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Abstract
Leptin is an adipose-derived hormone that plays an important role in the regulation of breathing. It has been demonstrated that obesity-related hypoventilation or apnea is closely associated with leptin signaling pathways. Perturbations of leptin signaling probably contribute to the reduced sensitivity of respiratory chemoreceptors to hypoxia/hypercapnia. However, the underlying mechanism remains incompletely understood. The present study is to test the hypothesis that leptin signaling contributes to modulating a hypoxic ventilatory response. The respiratory function was assessed in conscious obese Zucker rats or lean littermates treated with an injection of leptin. During exposure to hypoxia, the change in minute ventilation was lower in obese Zucker rats than chow-fed lean littermates or high fat diet-fed littermates. Such a change was abolished in all groups after carotid body denervation. In addition, the expression of phosphorylated signal transducers and activators of transcription 3 (pSTAT3), as well as putative O2-sensitive K+ channels including TASK-1, TASK-3 and TASK-2 in the carotid body, was significantly reduced in obese Zucker rats compared with the other two phenotype littermates. Chronic administration of leptin in chow-fed lean Zucker rats failed to alter basal ventilation but vigorously increased tidal volume, respiratory frequency, and therefore minute volume during exposure to hypoxia. Likewise, carotid body denervation abolished such an effect. In addition, systemic leptin elicited enhanced expression of pSTAT3 and TASK channels. In conclusion, these data demonstrate that leptin signaling facilitates hypoxic ventilatory responses probably through upregulation of pSTAT3 and TASK channels in the carotid body. These findings may help to better understand the pathogenic mechanism of obesity-related hypoventilation or apnea.
Highlights
Leptin, a peptide hormone secreted mainly by adipocytes, regulates multiple physiological functions including metabolism, cardiovascular activity, and breathing (Grill et al, 2002; Bassi et al, 2015)
The results suggest that the stimulatory effect of leptin on hypoxic ventilatory response (HVR) are closely associated with enhanced expression of pSTAT3 and TWIK-related acid-sensitive K (TASK) channels, which may contribute to the regulation of carotid body (CB)’s chemosensitivity
Chronic administration of leptin has no marked effects on basal ventilation but considerably enhances the HVR, accompanied by increased expression of pSTAT3
Summary
A peptide hormone secreted mainly by adipocytes, regulates multiple physiological functions including metabolism, cardiovascular activity, and breathing (Grill et al, 2002; Bassi et al, 2015). Accumulated evidence indicates the presence of ob-Rb in the CB cells (Porzionato et al, 2011; Messenger et al, 2013), and that leptin signaling contributes to CB-mediated ventilatory responses (Olea et al, 2015; Ribeiro et al, 2017). It remains controversial whether the CB mediates the acute effect of leptin on hypoxic ventilatory response (HVR) because leptin’s role may involve the change in gene expression and protein synthesis, requiring hours even days for full effects (Hall et al, 2010). We thereby predicted that the stimulatory effect of leptin on HVR may require chronic activation of CBs, but such a confirmation is yet to be put forward
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