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 an HF or control (CON) diet from ϳ2 to 6 months of age. After 3 months on the diet, mice were injected with 5-ethynyl-2=-deoxyuridine (EdU) then killed 4 weeks later. Cell proliferation, differentiation/maturation, and survival of new neurons in the dentate gyrus were assessed with immunofluorescence for EdU, Ki67, doublecortin (DCX), and NeuN. CON females had more proliferating cells (Ki67 ϩ) and neuroblasts/immature neurons (DCX ϩ) compared with CON males; however, HF diet reduced these cells 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.

Deficits in hippocampal neurogenesis in obesity-dependent and -independent type-2 diabetes mellitus mouse models

“…In the context of obesity-related T2DM, a high-fat diet was reported to impair the number of proliferating cells in the SGZ of the hippocampus in male, but not female rats 17 . In contrast, a recent study shows that high-fat diet compromises neurogenesis in C57BL/6 J females but not in males 18 .…”

“…In that regard, it should be noted that this study examined levels of hippocampal neurogenesis in male mice. Sex differences in levels of neurogenesis have been reported in T2DM related mouse models 17,18 . Thus, future studies should include a comparative analysis of neurogenesis in both sexes.…”

Sex differences in the effects of high-fat diet on mouse sciatic nerves

“…Male mice are more vulnerable than the females to the impacts of HFD on weight gain, metabolic alterations and deficits of learning, and hippocampal synaptic plasticity (Hwang et al, 2010). In contrast, HFD feeding decreases cell proliferation and the number of immature neurons in the dorsal subregion of the hippocampus of females only (Robison et al, 2020). HFD-induced lipotoxicity in the central nerves was less in females than in males (Morselli et al, 2016).…”

Neuroimaging of Sex/Gender Differences in Obesity: A Review of Structure, Function, and Neurotransmission

“…For instance, in control mice, levels of proliferating cells and neuroblasts are significantly higher in females than in males. However, when both sexes eat a high-fat diet, this difference disappears, suggesting that a high-fat diet contributes to a reduction in adult hippocampal neurogenesis in females only [ 38 ]. These preclinical results have yet to be replicated in humans.…”