Activation of the brain melanocortin system is required for leptin‐induced modulation of chemorespiratory function. (30th September 2014)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Acta physiologica. Volume 213:Number 4(2015:Apr.)
• Page Start: 893
• Page End: 901
• Publication Date: 2014-09-30
• Subjects: Physiology -- Periodicals; Physiology -- Research -- Periodicals; 612
• DOI: 10.1111/apha.12394
• Languages: English
• ISSNs: 1748-1708

Abstract

<abstract abstract-type="main" id="apha12394-abs-0001"> <title>Abstract</title> <sec id="apha12394-sec-0001" sec-type="section"> <p>Melanocortin receptors (MC3/4R) mediate most of the metabolic and cardiovascular actions of leptin.</p> </sec> <sec id="apha12394-sec-0002" sec-type="section"> <title>Aim</title> <p>Here, we tested if MC4R also contributes to leptin's effects on respiratory function.</p> </sec> <sec id="apha12394-sec-0003" sec-type="section"> <title>Methods</title> <p>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 (<italic>V</italic><sub>T</sub>), respiratory frequency (<italic>f</italic><sub>R</sub>) and pulmonary ventilation (<italic>V</italic><sub>E</sub>) were measured by whole‐body plethysmography during normocapnia or hypercapnia (7% CO<sub>2</sub>). Baseline mean arterial pressure (MAP), heart rate (HR) and metabolic rate were also measured. <italic>V</italic><sub>E</sub>, <italic>V</italic><sub>T</sub> and <italic>f</italic><sub>R</sub> 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<sup>−/−</sup>) and wild‐type mice.</p> </sec> <sec id="apha12394-sec-0004" sec-type="section"> <title>Results</title> <p>Leptin (5 <italic>μ</italic>g day<sup>−1</sup>) reduced body weight (~17%) and increased ventilatory response to hypercapnia, whereas SHU9119 (0.6 nmol day<sup>−1</sup>) increased body weight (~18%) and reduced ventilatory responses compared with control‐PBS group (Lep: 2119 ± 90 mL min<sup>−1</sup> kg<sup>−1</sup> and SHU9119: 997 ± 67 mL min<sup>−1</sup> kg<sup>−1</sup>, vs. PBS: 1379 ± 91 mL min<sup>−1</sup> kg<sup>−1</sup>). 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<sup>−1</sup> kg<sup>−1</sup>). The ventilatory response to hypercapnia was attenuated in the LepR/Nestin‐cre, LepR/POMC‐cre and MC4R<sup>−/−</sup> mice.</p> </sec> <sec id="apha12394-sec-0005" sec-type="section"> <title>Conclusion</title> <p>These results suggest that central MC4R mediate the effects of leptin on respiratory response to hypercapnia.</p> </sec> </abstract>