# Brain insulin resistance: a key pathological hub linking metabolic and neuropsychiatric comorbidities

## TL;DR

This paper explores how brain insulin resistance connects metabolic diseases with neuropsychiatric disorders, suggesting it as a key target for treatment.

## Contribution

The study identifies brain insulin resistance as a novel pathological hub linking metabolic and neuropsychiatric conditions.

## Key findings

- Brain insulin resistance disrupts limbic system function via the PI3K/Akt/mTOR pathway and TLR4/MyD88 inflammatory axis.
- These disruptions lead to neuropsychiatric phenotypes like amygdala hyperactivity and hippocampal atrophy.
- Targeting brain insulin resistance could improve both metabolic and neuropsychiatric outcomes.

## Abstract

The high rate of comorbidity between metabolic diseases and neuropsychiatric disorders suggests a shared underlying pathogenic mechanism. However, the biological basis of this relationship remains unclear. This study aims to clarify the role of brain insulin resistance (BIR) in linking metabolic dysfunction to neuropsychiatric symptoms based on existing evidence. The analysis shows that BIR disrupts limbic system function through two primary molecular pathways: (1) impairment of the PI3K/Akt/mTOR pathway, which decreases the expression of synaptic plasticity-related proteins and causes deficits in long-term potentiation (LTP); (2) activation of the TLR4/MyD88 inflammatory axis, promoting pro-inflammatory cytokine release from glial cells. These changes result in characteristic neuropsychiatric phenotypes, including amygdala hyperactivity (emotional disorders), hippocampal atrophy (memory impairment), and decreased prefrontal cortex (PFC) function (executive dysfunction). This review highlights that interventions targeting BIR might simultaneously improve metabolic outcomes and neuropsychiatric symptoms, providing a theoretical foundation for trans-diagnostic treatment models. The findings support the view of BIR as a modifiable interface for metabolic- neuropsychiatric comorbidities and advocate for the development of a multidisciplinary collaborative framework to facilitate mechanism-based precision therapy.