Table 1.

Targets of respiratory effects of leptin in animal models of OHS

Region	References	Animal model of OHS	Methods	Evidences
Fourth ventricle	Bassi et al., 2012 [60]	Leptin-deficient (ob/ob) mice	Mice received leptin into the fourth ventricle for four consecutive days. Baseline ventilation and ventilatory responses to CO2 were measured using plethysmography.	Central leptin increased ventilation and ventilatory response to hypercapnia Subcutaneous leptin administration did not change ventilation and ventilatory response to hypercapnia. lean pair-weighted ob/ob mice have impaired ventilatory response.
Ventrolateral medulla	Bassi et al., 2014 [22]	ob/ob mice	Mice received microinjections of leptin for 3 days in the Ventrolateral medulla. Ventilatory responses to CO2 were measured using plethysmography.	Increased minute ventilation, tidal volume, and ventilatory response to hypercapnia
Fourth ventricle and lateral ventricles	Yao et al., 2016 [24]	ob/ob mice	ICV administration of leptin followed by polysomnographic recording	Leptin administration in the fourth ventricle and lateral ventricles increased minute ventilation during nonflow-limited breathing in sleep. Inspiratory flow limitation were relieved by leptin administration to the lateral but not to the fourth cerebral ventricle
Carotid bodies	Ribeiro et al., 2018 [102]	Diet-induced obese Wistar rats	Intravenous leptin administration on ventilatory parameters in vivo. Leptin aplication on carotid sinus nerve activity ex vivo.	Leptin increases minute ventilation at the baseline and during hypoxia in control rats. In high-fat model, the effect of leptin in ventilation is blunted. High-fat rats presented an increased frequency of carotid cinus nerve at tha baseline, which is not affected by leptin.
Carotid bodies	Yuan et al., 2018 [85]	Obese Zucker rats	Ventilation was assessed in conscious obese Zucker rats or lean littermates that received an injection of leptin at the baseline and during hypoxia in control animais and rats with carotid body denervation. The expression of pSTAT3, as well as K + channel TASK-1 was evaluated in the carotid bodies.	Leptin signaling increases hypoxic ventilatory responses.Leptin administration is associated with changes in expression of pSTAT3 and TASK channels in the carotid bodies.
(?)	Berger et al., 2019 [55]	Diet-induced obese mice	A single dose of leptin or vehicle were administered intranasally or intraperitoneally, followed by sleep studies	Intranasal, but not intraperitoneal, leptin decreased the number of oxygen desaturation events in REM sleep, and increased ventilation in non-REM and REM sleep.
Carotid bodies	Caballero‐Eraso et al., 2019 [103]	C57BL/6J mice and LEPRb‐deficient db/db mice	Subcutaneous leptin infusion followed by baseline minute ventilation and the hypoxic ventilatory response (HVR) to 10% O2 measurementens in C57BL/6J mice before and after carotid bodies denervation. Expression of LEPRb in the carotid bodies of db/db mice followed by recording of breathing during sleep and wakefulness and on HVR	Leptin acts on LEPRb in the carotid bodies to stimulate breathing and HVR.
DMH	Pho et al., 2021 [35]	db/db mice	Mice were infected with Ad-LepRb or control Ad-mCherry virus into the DMH. Ventilation was measured during sleep as well as CO2 production after intracerebroventricular (ICV) of leptin or vehicle	After leptin receptor expression in DMH of db/db mice, ICV leptin increased inspiratory flow, tidal volume, and minute ventilation during NREM sleep
NTS	Amorim et al., 2021 [101]	LEPRb-Cre diet-induced obese mice	Designer receptors exclusively activated by designer drugs were selectively expressed in the LEPRb positive neurons of the NTS The effect of DREADD ligand, J60, on tongue muscle activity and breathing during sleep was measured.	Activation of LEPRb positive NTS neurons did not stimulate breathing or upper airway muscles during NREM and REM sleep