High fat diet-induced obesity causes sex-specific deficits in adult hippocampal neurogenesis in mice

Abstract Adult hippocampal neurogenesis (AHN) is suppressed by high fat (HF) diet and metabolic disease, including obesity and Type 2 diabetes. Deficits in AHN may contribute to cognitive decline and increased risk of dementia and mood disorders, which have higher prevalence in women. However, sex differences in the effects of HF diet/metabolic disease on AHN have yet to be thoroughly investigated. Herein, male and female C57BL/6J mice were fed HF or control (CON) diet from ∼2-6 months of age. After 3 months on the diet, mice were injected with EdU, then euthanized 4 weeks later. Cell proliferation, differentiation/maturation and survival of new neurons in the dentate gyrus was assessed with immunofluorescence for EdU, Ki67, doublecortin (DCX), and NeuN. CON females had more proliferating cells (Ki67+) and neuroblasts/immature neurons (DCX+) compared to CON males; however, HF diet reduced these in females to the levels of males. Diet did not affect neurogenesis in males. Further, the numbers of proliferating cells and immature neurons were inversely correlated with both weight gain and glucose intolerance in females only. These effects were robust in the dorsal hippocampus, which supports cognitive processes. Assessment of microglia in the dentate gyrus using immunofluorescence for Iba1 and CD68 uncovered sex-specific effects of diet, which may contribute to observed differences in neurogenesis. These findings demonstrate sex-specific effects of HF diet/metabolic disease on AHN, and highlight the potential for targeting neurogenic deficits to treat cognitive decline and reduce the risk of dementia associated with these conditions, particularly in females. Significance Statement Poor diet and metabolic disease, including obesity and Type 2 diabetes, are associated with an increased risk of neurodegenerative and neuropsychiatric disorders, including Alzheimer’s disease, anxiety, and depression. Impaired adult hippocampal neurogenesis may be one mechanism linking these conditions; however, it is unknown whether there are sex-specific effects of high fat diet/metabolic disease on neurogenesis, which could underlie the observed sex difference in these conditions (females more adversely affected than males). We report that high fat diet/metabolic disease impairs cell proliferation and the number of neuroblasts/immature neurons in the dorsal hippocampus, a region that supports cognitive function, in females only. Sex-specific effects of diet on microglia in the subgranular zone were also apparent.