title: Regulation of Blood Pressure, Appetite, and Glucose by Leptin After Inactivation of Insulin Receptor Substrate 2 Signaling in the Entire Brain or in Proopiomelanocortin Neurons.
abstract: Insulin receptor substrate 2 (IRS2) is one of the 3 major leptin receptor signaling pathways, but its role in mediating the chronic effects of leptin on blood pressure, food intake, and glucose regulation is unclear. We tested whether genetic inactivation of IRS2 in the entire brain (IRS2/Nestin-cre mice) or specifically in proopiomelanocortin (POMC) neurons (IRS2/POMC-cre mice) attenuates the chronic cardiovascular, metabolic, and antidiabetic effects of leptin. Mice were instrumented with telemetry probes for measurement of blood pressure and heart rate and with venous catheters for intravenous infusions. After a 5-day control period, mice received leptin infusion (2 μg/kg per minute) for 7 days. Compared with control IRS2(flox/flox) mice, IRS2/POMC-cre mice had similar body weight and food intake (33±1 versus 35±1 g and 3.6±0.5 versus 3.8±0.2 g per day) but higher mean arterial pressure (MAP) and heart rate (110±2 versus 102±2 mm Hg and 641±9 versus 616±5 bpm). IRS2/Nestin-cre mice were heavier (38±2 g), slightly hyperphagic (4.5±1.0 g per day), and had higher MAP and heart rate (108±2 mm Hg and 659±9 bpm) compared with control mice. Leptin infusion gradually increased MAP despite decreasing food intake by 31% in IRS2(flox/flox) and in Nestin-cre control mice. In contrast, leptin infusion did not change MAP in IRS2/Nestin-cre or IRS2/POMC-cre mice. The anorexic and antidiabetic effects of leptin, however, were similar in all 3 groups. These results indicate that IRS2 signaling in the central nervous system, and particularly in POMC neurons, is essential for the chronic actions of leptin to raise MAP but not for its anorexic or antidiabetic effects.
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson. jdocarmo@umc.edu.
authors.forename: Jussara M
authors.initials: JM
authors.lastname: do Carmo
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: da Silva
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Freeman
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson.
authors.forename: Ammar J
authors.initials: AJ
authors.lastname: Alsheik
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Adi
authors.affiliation: From the Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson.
authors.forename: John E
authors.initials: JE
authors.lastname: Hall
mesh_terms: D000818:Animals; D001066:Appetite / Q000502:physiology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D001794:Blood Pressure / Q000502:physiology*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D020738:Leptin; D011333:Pro-Opiomelanocortin
keywords: blood pressure; heart rate; insulin; obesity; proopiomelanocortin