Reversal of early-life high fat diet prevents spatial discrimination deficits corresponding with altered brain inflammatory and metabolic profiles in male C57BL/6J mice

Objectives: High-fat diet is well-known to contribute to systemic and central nervous system dysfunction and represents a modifiable risk factor for cognitive decline. A recent surge of new weight loss medications has demonstrated that caloric restriction by reduced overeating has been successful at mitigating peripheral markers of inflammation and metabolic dysfunction. However, less is known regarding such effects of dietary reversal within the brain. Methods: Male mice received high-fat diet (HFD; 60%kCal fat) from 6 weeks of age (JAX #380050). At 14 weeks, half of the mice were reversed (Rev = 9) to a standard diet (14%kCal fat) while the other half (HFD = 10) remained on HFD for an additional 2 months. Weight, frailty, peripheral cytokines, and behavior were recorded at baseline and again at 1 and 2 months after dietary reversal. Mice were sacrificed at 22 weeks of age and terminal measures of brain neuroinflammation and metabolism were evaluated. Results: In contrast to mice on continuous HFD, the mice in the Rev group lost weight, had lower frailty scores, preserved spatial discrimination, altered peripheral cytokine profiles, lower hippocampal GFAP, increased hippocampal MCP1 and IL4, improved hippocampal and midbrain insulin tone, and differentially altered TRIB3 in the hippocampus and midbrain. Discussion: Early dietary reversal was effective at preventing the inflammatory, metabolic, and cognitive effects of sustained HFD with divergent effects on metabolic markers (TRIB3) depending on brain region.