Insulin resistance in brain alters dopamine turnover and causes behavioral disorders.
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.
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; and.
Andre
A
Kleinridders
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; and.
Weikang
W
Cai
Department of Integrative Physiology and Pathobiology and.
Laura
L
Cappellucci
Department of Integrative Physiology and Pathobiology and.
Armen
A
Ghazarian
Graduate Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111.
William R
WR
Collins
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; and.
Sara G
SG
Vienberg
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.
Emmanuel N
EN
Pothos
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; and c.ronald.kahn@joslin.harvard.edu.
C Ronald
CR
Kahn
D000375:Aging / Q000473:pathology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D003863:Depression / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D007333:Insulin Resistance; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000928:Antidepressive Agents; D011972:Receptor, Insulin; D004298:Dopamine
diabetes; dopamine signaling; insulin receptor; mitochondrial function; monoamine oxidase