title: Role of Shp2 in forebrain neurons in regulating metabolic and cardiovascular functions and responses to leptin.
abstract: OBJECTIVE
  We examined whether deficiency of Src homology 2 containing phosphatase (Shp2) signaling in forebrain neurons alters metabolic and cardiovascular regulation under various conditions and if it attenuates the anorexic and cardiovascular effects of leptin. We also tested whether forebrain Shp2 deficiency alters blood pressure (BP) and heart rate (HR) responses to acute stress.
  
  
  METHODS
  Forebrain Shp2(-/-) mice were generated by crossing Shp2(flox/flox) mice with CamKIIα-cre mice. At 22-24 weeks of age, the mice were instrumented for telemetry for measurement of BP, HR and body temperature (BT). Oxygen consumption (VO2), energy expenditure and motor activity were monitored by indirect calorimetry.
  
  
  RESULTS
  Shp2/CamKIIα-cre mice were heavier (46±3 vs 32±1 g), hyperglycemic, hyperleptinemic, hyperinsulinemic and hyperphagic compared to Shp2(flox/flox) control mice. Shp2/CamKIIα-cre mice exhibited reduced food intake responses to fasting/refeeding and impaired regulation of BT when exposed to 15 and 30 °C ambient temperatures. Despite being obese and having many features of metabolic syndrome, Shp2/CamKIIα-cre mice had similar daily average BP and HR compared to Shp2(flox/flox) mice (112±2 vs 113±1 mm Hg and 595±34 vs 650±40 b.p.m.), but exhibited increased BP and HR responses to cold exposure and acute air-jet stress test. Leptin's ability to reduce food intake and to raise BP were markedly attenuated in Shp2/CamKIIα-cre mice.
  
  
  CONCLUSIONS
  These results suggest that forebrain Shp2 signaling regulates food intake, appetite responses to caloric deprivation and thermogenic control of body temperature during variations in ambient temperature. Deficiency of Shp2 signaling in the forebrain is associated with augmented cardiovascular responses to cold and acute stress but attenuated BP responses to leptin.
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: do Carmo
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: da Silva
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: P O
authors.initials: PO
authors.lastname: Sessums
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Ebaady
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Pace
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Rushing
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Davis
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Hall
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001831:Body Temperature; D002153:Calorimetry, Indirect; D004435:Eating; D004734:Energy Metabolism; D006339:Heart Rate; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons; D009765:Obesity; D010101:Oxygen Consumption; D016548:Prosencephalon / Q000473:pathology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency*; D054411:Receptors, Leptin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D054411:Receptors, Leptin; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
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