Metabolic Brain Disease

, Volume 28, Issue 1, pp 111–115 | Cite as

Undernutrition upregulates fumarate hydratase in the rat nucleus accumbens

  • E. Lizárraga-Mollinedo
  • C. Álvarez
  • E. Fernández-Millán
  • F. Escrivá
  • C. González-Martín
  • E. Salas
  • J. M. Pérez-Ortiz
  • L. F. Alguacil
Short Communication

Abstract

Previous comparative studies of fumarate hydratase (FH) protein density revealed that the enzyme was overexpressed in the striatum of rodents that are less influenced by rewarding stimuli, from cocaine to food. Therefore, we recently proposed FH as a potential striatal biomarker of brain reward deficiency and addiction vulnerability. This work has been focused to investigate FH activity in the Nucleus Accumbens (NAc) of undernourished rats, taking into account that malnutrition has been related to increased responsiveness to food and drug reward. To this end, we have studied adult female Wistar rats severely food restricted from the 16th day of intrauterine life until adulthood. Animals were sacrificed to dissect the NAc and obtain mitochondrial and cytosolic fractions after homogenisation and centrifugation. FH activity was measured by conversion of malate to fumarate, and protein levels were compared by Western blot analysis when fractions showed differences in activity. Undernutrition did not change cytosolic FH activity but led to a marked increase of mitochondrial FH activity (72 %) and protein content (50 %) in the NAc. This change was in the opposite direction that one would predict if it was related to addiction vulnerability of some kind, but strongly suggests that mitochondrial FH needs to be at some optimal level for normal reward responsiveness.

Keywords

Fumarate hydratase Malnutrition Nucleus accumbens Brain reward 

Notes

Acknowledgements

This work was supported by Grants ISCIII CP08/00188 and BFU 2011–25420 from Ministerio de Economía y Competitividad, S2010/BMD-2423 from Comunidad de Madrid and CCG97-UCM/SAL-30041 from Universidad Complutense de Madrid. CIBER de Diabetes y Enfermedades Metabólicas Asociadas is an initiative of ISCIII (Ministerio de Economía y Competitividad). The authors would also like to thank Amelia González López for excellent technical assistance.

References

  1. Adam J, Hatipoglu E, O'Flaherty L, Ternette N, Sahgal N, Lockstone H, Baban D, Nye E, Stamp GW, Wolhuter K, Stevens M, Fischer R, Carmeliet P, Maxwell PH, Pugh CW, Frizzell N, Soga T, Kessler BM, El-Bahrawy M, Ratcliffe PJ, Pollard PJ (2011) Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20:524–537PubMedCrossRefGoogle Scholar
  2. Alguacil LF, Stucchi P, del Olmo N, Herradón G, Ruiz-Gayo M (2010) Biomarkers and drug targets in addiction and obesity. Eur J Clin Pharmacol 66:S85Google Scholar
  3. Alguacil LF, Salas E, González-Martín C (2011a) Identification of new drug targets and biomarkers related to obesity and eating disorders: an approach based on reward deficit and addiction. Curr Pharm Des 17:462–470PubMedCrossRefGoogle Scholar
  4. Alguacil LF, Stucchi P, Salas E, del Olmo N, Herradón G, González-Martín C, Ruiz-Gayo M (2011b) Fumarate hydratase is upregulated in the striatum of animals with spontaneous and diet-induced inhibition of psychostimulant reward. Neuroscience Meeting Planner 688.11/JJ11 Washington, DC: Society for Neuroscience, OnlineGoogle Scholar
  5. Blum K, Braverman ER, Holder JM, Lubar JF, Monastra VJ, Miller D, Lubar JO, Chen TJ, Comings DE. (2000). Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. J Psychoactive Drugs 32(Suppl:i-iv):1–112Google Scholar
  6. Castillo C, Morales L, Alguacil LF, Salas E, Garrido E, Alonso E, Pérez-García C (2009a) Proteomic analysis of the nucleus accumbens of rats with different vulnerability to cocaine addiction. Neuropharmacology 57:41–48PubMedCrossRefGoogle Scholar
  7. Castillo C, Morales L, Salas E, Alguacil LF, Pérez-García C (2009b) Análisis del proteoma de la corteza cerebral de ratas con diferente vulnerabilidad a la adicción a la cocaína. Abstracts XIII Meeting SENC: 149Google Scholar
  8. Davis JF, Tracy AL, Schurdak JD, Tschöp MH, Lipton JW, Clegg DJ, Benoit SC (2008) Exposure to elevated levels of dietary fat attenuates psychostimulant reward and mesolimbic dopamine turnover in the rat. Behav Neurosci 122:1257–1263PubMedCrossRefGoogle Scholar
  9. Deschauer M, Gizatullina Z, Schulze A, Pritsch M, Knöppel C, Knape M, Zierz S, Gellerich FN (2006) Molecular and biochemical investigations in fumarase deficiency. Mol Genet Metab 88:146–152PubMedCrossRefGoogle Scholar
  10. Escrivá F, Rodríguez C, Cacho J, Álvarez C, Portha B, Pascual-Leone AM (1992) Glucose utilization and insulin action in adult rats submitted to prolonged food restriction. Am J Physiol Endocrinol Metab 263:E1–E7Google Scholar
  11. Fernández E, Martín MA, Fajardo S, Bailbé D, Gangnerau MN, Portha B, Escrivá F, Serradas P, Alvarez C (2006) Undernutrition does not alter the activation of β-cell neogenesis and replication in adult rats after partial pancreotectomy. Am J Physiol Endocrinol Metab 291:E913–E921PubMedCrossRefGoogle Scholar
  12. Gavete ML, Martín MA, Alvarez C, Escrivá F (2005) Maternal food restriction enhances insulin-induced GLUT-4 translocation and insulin signaling pathway in skeletal muscle from suckling rats. Endocrinology 146:3368–3378PubMedCrossRefGoogle Scholar
  13. Heimer L, Zahm DS, Churchill L, Kalivas PW, Wohltmann C (1991) Specificity in the projection patterns of accumbal core and shell in the rat. Neuroscience 41:89–125PubMedCrossRefGoogle Scholar
  14. Lizárraga-Mollinedo E, Fernández-Millán E, de Miguel-Santos L, Martínez-Honduvilla C, Alvarez C, Escrivá F (2010) Early undernutrition increases glycogen content and reduces the activated forms of GSK3, AMPK, p38 MAPK and JNK in the cerebral cortex of suckling rats. J Neurochem 112:123–133PubMedCrossRefGoogle Scholar
  15. Lizárraga-Mollinedo E, Fernández-Millán E, de Toro MJ, Martínez-Honduvilla CJ, Escrivá F, Alvarez C (2012) Early undernutrition induces glucagon resistance and insulin hypersensitivity in the liver of suckling rats. Am J Physiol Endocrinol Metab 302:E1070–E1077PubMedCrossRefGoogle Scholar
  16. Martín MA, Alvarez C, Goya L, Portha B, Pascual-Leone AM (1997) Insulin secretion in adult rats than had experienced different underfeeding patterns during their development. Am J Physiol Endocrinol Metab 272:E634–E640Google Scholar
  17. Mescam M, Vinnakota KC, Beard DA (2011) Identification of the catalytic mechanism and estimation of kinetic parameters for fumarase. J Biol Chem 286:21100–21109PubMedCrossRefGoogle Scholar
  18. Metzger S, Nusair S, Planer D, Barash V, Pappo O, Shilyansky J, Chajek-Shaul T (2004) Inhibition of hepatic gluconeogenesis and enhanced glucose uptake contribute to the development of hypoglycemia in mice bearing interleukin-1beta-secreting tumor. Endocrinology 145:5150–5156PubMedCrossRefGoogle Scholar
  19. Morales L, Del Olmo N, Valladolid-Acebes I, Fole A, Cano V, Merino B, Stucchi P, Ruggieri D, López L, Alguacil LF, Ruiz-Gayo M (2012) Shift of circadian feeding pattern by high-fat diets is coincident with reward deficits in obese mice. PLoS One 7:e36139PubMedCrossRefGoogle Scholar
  20. O'Flaherty L, Adam J, Heather LC, Zhdanov AV, Chung YL, Miranda MX, Croft J, Olpin S, Clarke K, Pugh CW, Griffiths J, Papkovsky D, Ashrafian H, Ratcliffe PJ, Pollard PJ (2010) Dysregulation of hypoxia pathways in fumarate hydratase-deficient cells is independent of defective mitochondrial metabolism. Hum Mol Genet 19:3844–3851PubMedCrossRefGoogle Scholar
  21. Sottocasa GL, Kuylenstierna B, Ernster L, Bergstrand A (1967) An electron-transport system associated with the outer membrane of liver mitochondria. A biochemical and morphological study. J Cell Biol 32:415–438PubMedCrossRefGoogle Scholar
  22. Tian Z, Liu Y, Usa K, Mladinov D, Fang Y, Ding X, Greene AS, Cowley AW Jr, Liang M (2009) Novel role of fumarate metabolism in dahl-salt sensitive hypertension. Hypertension 54:255–260PubMedCrossRefGoogle Scholar
  23. Tonkiss J, Shukitt-Hale B, Formica RN, Rocco FJ, Galler JR (1990) Prenatal protein malnutrition alters response to reward in adult rats. Physiol Behav 48:675–80PubMedCrossRefGoogle Scholar
  24. Valdomero A, Bussolino DF, Orsingher OA, Cuadra GR (2006) Perinatal protein malnutrition enhances rewarding cocaine properties in adult rats. Neuroscience 137:221–229PubMedCrossRefGoogle Scholar
  25. Valdomero A, Velazquez EE, de Olmos S, de Olmos JS, Orsingher OA, Cuadra GR (2007) Increased rewarding properties of morphine in perinatally protein-malnourished rats. Neuroscience 150:449–458PubMedCrossRefGoogle Scholar
  26. Yogev O, Naamati A, Pines O (2011) Fumarase: a paradigm of dual targeting and dual localized functions. FEBS J 278:4230–4242PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • E. Lizárraga-Mollinedo
    • 1
    • 2
  • C. Álvarez
    • 1
    • 2
  • E. Fernández-Millán
    • 2
  • F. Escrivá
    • 1
    • 2
  • C. González-Martín
    • 3
    • 4
  • E. Salas
    • 3
  • J. M. Pérez-Ortiz
    • 3
  • L. F. Alguacil
    • 3
    • 4
  1. 1.Bioquímica y Biología Molecular, Facultad FarmaciaUniversidad Complutense de MadridMadridSpain
  2. 2.CIBER de Diabetes y Enfermedades Metabólicas Asociadas, ISCIIIBarcelonaSpain
  3. 3.Unidad de Investigación TraslacionalHospital General Universitario de Ciudad RealCiudad RealSpain
  4. 4.Laboratorio de Farmacología y ToxicologíaUniversidad San Pablo CEUMadridSpain

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