High Fat Diet Increases Cognitive Decline and Neuroinflammation in a Model of Orexin Loss

Abstract

Midlife obesity is a risk factor for cognitive decline and is associated with the earlier onset of Alzheimer's disease (AD). Diets high in saturated fat can potentiate the onset of obesity, microglial activation, and neuroinflammation. Signaling deficiencies in the hypothalamic peptide orexin A (OXA) and/or orexin fiber loss are linked to neurodegeneration in humans and animal models. Prior studies in orexin/ataxin‐3 (O/A3) mice, a transgenic mouse model of orexin neurodegeneration, demonstrate that OXA treatment improves cognitive processes. In separate studies we have demonstrate that OXA can suppress neuroinflammation and is neuroprotective against the saturated fatty acid palmitate. Our overall hypothesis is that OXA treatment attenuates hippocampal neuroinflammation and prevents cognitive decline in obesity during high fat diet (HFD) feeding. Our short term goal for this project is to determine if OXA loss increases neuroinflammation and impairs cognition during HFD feeding. To examine this, we tested male O/A3 mice (7–8 mo. of age) in a two‐way active avoidance (TWAA) hippocampus‐dependent memory task. We tested whether 1) OXA loss impaired cognitive function; 2) HFD worsened cognitive impairment; and 3) HFD increased microglial activation and neuroinflammation. We show that O/A3 mice have significant impairments in TWAA task learning vs. wild type (WT) mice (increased escapes p<0.05, reduced avoidances p<0.0001). Mice were then placed on HFD (45% total fat, 31.4% saturated fat) or remained on normal chow (NC; 4% total fat and 1% saturated fat), and TWAA was retested at 2 and 4 weeks. Learning impairment was evident at both 2 and 4 weeks in O/A3 mice fed HFD for following diet exposure vs. WT mice on normal chow or HFD (increased escapes, reduced avoidances p<0.05). Additionally, O/A3 mice had increased gene expression of the microglial activation marker, Iba‐1 (measured via qRT‐PCR, p<0.001). Characterization of the microglial immune response (M1 neurotoxic vs. M2 protective phenotypes) is ongoing and will include gene and protein markers (such as TNF‐α, iNOS, UCP2, and Arg1). Collectively, our results indicate that OXA loss impairs memory, and that HFD accelerates hippocampus‐dependent learning deficits and the onset of neuroinflammation. Future studies will focus on restoration of OXA within hippocampal circuits to reduce neuroinflammation and improve cognitive functionSupport or Funding InformationThis work was funded by the US Department of Veterans Affairs BLR&D IK2 BX001686 and IS1 BX003083A (to TAB), the University of Minnesota Healthy Foods, Healthy Lives Institute (to JPN and TAB), MnDRIVE Brain Conditions Fellowship in Neuromodulation (to CMD), and the Minnesota Veterans Medical Research & Education Foundation (to TAB).