Leptin acts in the carotid bodies to increase minute ventilation during wakefulness and sleep and augment the hypoxic ventilatory response

Abstract

Key points Leptin is a potent respiratory stimulant. A long functional isoform of leptin receptor, LepRb, was detected in the carotid body (CB), a key peripheral hypoxia sensor. However, the effect of leptin on minute ventilation (VE) and the hypoxic ventilatory response (HVR) has not been sufficiently studied. We report that LepRb is present in approximately 74% of the CB glomus cells. Leptin increased carotid sinus nerve activity at baseline and in response to hypoxia in vivo. Subcutaneous infusion of leptin increased VE and HVR in C57BL/6J mice and this effect was abolished by CB denervation. Expression of LepRb in the carotid bodies of LepRb deficient obese db/db mice increased VE during wakefulness and sleep and augmented the HVR. We conclude that leptin acts on LepRb in the CBs to stimulate breathing and HVR, which may protect against sleep disordered breathing in obesity. Abstract Leptin is a potent respiratory stimulant. The carotid bodies (CB) express the long functional isoform of leptin receptor, LepRb, but the role of leptin in CB has not been fully elucidated. The objectives of the current study were (1) to examine the effect of subcutaneous leptin infusion on minute ventilation (VE) and the hypoxic ventilatory response to 10% O2 (HVR) in C57BL/6J mice before and after CB denervation; (2) to express LepRb in CB of LepRb‐deficient obese db/db mice and examine its effects on breathing during sleep and wakefulness and on HVR. We found that leptin enhanced carotid sinus nerve activity at baseline and in response to 10% O2 in vivo. In C57BL/6J mice, leptin increased VE from 1.1 to 1.5 mL/min/g during normoxia (P < 0.01) and from 3.6 to 4.7 mL/min/g during hypoxia (P < 0.001), augmenting HVR from 0.23 to 0.31 mL/min/g/ΔFnormalIO2 (P < 0.001). The effects of leptin on VE and HVR were abolished by CB denervation. In db/db mice, LepRb expression in CB increased VE from 1.1 to 1.3 mL/min/g during normoxia (P < 0.05) and from 2.8 to 3.2 mL/min/g during hypoxia (P < 0.02), increasing HVR. Compared to control db/db mice, LepRb transfected mice showed significantly higher VE throughout non‐rapid eye movement (20.1 vs. −27.7 mL/min respectively, P < 0.05) and rapid eye movement sleep (16.5 vs 23.4 mL/min, P < 0.05). We conclude that leptin acts in CB to augment VE and HVR, which may protect against sleep disordered breathing in obesity.

Exploring the Mediators that Promote Carotid Body Dysfunction in Type 2 Diabetes and Obesity Related Syndromes

“…In Wistar rats, intravenous [22,84] and intracarotid [22] administration of leptin increased basal ventilation and ventilation in response to ischemic hypoxia, assessed by the occlusion of the common carotid artery, in a dose-dependent manner. In the same line of evidence, subcutaneous leptin administration in C57BL/6J mice increased minute ventilation and hypoxic ventilatory response, effects abolished by the CSN resection [83]. These results, together with the findings that CSN resection decreased in approximately 30% of subjects the spontaneous ventilation induced by acute leptin intracarotid administration (90 and 270 ng/mL) ( Figure 3), confirmed that the CB contributes to the effects of leptin on basal ventilation and in response to acute hypoxia.…”

“…The work of Porzionato et al [81] was then corroborated by Messenger et al [82] as they described that rat CB cells express the Ob-Rb and that these receptors overlap in distribution with cells expressing tyrosine hydroxylase, indicating the presence of this leptin receptor in CB type I cells. More recently, the presence of Ob-Rb isoforms was also described in mice type I and type II cells [83]. Altogether, these findings support the idea that the effects of leptin on ventilation are, at least in part, mediated by CB chemoreceptors.…”

“…In agreement with the effects of leptin as a sympathetic activator, leptin increased electrophysiological sympathetic nervous system activity, measured at the cervical sympathetic chain, in control animals, but in HF animals, the rise in sympathetic activity induced by the HF diet was not modified after leptin administration or CSN resection [86]. Alongside these blunted effects on ventilation and on the sympathetic activity produced by a HF diet and the absence of effects of CSN resection in these animals, leptin was unable to modify the increase in basal CSN electrophysiological activity induced by 3 weeks of HF diet in rats [22], while in control rats and mice, leptin augmented basal CSN chemoreceptor activity [22,64,83]. Additionally, 3 weeks of HF diet increased the expression of leptin receptor Ob-R (short and long form) by 35% [22], suggesting a feed-forward mechanism to increase CB activity or the saturation of Ob-R leptin receptors during hyperleptinemic states, in parallel to what is described in the central nervous system [87].…”

The Role of Animal Models in Developing Pharmacotherapy for Obstructive Sleep Apnea

“…Recently, our lab discovered that the carotid bodies respond to leptin, with downstream effects on minute ventilation and HVR [73]. We showed that the long functional isoform of leptin receptor (LepR b ) is expressed in approximately 74% of glomus cells in carotid body and that leptin infusion increased carotid sinus nerve activity in vivo.…”

Effects of different obesity-related adipokines on the occurrence of obstructive sleep apnea

“…Research on obese mice with leptin deficiency (ob/ob) shows that leptin can stabilize pharyngeal patency and ameliorate hypoventilation and upper airway obstruction in obesity [32,33], and that leptin replacement therapy can improve minute ventila- [34]. Besides, leptin acts on LepRb in the carotid body to stimulate breathing and the hypoxic ventilatory response, which may protect against sleep disordered breathing in obesity [35]. These findings indicate that leptin has the potential to be used in the treatment of OSA and obesity hypoventilation with relative leptin deficiency.…”