Major mental illnesses such as schizophrenia (SZ) and bipolar disorder (BP) frequently accompany metabolic conditions, but their relationship is still unclear, in particular at the mechanistic level. We implemented an approach of “from population to neuron”, combining population-based epidemiological analysis with neurobiological experiments using cell and animal models based on a hypothesis built from the epidemiological study. We characterized high-quality population data, olfactory neuronal cells biopsied from patients with SZ or BP, and healthy subjects, as well as mice genetically modified for insulin signaling. We accessed the Danish Registry and observed (1) a higher incidence of diabetes in people with SZ or BP and (2) higher incidence of major mental illnesses in people with diabetes in the same large cohort. These epidemiological data suggest the existence of common pathophysiological mediators in both diabetes and major mental illnesses. We hypothesized that molecules associated with insulin resistance might be such common mediators, and then validated the hypothesis by using two independent sets of olfactory neuronal cells biopsied from patients and healthy controls. In the first set, we confirmed an enrichment of insulin signaling-associated molecules among the genes that were significantly different between SZ patients and controls in unbiased expression profiling data. In the second set, olfactory neuronal cells from SZ and BP patients who were not pre-diabetic or diabetic showed reduced IRS2 tyrosine phosphorylation upon insulin stimulation, indicative of insulin resistance. These cells also displayed an upregulation of IRS1 protein phosphorylation at serine-312 at baseline (without insulin stimulation), further supporting the concept of insulin resistance in olfactory neuronal cells from SZ patients. Finally, Irs2 knockout mice showed an aberrant response to amphetamine, which is also observed in some patients with major mental illnesses. The bi-directional relationships between major mental illnesses and diabetes suggest that there may be common pathophysiological mediators associated with insulin resistance underlying these mental and physical conditions.
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We thank Yukiko Y. Lema for organizing the manuscript and figures, Drs. Melissa A. Landek-Salgado and Nao J. Gamo for critical reading of the manuscript. AS and KI are supported by the National Institute of Mental Health MH-105660 and Maryland Stem Cell Research Fund. AS is also supported by MH-094268 Silvio O. Conte center, MH-092443, and MH-107730, as well as foundation grants from Stanley, S-R/RUSK, BBRF. TS is supported by Kakenhi from the Ministry of Education, Culture, Sports, Science and Technology in Japan, and was funded in part by the Takeda and Kyoto University Basic and Clinical Research Project for CNS Drugs (supported in part by Takeda Pharmaceutical Co. Ltd). TML was supported by an unrestricted grant from the Stanley Medical Research Institute. PBM was supported by grants from the Danish Strategic Research Council, the Faculty of Social Sciences at Aarhus University, the Lundbeck Foundation, the Stanley Medical Research Institute, and a European Research Council advanced grant (GA 2948338). WWE was supported by NIMH grant 1R34MH007760-01.
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Takayanagi, Y., Ishizuka, K., Laursen, T.M. et al. From population to neuron: exploring common mediators for metabolic problems and mental illnesses. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-00939-5