title: Brain-mediated antidiabetic, anorexic, and cardiovascular actions of leptin require melanocortin-4 receptor signaling.
abstract: We previously demonstrated that leptin has powerful central nervous system (CNS)-mediated antidiabetic actions. In this study we tested the importance of melanocortin-4 receptors (MC4Rs) for leptin's ability to suppress food intake, increase blood pressure (BP) and heart rate (HR), and normalize glucose levels in insulin-dependent diabetes. MC4R knockout (MC4R-KO) and control wild-type (WT) rats were implanted with intracerebroventricular (ICV) cannula and BP and HR were measured 24 h/day by telemetry. After 5-day control period, an injection of streptozotocin (50 mg/kg, ip) was used to induce diabetes. Eight days after injection, an osmotic pump was implanted subcutaneously and connected to the ICV cannula to deliver leptin (15 μg/day) for 7 days. At baseline, MC4R-KO rats were hyperphagic and 40% heavier than WT rats. Despite obesity, BP was similar (112 ± 2 vs. 111 ± 2 mmHg) and HR was lower in MC4R-KO rats (320 ± 6 vs. 347 ± 5 beats/min). Induction of diabetes increased food intake (30%) and reduced BP (∼17 mmHg) and HR (∼61 beats/min) in WT rats, while food intake, BP, and HR were reduced by ∼10%, 7 mmHg, and 33 beats/min, respectively, in MC4R-KO rats. Leptin treatment normalized blood glucose (437 ± 10 to 136 ± 18 mg/dl), reduced food intake (40%), and increased HR (+60 beats/min) and BP (+9 mmHg) in WT rats. Only modest changes in blood glucose (367 ± 16 to 326 ± 23 mg/dl), food intake (5%), HR (+16 beats/min) and BP (+4 mmHg) were observed in MC4R-KO rats. These results indicate that intact CNS MC4R signaling is necessary for leptin to exert its chronic antidiabetic, anorexic, and cardiovascular actions.
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi alexandre.silva@baraodemaua.br.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: da Silva
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Frank T
authors.initials: FT
authors.lastname: Spradley
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: John E
authors.initials: JE
authors.lastname: Hall
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Jussara M
authors.initials: JM
authors.lastname: do Carmo
mesh_terms: D000818:Animals; D000855:Anorexia / Q000378:metabolism* / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000517:prevention & control; D004435:Eating / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects*; D020738:Leptin / Q000008:administration & dosage* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism*
chemical_list: D020738:Leptin; C574273:MC4R protein, mouse; D044105:Receptor, Melanocortin, Type 4; D005947:Glucose
keywords: blood pressure; food intake; heart rate; insulin; leptin; melanocortin; streptozotocin