Chronological Dynamics of Neuroinflammatory Responses in a High-Fat Diet Mouse Model

Abstract

Obesity is known to affect various tissues and contribute to conditions such as neuroinflammation. However, the specific mechanisms and time-dependent progression of these effects across different tissues remain unclear. In this study, we monitored gene expression at intervals to examine the effects of a high-fat diet (HFD) on brain, liver, adipose, and muscle tissues in male C57/BJ mice, with a particular focus on neuroinflammation. Early inflammatory responses exhibit a progression that starts in the liver, extends to adipose tissue, and subsequently involves muscle and brain tissues. Although the brain did not show significant gene expression of inflammatory responses, mechanisms leading to neuroinflammation increased after 24 weeks, possibly through systemic chronic inflammation (SCI). Notably, mitochondrial complex I activity serves as a biomarker to indicate the inflammatory transition from the liver to adipose and other tissues caused by SCI. These similar gene expression dynamics were also observed in the hippocampus of Alzheimer’s patients and in an Alzheimer’s mouse model treated with a HFD. These results suggest that initially, the brain suppresses inflammatory responses, including interferon-gamma (IFN-γ), more than other tissues in response to a HFD. However, at the onset of SCI, the brain eventually exhibits inflammatory dynamics similar to those of other tissues. This underscores the significance of our findings, indicating that the early kinetics of chronic IFN-γ response and mitochondrial complex I activity inhibition serve as crucial biomarkers, emerging early in various conditions, including obesity and aging.