Intermittent Hypoxia Exacerbates Anxiety in High-fat Diet-Induced Diabetic Mice by Inhibiting TREM2-Regulated IFNAR1 Signaling

Over the past few decades, the incidence of type 2 diabetes mellitus (T2DM) has been on the rise, becoming a global public health issue. T2DM not only affects patients’ metabolic levels but also has profound impacts on cognitive function and mental health. Studies have shown that patients with T2DM exhibit brain structural abnormalities, a decline in learning and memory abilities, and a higher proportion of patients show mild cognitive impairment accompanied by anxiety disorders. Additionally, T2DM patients often have obstructive sleep apnea (OSA), and the two conditions are mutually reinforcing risk factors. Although research indicates a strong relationship between OSA and cognitive impairment, there is currently relatively little research on how OSA exacerbates cognitive dysfunction and anxiety symptoms in T2DM patients. To explore this issue, Ni and colleagues conducted a study and found that in T2DM patients, OSA may exacerbate anxiety symptoms by regulating the TREM2 and IFNAR1 signaling pathways.

The preliminary study was conducted by Chen Guoxuan and Xie Yunqi, with experimental design advice from Lu Yapeng, Wang Dan, and Luo Qianqian. The research report was published in the “Journal of Neuroinflammation,” with equal contributions from Ni and Niu et al. (2024).

In the study, a T2DM model was constructed, using a 60% high-fat diet (HFD) combined with intermittent hypoxia (IH) to simulate OSA conditions. The spatial learning, memory abilities, and anxiety levels of the mice were tested. The study found that HFD mice exhibited significant cognitive impairment and anxiety behaviors, accompanied by a significant reduction in synapses. IH was found to significantly exacerbate the anxiety of HFD mice, potentially through the upregulation of TREM2, which inhibits the IFNAR1-STAT1 pathway, thereby reducing pro-inflammatory microglial activation. In contrast, TREM2 was significantly reduced in HFD mice subjected to combined IH treatment, as well as HG-treated microglial cells, leading to further activation of the IFNAR1-STAT1 pathway and increased pro-inflammatory microglial activation.

The highlights of this study include: the identification of TREM2 as a compensatory upregulated factor in the brains of T2DM mice, and the demonstration that TREM2 can negatively regulate the activation of pro-inflammatory microglia through the IFNAR1-STAT1 pathway. This study not only provides new insights into the interaction mechanisms between T2DM and OSA but also suggests that modulating the TREM2 and IFNAR1 signaling pathways could be a potential strategy for treating cognitive dysfunction and anxiety in patients with T2DM and OSA. Additionally, the inspiration to use TREM2 activation or IFNAR1 inhibition as potential targets for treating cognitive impairment in various neurological or non-neurological diseases opens up new therapeutic strategies for neurodegenerative diseases such as Alzheimer’s disease.