Early exposure to high-fat diet impairs central and peripheral metabolic function: Impacts on cognition and mitochondrial function

The impact of overnutrition early in life is not restricted to the onset of cardiovascular and metabolic diseases, but also affects critical brain functions related to cognition. This study aimed to evaluate the relationship between peripheral metabolic and bioenergetic changes induced by high-fat diet (HFD) and their impact on hippocampal cognitive functions in juvenile mice. To this purpose, three-week-old male C57BL/6 mice received a HFD or control diet for seven weeks, associated with two low doses of streptozotocin (STZ) or vehicle, to accelerate the metabolic dysfunction. HFD induced metabolic changes in mice, particularly related to glucose metabolism, in spite of the absence of obesity and changes in lipid profile. HFD exposure starting from weaning impaired recognition and spatial memories in mice, without inducing a depressive-like behavior. Increased immunoreactivity for GFAP and a trend towards a decrease in NeuN staining were verified in the hippocampus of HFD-fed mice. HFD caused a bioenergetic impairment in the hippocampus, characterized by a decrease in both O2 consumption related to ATP production and in the maximum respiratory capacity. The thermogenic capacity of brown adipose tissue was impaired by HFD, here verified through the absence of a decrease in O2 consumption after UCP-1 inhibition and increase in the reserve respiratory capacity. Impaired mitochondria function was also observed in the liver of HFD mice, while no changes were verified in O2 consumption in the heart of juvenile mice. These results indicate that the introduction of a HFD early in life has a detrimental impact on bioenergetic and mitochondrial function of tissues with metabolic and thermogenic activities, which is likely related to hippocampal metabolic changes and cognitive impairment. Highlights ### Competing Interest Statement The authors have declared no competing interest.