Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance

Abstract

Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies, impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in vivo molecular mechanisms of brain IR until recently have proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared with age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM+ exosomes in subjects with MDD as compared with age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM+ exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM+ exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM+ exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.

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Fig. 1: Increased number of L1CAM+ exosomes in subjects with MDD as compared with controls.
Fig. 2: Increased in vivo IRS-1 protein expression in L1CAM+ exosomes in subjects with MDD as compared with age- and sex-matched controls.
Fig. 3: Sex-specific differences in phosphorylation of IRS-1 in L1CAM+ exosomes of subjects with MDD.

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Acknowledgements

This work was supported by a grant from the Robertson Therapeutic Development Foundation to CN, 1R21 MH093948-01A1 (SPO #50260) to NR, a grant from the Hearst Foundation to NR and CN, and, by a grant from the Hope for Depression Foundation (HDRF) to BMC and CN. All data and code will be made available upon request to the corresponding author.

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CN, NR, and BB conceived statistical analyses, figures, and tables as well as interpreted the data. CN wrote the manuscript. NR contributed to the writing. CN, BB, BMC, and NR conceived and designed the study. KW contributed to the statistical analyses. CN, PdA, and JD designed and performed the molecular experiments. NR, JK, JM, and FL supervised the recruitment in the respective study sites. All authors discussed and provide inputs to the research.

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Correspondence to Carla Nasca or Natalie Rasgon.

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Nasca, C., Dobbin, J., Bigio, B. et al. Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-0804-7

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