Obesity, metabolic syndrome (MetS) and type 2 diabetes (T2D) are associated with decreased cognitive function. While weight loss and T2D remission result in improvements in metabolism and vascular function, it is less clear if these benefits extend to cognitive performance. Here, we highlight the malleable nature of MetS-associated cognitive dysfunction using a mouse model of high fat diet (HFD)-induced MetS. While learning and memory was generally unaffected in mice with type 1 diabetes (T1D), multiple cognitive impairments were associated with MetS, including deficits in novel object recognition, cued fear memory, and spatial learning and memory. However, a brief reduction in dietary fat content in chronic HFD-fed mice led to a complete rescue of cognitive function. Cerebral blood volume (CBV), a measure of vascular perfusion, was decreased during MetS, was associated with long term memory, and recovered following the intervention. Finally, repeated infusion of plasma collected from age-matched, low fat diet-fed mice improved memory in HFD mice, and was associated with a distinct metabolic profile. Thus, the cognitive dysfunction accompanying MetS appears to be amenable to treatment, related to cerebrovascular function, and mitigated by systemic factors.
Keywords: ADMA, Asymmetric dimethylarginine; BDNF, Brain-derived neurotrophic factor; BW, Body weight; Br Fat, Brown adipose tissue; Brain; C-X-C motif, Chemokine; CBV, Cerebral blood volume; CH, Cholesterol; Cerebrovascular; Cognitive; Cxcl1, Ligand 1; DG, Diacylglycerol; Diabetes; FFA, Free fatty acids; GL, Glycerolipid; GLP-1, Glucagon-like peptide 1; GPL, Glycerophospholipid; GlcCer, Glucosylceramide; HFD, High fat diet; IFNγ, Interferon-γ; IL-10, Interleukin-10; IL-12p70, Interleukin-12p70; IL-6, Interleukin-6; IR, Insulin resistance; ITT, Insulin tolerance test; Il-1b, Interleukin-1β; KB, Total ketone bodies; LFD, Low fat diet; LPA, Lysophosphatidic acid; MetS, Metabolic syndrome; Metabolic syndrome; OGTT, Oral glucose tolerance test; Obesity; PC, Phosphatidylcholine; PE, Phosphatidylethanolamine; PG, Phosphatidylglycerol; PGP, Phosphatidylglycerolphosphate; PI, Phosphatidylinositol; PS, Phosphatidylserine; Plasma; SC Fat, Subcutaneous adipose tissue; T1D, Type 1 Diabetes; T2D, Type 2 Diabetes; TG, Triglycerides; TNFα, Tumor necrosis factor-α; V Fat, Visceral adipose tissue.