Activation of the brain melanocortin system is required for leptin-induced modulation of chemorespiratory function

Abstract

Melanocortin receptors (MC3/4R) mediate most of the metabolic and cardiovascular actions of leptin.

Aim: Here, we tested if MC4R also contributes to leptin's effects on respiratory function.

Methods: After control measurements, male Holtzman rats received daily microinjections of leptin, SHU9119 (MC3/4R antagonist) or SHU9119 combined with leptin infused into the brain lateral ventricle for 7 days. On the 6th day of treatment, tidal volume (VT ), respiratory frequency (fR ) and pulmonary ventilation (VE ) were measured by whole-body plethysmography during normocapnia or hypercapnia (7% CO2 ). Baseline mean arterial pressure (MAP), heart rate (HR) and metabolic rate were also measured. VE , VT and fR were also measured in mice with leptin receptor deletion in the entire central nervous system (LepR/Nestin-cre) or only in proopiomelanocortin neurones (LepR/POMC-cre) and in MC4R knockout (MC4R(-/-) ) and wild-type mice.

Results: Leptin (5 μg day(-1) ) reduced body weight (~17%) and increased ventilatory response to hypercapnia, whereas SHU9119 (0.6 nmol day(-1) ) increased body weight (~18%) and reduced ventilatory responses compared with control-PBS group (Lep: 2119 ± 90 mL min(-1) kg(-1) and SHU9119: 997 ± 67 mL min(-1) kg(-1) , vs. PBS: 1379 ± 91 mL min(-1) kg(-1) ). MAP increased after leptin treatment (130 ± 2 mmHg) compared to PBS (106 ± 3 mmHg) or SHU9119 alone (109 ± 3 mmHg). SHU9119 prevented the effects of leptin on body weight, MAP (102 ± 3 mmHg) and ventilatory response to hypercapnia (1391 ± 137 mL min(-1) kg(-1) ). The ventilatory response to hypercapnia was attenuated in the LepR/Nestin-cre, LepR/POMC-cre and MC4R(-/-) mice.

Conclusion: These results suggest that central MC4R mediate the effects of leptin on respiratory response to hypercapnia.

Keywords: MC3/4 receptor; blood pressure; central chemoreception; hypercapnia; leptin; melanocortin system.