevalence of obstructive sleep apnoea (OSA) in obese humans²³ and the established role of leptin as a respiratory stimulant and appetite suppressant in the mouse raised the possibility that sleep apnoea could be a leptin deficient state. Several groups have shown, however, that patients with OSA have even higher circulating leptin levels (approximately 50%) than subjects without OSA matched for age and body mass index.^24–26 This finding suggests that, independent of the known relationship between obesity and increased circulating leptin levels, OSA could represent a leptin resistant state. Two groups have shown that treatment of OSA with nasal continuous positive airway pressure (NCPAP) for 6 months is associated with a reduction in circulating leptin to a level similar to individuals without OSA.^24,26 The physiological explanation for the fall in circulating leptin levels in patients with OSA treated with NCPAP has not been fully elucidated, but some plausible explanations include a reduction in visceral fat accumulation,²⁷ reduction in muscle sympathetic nerve activity,²⁸ reduced level of stress,²⁹ and a change in insulin responsiveness³⁰ with NCPAP treatment. The fact that circulating leptin levels fall with NCPAP treatment of OSA, however, suggests that OSA may be a stimulant of leptin production rather than a consequence of the action of leptin.

“A profound degree of leptin resistance may underpin the development of the obesity hypoventilation syndrome”

The obesity hypoventilation syndrome (OHS) is characterised by obesity and hypercapnia while awake in the absence of an alternative neuromuscular, mechanical, or metabolic explanation for hypoventilation. Most patients with OHS suffer from OSA and in many (but not all) cases treatment of OSA with NCPAP restores daytime eucapnia.^31,32 In some patients OHS cannot be explained on the basis of OSA,³³ and daytime hypercapnia appears to result from inadequate physiological compensation for the development of obesity alone. This condition remains an enigma. Why do certain obese individuals hypoventilate during wakefulness while others with similar or greater levels of obesity do not? Could leptin be the key to understanding this conundrum?

The paper by Phipps and colleagues³⁴ in this issue of Thorax contributes an interesting additional piece of information. The authors discovered that the mean serum leptin level was twice as high in a group of 12 hypercapnic obese humans as in a group of 44 eucapnic individuals with a similar percentage of body fat. Both groups had a mean apnoea-hypopnoea index in the severe OSA range but were not significantly different from each other. This finding raises the intriguing possibility that a profound degree of leptin resistance (more than that observed with eucapnic obesity or OSA alone) underpins the development of OHS. If this is the case, then leptin or analogues of leptin could have a role in the treatment of OHS. However, this preliminary finding by Phipps and colleagues will require further exploration to determine whether the marked increase in serum leptin levels found in patients with OHS truly signals a causative mechanism or whether it is simply an epiphenomenon of the condition. In particular, it would be interesting to know whether serum leptin levels are raised in patients with OHS but without significant OSA compared with patients with a similar level of simple obesity, whether leptin levels are increased in non-obese patients with hypoventilation, and whether the serum leptin level in patients with OHS reverts with treatment to the level observed in simple obesity, as might be expected if the increased serum leptin levels are a consequence rather than a causative factor in OHS. These questions and others with regard to the potential respiratory modulating role of leptin in humans, an exciting new research area, will probably find an answer within the next few years.