title: Amelioration of Metabolic Syndrome-Associated Cognitive Impairments in Mice via a Reduction in Dietary Fat Content or Infusion of Non-Diabetic Plasma.
abstract: 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.
authors: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Lance A
authors: LA
authors: Johnson
authors: Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Kristen L
authors: KL
authors: Zuloaga
authors: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Tara L
authors: TL
authors: Kugelman
authors: Swiss Federal Institute of Technology, Zurich, Switzerland; 4Quant, Paul Scherrer Institute, Villigen, Switzerland.
authors: Kevin S
authors: KS
authors: Mader
authors: Department of Pharmaceutical Sciences, and the Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
authors: Jeff T
authors: JT
authors: Morré
authors: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Damian G
authors: DG
authors: Zuloaga
authors: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Sydney
authors: S
authors: Weber
authors: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Tessa
authors: T
authors: Marzulla
authors: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Amelia
authors: A
authors: Mulford
authors: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Dana
authors: D
authors: Button
authors: Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Jonathan R
authors: JR
authors: Lindner
authors: Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239, USA; Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Nabil J
authors: NJ
authors: Alkayed
authors: Department of Pharmaceutical Sciences, and the Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
authors: Jan F
authors: JF
authors: Stevens
authors: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA; Departments of Neurology and Radiation Medicine, Division of Neuroscience, ONPRC. Electronic address: raberj@ohsu.edu.
authors: Jacob
authors: J
authors: Raber
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002560:Cerebrovascular Circulation; D016000:Cluster Analysis; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism*; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D018782:Maze Learning; D024821:Metabolic Syndrome / Q000150:complications* / Q000378:metabolism* / Q000503:physiopathology; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D009765:Obesity / Q000378:metabolism; D021641:Recognition, Psychology; D015431:Weight Loss
chemical_list: D004041:Dietary Fats
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