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Animal Models

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.

Design:

Forebrain Shp2−/− mice were generated by crossing Shp2flox/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 Shp2flox/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 Shp2flox/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.

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References

  1. Zhang EE, Chapeau E, Hagihara K, Feng GS . Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc Natl Acad Sci USA 2004; 101: 16064–16069.

    Article  CAS  Google Scholar 

  2. Kloek C, Haq AK, Dunn SL, Lavery HJ, Banks AS, Myers MG Jr. . Regulation of Jak kinases by intracellular leptin receptor sequences. J Biol Chem 2002; 277: 41547–41555.

    Article  CAS  Google Scholar 

  3. Bjorbaek C, Buchholz RM, Davis SM, Bates SH, Pierroz DD, Gu H et al. Divergent roles of SHP-3 in ERK activation by leptin receptors. J Biol Chem 2001; 276: 4747–4755.

    Article  CAS  Google Scholar 

  4. East JB, Royer AR, Middlemas DS . The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS/MAPK pathway by the brain-derived neurotrophic factor. J Neurochem 2006; 97: 834–845.

    Article  Google Scholar 

  5. Myers MP, Anderson JN, Cheng A, Tremblay ML, Horvath CM, Parisien JP et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J Biol Chem 2001; 276: 47771–47774.

    Article  CAS  Google Scholar 

  6. Lou PH, Yang G, Huang L, Cui Y, Pourbahrami T, Radda GK et al. Reduced body weight and increased energy expenditure in transgenic mice over-expressing soluble leptin receptor. PLoS One 2010; 20: e11669.

    Article  Google Scholar 

  7. Singh A, Wirtz M, Parker N, Hogan M, Strahler J, Michailidis G et al. Leptin-mediated changes in hepatic mitochondrial metabolism, structure and protein levels. Proc Natl Acad Sci USA 2009; 106: 13100–13105.

    Article  CAS  Google Scholar 

  8. Shek EW, Brands MW, Hall JE . Chronic leptin infusion increases arterial pressure. Hypertension 1998; 31: 409–414.

    Article  CAS  Google Scholar 

  9. Hall JE, da Silva AA, do Carmo JM, Dubinion J, Hamza S, Munusamy S et al. Obesity-induced hypertension: role of sympathetic nervous system, leptin and melanocortins. J Biol Chem 2010; 285: 17271–17276.

    Article  CAS  Google Scholar 

  10. da Silva AA, do Carmo JM, Dubinion J, Hall JE . The role of leptin and central nervous system melanocortins in obesity hypertension. Curr Opion Nephrol Hypertens 2013; 22: 135–140.

    Article  CAS  Google Scholar 

  11. do Carmo JM, da Silva AA, Cai Z, Lin S, Dubinion JH, Hall JE . Control of blood pressure, appetite and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons. Hypertension 2011; 57: 918–926.

    Article  CAS  Google Scholar 

  12. Tallam LS, da Silva AA, Hall JE . Melanocortin-4 receptor mediates chronic cardiovascular and metabolic actions of leptin. Hypertension 2006; 48: 58–64.

    Article  CAS  Google Scholar 

  13. Krajewska M, Banares S, Zhang EE, Huang X, Scadeng M, Jhala US et al. Development of diabesity in mice with neuronal deletion of Shp2 tyrosine phosphatase. Am J Pathol 2008; 172: 1312–1324.

    Article  CAS  Google Scholar 

  14. Mark AL, Shafer RA, Correia ML, Morgan DA, Sigmund CD, Haynes WG . Contrasting blood pressure effects of obesity in leptin deficient ob/ob mice and agouti yellow obese mice. J Hypertens 1999; 17: 1949–1953.

    Article  CAS  Google Scholar 

  15. do Carmo JM, Bassi M, da Silva AA, Hall JE . Control of cardiovascular, metabolic and respiratory functions during prolonged obesity in leptin-deficient and diet-induced obese mice. Hypertension 2008; 15: 109 2008.

    Google Scholar 

  16. Ozata M, Ozdemir IC, Licinio J . Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 1999; 10: 3686–3695.

    Article  Google Scholar 

  17. Farooqi S, O'Rahilly S . Genetics of obesity in humans. Endocr Rev 2006; 27: 710–718.

    Article  CAS  Google Scholar 

  18. Williams TD, Chambers JB, Henderson RP, Rashotte ME, Overton JM . Cardiovascular responses to caloric restriction and thermoneutrality in C57BL/6J mice. Am J Physiol Regul Integr Comp Physiol 2002; 282: R1459–R1467.

    Article  CAS  Google Scholar 

  19. Muralidhara DV, Shetty PS . Cold-induced thermogenesis in rats nutritionally deprived early in life. Indian J Physiol Pharmacol 1987; 31: 149–158.

    CAS  PubMed  Google Scholar 

  20. Overton JM, Williams TD, Chambers JB, Rashotte ME . Central leptin attenuates the cardiovascular and metabolic effects of fasting in rats. Hypertension 2001; 37: 663–669.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the National Heart, Lung and Blood Institute Grant PO1HL-51971 and by a Scientist Development Grant from the American Heart Association to JM do Carmo.

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Correspondence to J M do Carmo.

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Supplementary Information accompanies this paper on International Journal of Obesity website

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do Carmo, J., da Silva, A., Sessums, P. et al. Role of Shp2 in forebrain neurons in regulating metabolic and cardiovascular functions and responses to leptin. Int J Obes 38, 775–783 (2014). https://doi.org/10.1038/ijo.2013.177

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