Central leptin replacement enhances chemorespiratory responses in leptin-deficient mice independent of changes in body weight

Abstract

Previous studies showed that leptin-deficient (ob/ob) mice develop obesity and impaired ventilatory responses to CO₂ $\left( {{{\dot{V}}_{{{\text{E}}\,}}}{ - }\,{\text{C}}{{\text{O}}_{{2}}}} \right)$. In this study, we examined if leptin replacement improves chemorespiratory responses to hypercapnia (7 % CO₂) in ob/ob mice and if these effects were due to changes in body weight or to the direct effects of leptin in the central nervous system (CNS). ${\dot{V}_{{{\text{E}}\,}}}{\text{ - C}}{{\text{O}}_{{2}}}$ was measured via plethysmography in obese leptin-deficient- (ob/ob) and wild-type- (WT) mice before and after leptin (10 μg/2 μl day) or vehicle (phosphate buffer solution) were microinjected into the fourth ventricle for four consecutive days. Although baseline ${\dot{V}_{\text{E}}}$ was similar between groups, obese ob/ob mice exhibited attenuated ${\dot{V}_{{{\text{E}}\,}}}{ - }\,{\text{C}}{{\text{O}}_{{2}}}$ compared to WT mice (134 ± 9 versus 196 ± 10 ml min⁻¹). Fourth ventricle leptin treatment in obese ob/ob mice significantly improved ${\dot{V}_{{{\text{E}}\,}}}{ - }\,{\text{C}}{{\text{O}}_{{2}}}$ (from 131 ± 15 to 197 ± 10 ml min⁻¹) by increasing tidal volume (from 0.38 ± 0.03 to 0.55 ± 0.02 ml, vehicle and leptin, respectively). Subcutaneous leptin administration at the same dose administered centrally did not change ${\dot{V}_{{{\text{E}}\,}}}{ - }\,{\text{C}}{{\text{O}}_{{2}}}$ in ob/ob mice. Central leptin treatment in WT had no effect on ${\dot{V}_{{{\text{E}}\,}}}{ - }\,{\text{C}}{{\text{O}}_{{2}}}$. Since the fourth ventricle leptin treatment decreased body weight in ob/ob mice, we also examined ${\dot{V}_{{{\text{E}}\,}}}{ - }\,{\text{C}}{{\text{O}}_{{2}}}$ in lean pair-weighted ob/ob mice and found it to be impaired compared to WT mice. Thus, leptin deficiency, rather than obesity, is the main cause of impaired ${\dot{V}_{{{\text{E}}\,}}}{ - }\,{\text{C}}{{\text{O}}_{{2}}}$ in ob/ob mice and leptin appears to play an important role in regulating chemorespiratory response by its direct actions on the CNS.