Single-cell RNA sequencing identifies hippocampal microglial dysregulation in diet-induced obesity
Rosemary E. Henn,
Kai Guo,
Sarah E. Elzinga,
Mohamed H. Noureldein,
Faye E. Mendelson,
John M. Hayes,
Diana M. Rigan,
Masha G. Savelieff,
Junguk Hur,
Eva L. Feldman
Affiliations
Rosemary E. Henn
Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA
Kai Guo
Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA
Sarah E. Elzinga
Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA
Mohamed H. Noureldein
Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA
Faye E. Mendelson
Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA
John M. Hayes
Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA
Diana M. Rigan
Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA
Masha G. Savelieff
NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA
Junguk Hur
Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND, USA
Eva L. Feldman
Department of Neurology, University of Michigan, Ann Arbor, MI, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA; Corresponding author
Summary: Obesity is a growing global concern in adults and youth 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.
