title: Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity.
abstract: Adipose tissue is a known source of proinflammatory cytokines in obese humans and animal models, including the db/db mouse, in which obesity arises as a result of leptin receptor insensitivity. Inflammatory cytokines induce cognitive deficits across numerous conditions, but no studies have determined whether obesity-induced inflammation mediates synaptic dysfunction. To address this question, we used a treadmill training paradigm in which mice were exposed to daily training sessions or an immobile belt, with motivation achieved by delivery of compressed air on noncompliance. Treadmill training prevented hippocampal microgliosis, abolished expression of microglial activation markers, and also blocked the functional sensitization observed in isolated cells after ex vivo exposure to lipopolysaccharide. Reduced microglial reactivity with exercise was associated with reinstatement of hippocampus-dependent memory, reversal of deficits in long-term potentiation, and normalization of hippocampal dendritic spine density. Because treadmill training evokes broad responses not limited to the immune system, we next assessed whether directly manipulating adiposity through lipectomy and fat transplantation influences inflammation, cognition, and synaptic plasticity. Lipectomy prevents and fat transplantation promotes systemic and central inflammation, with associated alterations in cognitive and synaptic function. Levels of interleukin 1β (IL1β) emerged as a correlate of adiposity and cognitive impairment across both the treadmill and lipectomy studies, so we manipulated hippocampal IL1 signaling using intrahippocampal delivery of IL1 receptor antagonist (IL1ra). Intrahippocampal IL1ra prevented synaptic dysfunction, proinflammatory priming, and cognitive impairment. This pattern supports a central role for IL1-mediated neuroinflammation as a mechanism for cognitive deficits in obesity and diabetes.
authors: Department of Physiology and Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912.
authors: Joanna R
authors: JR
authors: Erion
authors: Marlena
authors: M
authors: Wosiski-Kuhn
authors: Aditi
authors: A
authors: Dey
authors: Shuai
authors: S
authors: Hao
authors: Catherine L
authors: CL
authors: Davis
authors: Norman K
authors: NK
authors: Pollock
authors: Alexis M
authors: AM
authors: Stranahan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000378:metabolism*; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000502:physiology*; D009765:Obesity / Q000378:metabolism*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010805:Physical Conditioning, Animal; D013569:Synapses / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta
keywords: diabetes; hippocampus; inflammation; microglia; obesity; synapse