Intranasal Leptin Relieves Sleep-disordered Breathing in Mice with Diet-induced Obesity

Abstract

Rationale: Leptin treats upper airway obstruction and alveolar hypoventilation in leptin-deficient ob/ob mice. However, obese humans and mice with diet-induced obesity (DIO) are resistant to leptin because of poor permeability of the blood-brain barrier. We propose that intranasal leptin will bypass leptin resistance and treat sleep-disordered breathing in obesity. Objectives: To assess if intranasal leptin can treat obesity hypoventilation and upper airway obstruction during sleep in mice with DIO. Methods: Male C57BL/6J mice were fed with a high-fat diet for 16 weeks. A single dose of leptin (0.4 mg/kg) or BSA (vehicle) were administered intranasally or intraperitoneally, followed by either sleep studies (n = 10) or energy expenditure measurements (n = 10). A subset of mice was treated with leptin daily for 14 days for metabolic outcomes (n = 20). In a separate experiment, retrograde viral tracers were used to examine connections between leptin receptors and respiratory motoneurons. Measurements and Main Results: Acute intranasal, but not intraperitoneal, leptin decreased the number of oxygen desaturation events in REM sleep, and increased ventilation in non-REM and REM sleep, independently of metabolic effects. Chronic intranasal leptin decreased food intake and body weight, whereas intraperitoneal leptin had no effect. Intranasal leptin induced signal transducer and activator of transcription 3 phosphorylation in hypothalamic and medullary centers, whereas intraperitoneal leptin had no effect. Leptin receptor-positive cells were synaptically connected to respiratory motoneurons. Conclusions: In mice with DIO, intranasal leptin bypassed leptin resistance and significantly attenuated sleep-disordered breathing independently of body weight.

Carotid Body and Metabolic Syndrome: Mechanisms and Potential Therapeutic Targets

“…Leptin-deficient ob/ob mice, hyperleptinemic and leptin resistant DIO mice, and New Zealand obese mice (NZO) hypoventilate during sleep, and retain CO 2 [ 157 , 171 , 172 , 173 ], similarly to patients with OHS. This defect was reversed by leptin delivery beyond the blood–brain barrier by intracerebroventricular [ 160 ] or intranasal routes [ 174 ]. In addition, both leptin deficiency and leptin resistance have a detrimental effect on upper airway collapsibility, leading to OSA [ 171 , 172 , 173 ], which has also been relieved by leptin delivery to the CNS [ 160 , 174 ].…”

“…This defect was reversed by leptin delivery beyond the blood–brain barrier by intracerebroventricular [ 160 ] or intranasal routes [ 174 ]. In addition, both leptin deficiency and leptin resistance have a detrimental effect on upper airway collapsibility, leading to OSA [ 171 , 172 , 173 ], which has also been relieved by leptin delivery to the CNS [ 160 , 174 ].…”

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

“…Yao et al suggested the dorsomedial hypothalamus and nucleus tractus solitarius as the main site of the effects of leptin on ventilatory control, such as leptin relieving upper airway obstruction through the dorsomedial hypothalamus and its effect on respiratory pump muscles mediated by the nucleus tractus solitarius; however, the latter effect may be inhibited by increases in circulating leptin or even by leptin resistance [31]. 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].…”

“…Lately, Berger et al found that intranasal leptin can reduce the number of oxygen desaturation events during rapid eye movement (REM) sleep and increase ventilation during non-REM and REM sleep in mice with diet-induced obesity. The authors thus suggested a new method of administration that bypasses leptin resistance and significantly attenuates sleep-disordered breathing independently of body weight [34]. This innovative approach demonstrates the potential of intranasal leptin for OSA treatment and provides us with new ideas, but it lacks strong evidence from clinical trial.…”

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

“…Leptin resistance has multiple mechanisms, but limited permeability of the BBB plays a key role [95][96][97][98]. Berger and colleagues [71] administered leptin intranasally in mice in an effort to bypass the BBB. Intranasal leptin increased ventilation during NREM and REM sleep and decreased the number of oxygen desaturation events in REM sleep (Table 1).…”