Role of Shp2 in forebrain neurons in regulating metabolic and cardiovascular functions and responses to leptin

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 Sh...

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Published in:	International Journal of Obesity Vol. 38; no. 6; pp. 775 - 783
Main Authors:	do Carmo, J M, da Silva, A A, Sessums, P O, Ebaady, S H, Pace, B R, Rushing, J S, Davis, M T, Hall, J E
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-06-2014 Nature Publishing Group
Subjects:	631/378 631/443/319 631/443/592 631/80/86 Ambient temperature Animals Appetite Attenuation Biological and medical sciences Biological control systems Biophysics Blood Pressure Body Temperature Calorimetry Calorimetry, Indirect Cardiovascular system Deprivation Eating Energy expenditure Energy Metabolism Epidemiology Esterases Flox Food Food intake Forebrain Genetic aspects Health Promotion and Disease Prevention Heart Rate Homology Internal Medicine Intracellular Signaling Peptides and Proteins Kinases Laboratory animals Leptin Leptin - metabolism Male Medical sciences Medicine Medicine & Public Health Metabolic Diseases Metabolic disorders Metabolic syndrome Metabolism Mice Mice, Transgenic Motor activity Nervous system Neurons Obesity original-article Oxygen Consumption Phosphatase Physiology Properties Prosencephalon - pathology Protein Tyrosine Phosphatase, Non-Receptor Type 11 - deficiency Proteins Public Health Receptors, Leptin - metabolism Signal Transduction Signaling Telemetry Weaning United States > US blood pressure heart rate thermoneutrality energy expenditure acute stress food intake Obesity Nutrition Cardiac frequency Acute Nutrition disorder Metabolic diseases Adipokine Protein tyrosine phosphatase 2 Metabolism Stress Heart rate Neuron Food intake Energetic cost Leptin Arterial pressure Blood pressure Hemodynamics Circulatory system Nutritional status
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Summary:	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. Design: 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. Conclusion: 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0307-0565 1476-5497
DOI:	10.1038/ijo.2013.177