High fat diet increases cognitive decline and neuroinflammation in a model of orexin loss.

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 potentiate the onset of obesity, microglial activation, and neuroinflammation. Signaling deficiencies in the hypothalamic peptide orexin and/or orexin fiber loss are linked to neurodegeneration, cognitive impairment, and neuroinflammation. Prior studies show that orexin is neuroprotective, suppresses neuroinflammation, and that treatment with orexin improves cognitive processes in orexin/ataxin-3 (O/A3) mice, a transgenic mouse model of orexin neurodegeneration. Our overall hypothesis is that loss of orexin contributes to high fat diet (HFD)-induced hippocampal neuroinflammation and cognitive decline. 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) orexin loss impaired cognitive function; (2) HFD worsened cognitive impairment; and (3) HFD increased microglial activation and neuroinflammation. O/A3 mice showed 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). Further characterization of the microglial immune response genes in hippocampal tissue revealed a significant increase in CX3 chemokine receptor 1 (CX3CR1), tumor necrosis factor-alpha (TNF-α) and the mitochondria-associated enzyme immune responsive gene-1 (Irg1). Collectively, our results indicate that orexin loss impairs memory, and that HFD accelerates hippocampus-dependent learning deficits and the onset of neuroinflammation.