Single-cell RNA sequencing identifies hippocampal microglial dysregulation in diet-induced obesity

Obesity is a growing global concern in adults and youth along with a parallel rise in associated complications, including cognitive impairment. Obesity induces brain inflammation and activates microglia, which contribute to cognitive impairment by aberrantly phagocytosing synaptic spines. Local and systemic signals, such as inflammatory cytokines and metabolites likely participate in obesity-induced microglial activation. However, the precise mechanisms mediating microglial activation during obesity remain incompletely understood. Herein, we leveraged our mouse model of high-fat diet (HFD)-induced obesity, which mirrors human obesity, and develops hippocampal-dependent cognitive impairment. We assessed hippocampal microglial activation by morphological and single-cell transcriptomic analysis to evaluate this heterogeneous, functionally diverse, and dynamic class of cells over time after 1 and 3 months of HFD. HFD altered cell-to-cell communication, particularly immune modulation and cellular adhesion signaling, and induced a differential gene expression signature of protein processing in the endoplasmic reticulum in a time-dependent manner. Single cell RNA sequencing analysis of microglia isolated from hippocampus of either a 60% HFD enriched with saturated fatty acids (HFD) or a control diet containing 10% fat (SD) beginning at 5-wk-old male C57BL/6J mice. To determine time-dependent changes in microglia in response to HFD, mice were divided into two cohorts and fed for 1 mo or 3 mo. Hashtagging was used to multiple cells from three animals into each run.