title: Differential control of metabolic and cardiovascular functions by melanocortin-4 receptors in proopiomelanocortin neurons.
abstract: We examined the role of melanocortin-4 receptors (MC4R) in proopiomelanocortin (Pomc) neurons in regulating metabolic and cardiovascular functions. Using Cre-loxP technology, we selectively rescued MC4R in Pomc neurons of mice with whole body MC4R deficiency (MC4R-Pomc-Cre mice). Body weight, food intake, and whole body oxygen consumption (Vo2) were determined daily, and blood pressure (BP), heart rate (HR), and body temperature were measured 24 h/day by telemetry. An intracerebroventricular cannula was placed in the right lateral ventricle for intracerebroventricular infusions. Littermate MC4R-deficient (LoxTB-MC4R) mice were used as controls. After control measurements, the MC4R antagonist (SHU-9119; 1 nmol/h) was infused intracerebroventricularly for 7 days. Compared with LoxTB-MC4R mice, MC4R-Pomc-Cre mice were less obese (47 ± 2 vs. 52 ± 2 g) and had increased energy expenditure (2,174 ± 98 vs. 1,990 ± 68 ml·kg⁻¹·min⁻¹), but food intake (4.4 ± 0.2 vs. 4.3 ± 0.3 g/day), BP (112 ± 1 vs. 109 ± 3 mmHg), and HR [557 ± 9 vs. 551 ± 14 beats per minute (bpm)] were similar between groups. Chronic SHU-9119 infusion increased food intake (4.2 ± 0.2 to 6.1 ± 0.5 g/day) and body weight (47 ± 2 to 52 ± 2 g) in MC4R-Pomc-Cre mice, while no changes were observed in LoxTB-MC4R mice. Chronic SHU-9119 infusion also increased BP and HR by 5 ± 1 mmHg and 60 ± 8 bpm in MC4R-Pomc-Cre mice without altering BP or HR in LoxTB-MC4R mice. These results indicate that MC4Rs in Pomc neurons are important for regulation of energy balance. In contrast, while activation of MC4R in Pomc neurons facilitates the BP response to acute stress, our data do not support a major role of MC4R in Pomc neurons in regulating baseline BP and HR.
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
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 S
authors.initials: JS
authors.lastname: Rushing
authors.forename: Benjamin
authors.initials: B
authors.lastname: Pace
authors.forename: John E
authors.initials: JE
authors.lastname: Hall
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D001831:Body Temperature; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004435:Eating; D004734:Energy Metabolism / Q000187:drug effects; D005951:Glucose Tolerance Test; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects; D057967:Infusions, Intraventricular; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000378:metabolism; D018670:Monitoring, Ambulatory / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption; D010456:Peptides, Cyclic / Q000008:administration & dosage; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013312:Stress, Physiological; D013686:Telemetry; D013997:Time Factors; D000071256:Uncoupling Protein 1; D015430:Weight Gain; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D001786:Blood Glucose; D007473:Ion Channels; C574273:MC4R protein, mouse; D024101:Mitochondrial Proteins; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D011993:Recombinant Fusion Proteins; D000071256:Uncoupling Protein 1; C079282:melanotan-II; D049452:Green Fluorescent Proteins; C103272:SHU 9119; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; D009074:Melanocyte-Stimulating Hormones; C045073:Cre recombinase; D019426:Integrases
keywords: blood pressure; energy expenditure; heart rate; hypertension; melanocortin; obesity; sympathetic nervous system