New Insight Into Obesity’s Effect on Brain Health

Modeling the innate inflammatory cGAS/STING pathway: sexually dimorphic effects on microglia and cognition in obesity and prediabetes

Obesity, prediabetes, and diabetes are global healthcare problems that have now been associated with cognitive impairment. The current understanding is that these metabolic dysfunctions promote cognitive impairment through increased inflammation in the brain. However, the exact inflammatory mechanisms underlying metabolic disorder-induced cognitive impairment has yet to be understood.

Within the brain, the cGAS/STING pathway surveys cells for markers of infection or stress and initiates an inflammatory response upon detection. Recent studies indicate that cGAS/STING signaling is dysregulated in obesity and may promote the progression of neurodegenerative diseases, such as Alzheimer’s. Therefore, the cGAS/STING pathway may be a mechanistic “bridge” between obesity, prediabetes, and cognitive impairment.  

 In the current study, researchers used pre-clinical models lacking the cGAS gene and fed them a high-fat diet (HFD) to induce obesity. As they do not express cGAS, the cGAS/STING pathway is impaired in this animal model, so researchers can explore if inflammatory cGAS/STING signaling is involved in obesity-induced cognitive impairment.  

Particularly interesting results from the study were the following:

            - HFD did not induce an inflammatory response in pre-clinical models lacking cGAS

            - Male and female cGAS-deficient animals displayed differences in brain inflammation and cognition in response to HFD

These results suggest that the cGAS/STING pathway may play a role in HFD-induced inflammation that differs based on sex. In the future, researchers can use this novel animal model further to explore the role of inflammation in obesity-driven cognitive impairment.