Leptin into the ventrolateral medulla facilitates chemorespiratory response in leptin‐deficient (ob/ob) mice

Abstract

Aim Leptin, an adipocyte-derived hormone, is suggested to participate in the central control of breathing. We hypothesized that leptin may facilitate ventilatory responses to chemoreflex activation by acting on respiratory nuclei of the ventrolateral medulla. The baseline ventilation and the ventilatory responses to CO2 were evaluated before and after daily injections of leptin into the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) for 3 days in obese leptin-deficient (ob/ob) mice. Methods Male ob/ob mice (40–45 g, n = 7 per group) received daily microinjections of vehicle or leptin (1 μg per 100 nL) for 3 days into the RTN/pFRG. Respiratory responses to CO2 were measured by whole-body plethysmography. Results Unilateral microinjection of leptin into the RTN/pFRG in ob/ob mice increased baseline ventilation (VE) from 1447 ± 96 to 2405 ± 174 mL min−1 kg−1 by increasing tidal volume (VT) from 6.4 ± 0.4 to 9.1 ± 0.8 mL kg−1 (P < 0.05). Leptin also enhanced ventilatory responses to 7% CO2 (Δ = 2172 ± 218 mL min−1 kg−1, vs. control: Δ = 1255 ± 105 mL min−1 kg−1), which was also due to increased VT (Δ = 4.71 ± 0.51 mL kg−1, vs. control: Δ = 2.27 ± 0.20 mL kg−1), without changes in respiratory frequency. Leptin treatment into the RTN/pFRG or into the surrounding areas decreased food intake (83 and 70%, respectively), without significantly changing body weight. Conclusion The present results suggest that leptin acting in the respiratory nuclei of the ventrolateral medulla improves baseline VE and VT and facilitates respiratory responses to hypercapnia in ob/ob mice.

Control of respiratory and cardiovascular functions by leptin

“…Our data suggest that the effects of leptin on ventilation depend on activation of the brain–melanocortin system. We also demonstrated attenuated ventilatory responses to CO 2 in mice with LR deficiency specifically in POMC neurons, reinforcing the concept that leptin-induced improvement of ventilatory function is mediated by the brain melanocortin system [6,7]. …”

“…We found that chronic central MC3/4R antagonism for 6 days reduced the ventilatory response to hypercapnia and abolished leptin's ability to increase baseline ventilation in rats [6,7]. Our data suggest that the effects of leptin on ventilation depend on activation of the brain–melanocortin system.…”

“…Therefore, preautonomic neurons in the RVLM may express leptin receptors which allow cardiovascular effects of leptin by directly increasing the activity of these neurons [4]. Moreover, administration of leptin for 3 consecutive days into the RVLM increased baseline ventilation and ventilatory response to hypercapnia in ob/ob mice [6,7]. Although multiple mechanisms involved in chemoreception at level of the ventral surface of the medulla have been described including modulation of glutamatergic neurons of the retrotrapezoid nuclei (RTN) [42] and purinergic glial cells that release adenosine 5′ triphosphate (ATP) in response to CO 2 stimulation [71, 92], the mechanisms by which leptin contributes to the chemoreflex is still unclear and remains as an important area for investigation.…”

“…Strong evidence shows that leptin requires activation of the brain melanocortin system, including activation of proopiomelanocortin (POMC) neurons and melanocortin 4 receptors (MC4R) to exert most of its effects on blood pressure (BP) and ventilatory function [6,7,22,77]. …”

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

“…In addition to its effects to reduce food intake and body weight and to increase sympathetic nervous system activity (SNA) and blood pressure (BP), central leptin administration also enhances baseline respiratory activity and chemorespiratory responses to carbon dioxide (CO 2 ) (Bassi et al ., 2012, Bassi et al ., 2014, Hall et al ., 2010, Inyushkina et al ., 2010). However, the central mechanisms activated by leptin to facilitate respiratory responses are still unclear.…”