title: Reduced metabolism in the hypothalamus of the anorecticanx/anxmouse.
abstract: The anorecticanx/anxmouse exhibits a mitochondrial complex I dysfunction that is related to aberrant expression of hypothalamic neuropeptides and transmitters regulating food intake. Hypothalamic activity, i.e. neuronal firing and transmitter release, is dependent on glucose utilization and energy metabolism. To better understand the role of hypothalamic activity in anorexia, we assessed carbohydrate and high-energy phosphate metabolism,in vivoandin vitro, in theanx/anxhypothalamus. In the fasted state, hypothalamic glucose uptake in theanx/anxmouse was reduced by ~50% of that seen in wild-type (wt) mice (P< 0.05). Under basal conditions,anx/anxhypothalamus ATP and glucose 6-P contents were similar to those in wt hypothalamus, whereas phosphocreatine was elevated (~2-fold;P< 0.001) and lactate was reduced (~35%;P< 0.001). Theanx/anxhypothalamus had elevated total AMPK (~25%;P< 0.05) and GLUT4 (~60%;P< 0.01) protein contents, whereas GLUT1 and GLUT3 were similar to that of wt hypothalamus. Interestingly, the activation state of AMPK (ratio of phosphorylated AMPK/total AMPK) was significantly decreased in hypothalamus of theanx/anxmouse (~60% of that in wt;P< 0.05). Finally, during metabolic stress (ischemia), accumulation of lactate (measure of glycolysis) and IMP and AMP (breakdown products of ATP) were ~50% lower inanx/anxvs wt hypothalamus. These data demonstrate that carbohydrate and high-energy phosphate utilization in theanx/anxhypothalamus are diminished under basal and stress conditions. The decrease in hypothalamic metabolism may contribute to the anorectic behavior of theanx/anxmouse, i.e. its inability to regulate food intake in accordance with energy status.
authors.affiliation: Department of Molecular Medicine and SurgeryKarolinska Institutet, Stockholm, Sweden.|Center for Molecular MedicineKarolinska University Hospital, Stockholm, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Bergström
authors.affiliation: Department of Molecular Medicine and SurgeryKarolinska Institutet, Stockholm, Sweden.|Center for Molecular MedicineKarolinska University Hospital, Stockholm, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lindfors
authors.affiliation: Department of Clinical NeuroscienceCenter for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Svedberg
authors.affiliation: Department of Molecular Medicine and SurgeryKarolinska Institutet, Stockholm, Sweden.|Center for Molecular MedicineKarolinska University Hospital, Stockholm, Sweden.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Johansen
authors.affiliation: Department of Clinical NeuroscienceCenter for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Häggkvist
authors.affiliation: Department of Molecular Medicine and SurgeryKarolinska Institutet, Stockholm, Sweden.|Center for Molecular MedicineKarolinska University Hospital, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Schalling
authors.affiliation: Department of Medical Biochemistry and BiophysicsKarolinska Institutet, Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.affiliation: Department of Physical TherapyAriel University, Ariel, Israel.
authors.forename: Abram
authors.initials: A
authors.lastname: Katz
authors.affiliation: Department of Molecular Medicine and SurgeryKarolinska Institutet, Stockholm, Sweden ida.nilsson@ki.se.|Center for Molecular MedicineKarolinska University Hospital, Stockholm, Sweden.
authors.forename: Ida A K
authors.initials: IA
authors.lastname: Nilsson
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000855:Anorexia / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism; D050260:Carbohydrate Metabolism / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D010725:Phosphocreatine / Q000378:metabolism
chemical_list: D010725:Phosphocreatine; D019344:Lactic Acid; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D005947:Glucose
keywords: AMPK; ATP; glucose uptake; lactate; phosphocreatine