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Insulin resistance in brain alters dopamine turnover and causes behavioral disorders.
Kleinridders, Andre; Cai, Weikang; Cappellucci, Laura; Ghazarian, Armen; Collins, William R; Vienberg, Sara G; Pothos, Emmanuel N; Kahn, C Ronald.
Afiliação
  • Kleinridders A; Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; and.
  • Cai W; Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; and.
  • Cappellucci L; Department of Integrative Physiology and Pathobiology and.
  • Ghazarian A; Department of Integrative Physiology and Pathobiology and.
  • Collins WR; Graduate Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111.
  • Vienberg SG; Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; and.
  • Pothos EN; Department of Integrative Physiology and Pathobiology and Graduate Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111.
  • Kahn CR; Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; and c.ronald.kahn@joslin.harvard.edu.
Proc Natl Acad Sci U S A ; 112(11): 3463-8, 2015 Mar 17.
Article em En | MEDLINE | ID: mdl-25733901
Diabetes and insulin resistance are associated with altered brain imaging, depression, and increased rates of age-related cognitive impairment. Here we demonstrate that mice with a brain-specific knockout of the insulin receptor (NIRKO mice) exhibit brain mitochondrial dysfunction with reduced mitochondrial oxidative activity, increased levels of reactive oxygen species, and increased levels of lipid and protein oxidation in the striatum and nucleus accumbens. NIRKO mice also exhibit increased levels of monoamine oxidase A and B (MAO A and B) leading to increased dopamine turnover in these areas. Studies in cultured neurons and glia cells indicate that these changes in MAO A and B are a direct consequence of loss of insulin signaling. As a result, NIRKO mice develop age-related anxiety and depressive-like behaviors that can be reversed by treatment with MAO inhibitors, as well as the tricyclic antidepressant imipramine, which inhibits MAO activity and reduces oxidative stress. Thus, insulin resistance in brain induces mitochondrial and dopaminergic dysfunction leading to anxiety and depressive-like behaviors, demonstrating a potential molecular link between central insulin resistance and behavioral disorders.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Comportamento Animal / Encéfalo / Resistência à Insulina / Dopamina Tipo de estudo: Etiology_studies Limite: Animals Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Comportamento Animal / Encéfalo / Resistência à Insulina / Dopamina Tipo de estudo: Etiology_studies Limite: Animals Idioma: En Ano de publicação: 2015 Tipo de documento: Article