title: 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 CO(2) (V(E) - CO(2)). In this study, we examined if leptin replacement improves chemorespiratory responses to hypercapnia (7 % CO(2)) 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). V(E) - CO(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 V(E) was similar between groups, obese ob/ob mice exhibited attenuated V(E) - CO(2) compared to WT mice (134 ± 9 versus 196 ± 10 ml min(-1)). Fourth ventricle leptin treatment in obese ob/ob mice significantly improved V(E) - CO(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 V(E) - CO(2) in ob/ob mice. Central leptin treatment in WT had no effect on V(E) - CO(2). Since the fourth ventricle leptin treatment decreased body weight in ob/ob mice, we also examined V(E) - CO(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 V(E) - CO(2) in ob/ob mice and leptin appears to play an important role in regulating chemorespiratory response by its direct actions on the CNS.
authors.affiliation: Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, 1680 Humaita St. Araraquara, São Paulo, Brazil. mbassi@foar.unesp.br
authors.forename: Mirian
authors.initials: M
authors.lastname: Bassi
authors.forename: Humberto
authors.initials: H
authors.lastname: Giusti
authors.forename: Cristiane Mota
authors.initials: CM
authors.lastname: Leite
authors.forename: Janete A
authors.initials: JA
authors.lastname: Anselmo-Franci
authors.forename: Jussara M
authors.initials: JM
authors.lastname: do Carmo
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: da Silva
authors.forename: John E
authors.initials: JE
authors.lastname: Hall
authors.forename: Eduardo
authors.initials: E
authors.lastname: Colombari
authors.forename: Mogens L
authors.initials: ML
authors.lastname: Glass
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000166:cytology / Q000378:metabolism; D002245:Carbon Dioxide / Q000097:blood / Q000494:pharmacology; D006720:Homozygote; D006935:Hypercapnia / Q000503:physiopathology*; D007276:Injections, Intraventricular; D020738:Leptin / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000503:physiopathology; D012123:Pulmonary Ventilation / Q000187:drug effects*
chemical_list: D020738:Leptin; D002245:Carbon Dioxide