Juvenile exposure to a high fat diet promotes behavioral and limbic alterations in the absence of obesity

MENAFRA M; MERCOGLIANO MF; BRITES F; VINUESA A, POMILIO ; VINUESA A, POMILIO ; BONAVENTURA MM; BONAVENTURA MM; SCHILLACI R; SCHILLACI R; BEAUQUIS J; BEAUQUIS J; POMILIO C; GARAY L; LUX LANTOS V; SARAVIA FLAVIA; POMILIO C; GARAY L; LUX LANTOS V; SARAVIA FLAVIA; MENAFRA M; MERCOGLIANO MF; BRITES F

PSYCHONEUROENDOCRINOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2016 vol. 72 p. 22 - 33

0306-4530

tThe incidence of metabolic disorders including obesity, type 2 diabetes and metabolic syndrome haveseriously increased in the last decades. These diseases ? with growing impact in modern societies ?constitute major risk factors for neurodegenerative disorders such as Alzheimer?s disease (AD), sharinginsulin resistance, inflammation and associated cognitive impairment. However, cerebral cellular andmolecular pathways involved are not yet clearly understood. Thus, our aim was to study the impact ofa non-severe high fat diet (HFD) that resembles western-like alimentary habits, particularly involvingjuvenile stages where the brain physiology and connectivity are in plain maturation. To this end, one-month-old C57BL/6J male mice were given either a control diet or HFD during 4 months. Exposure to HFDproduced metabolic alterations along with changes in behavioral and central parameters, in the absenceof obesity. Two-month-old HFD mice showed increased glycemia and plasmatic IL1 but these valuesnormalized at the end of the HFD protocol at 5 months of age, probably representing an acute responsethat is compensated at later stages. After four months of HFD exposure, mice presented dyslipidemia,increased Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, hepatic insulin resistance andinflammation. Alterations in the behavioral profile of the HFD group were shown by the impediment innest building behavior, deficiencies in short and mid-term spatial memories, anxious and depressive-like behavior. Regarding the latter disruptions in emotional processing, we found an increased neuralactivity in the amygdala, shown by a greater number of c-Fos+ nuclei. We found that hippocampal adultneurogenesis was decreased in HFD mice, showing diminished cell proliferation measured as Ki67+ cellsand neuronal differentiation in SGZ by doublecortin labeling. These phenomena were accompanied by aneuroinflammatory and insulin-resistant state in the hippocampus, depicted by a reactive phenotype inIba1+ microglia cells (increased in number and soma size) and an impaired response to insulin given bydecreased phosphorylated Akt levels and increased levels of inhibitory phosphorylation of IRS1. Our dataportray a set of alterations in behavioral and neural parameters as a consequence of an early-life exposureto a quite moderate high fat diet, many of which can resemble AD-related features. These results highlyemphasize the need to study how metabolic and neurodegenerative disorders are interrelated in deep,thus allowing the finding of successful preventive and therapeutic approaches.