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

作者：Bassi M^*; Nakamura N B; Furuya W I; Colombari D S A; Menani J V; do Carmo J M; da Silva A A; Hall J E; Colombari E

来源：Acta Physiologica, 2015, 213(4): 893-901.

DOI：10.1111/apha.12394

• blood pressure
• central chemoreception
• hypercapnia
• leptin
• MC3/4 receptor
• melanocortin system

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 (V-T), respiratory frequency (f(R)) and pulmonary ventilation (V-E) 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. V-E, V-T and f(R) 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 mu g day(-1)) reduced body weight (similar to 17%) and increased ventilatory response to hypercapnia, whereas SHU9119 (0.6 nmol day(-1)) increased body weight (similar to 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.

• 出版日期2015-4