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 1␤ (IL1␤) 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.

Blood–brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor-deficient mice

“…Testing in both paradigms was carried out between 18:00 and 22:00 h (lights-off at 1800) under red light illumination, as described. 4,5,30 Testing in the Y-maze involved (6) left/right choices, with correct choices expressed relative to the total number of potential alternations. Novel object recognition testing involved 10-min exposure to two identical objects, followed by 30 min in the home cage, after which the mouse was returned to the arena in the presence of one novel and one familiar object.…”

“…Peripheral inflammation increases BBB permeability, but also influences cells of the central nervous system (CNS) via BBB-independent mechanisms. 23 Obesity increases inflammatory cytokines in multiple brain regions, including the hippocampus, [4][5][6] but there has been no investigation into whether these effects are mediated by, or independent of, BBB leakiness.…”

“…26 Diabetes also promotes PKCb-mediated cerebrovascular breakdown in the retina, 27 but mechanisms for BBB breakdown in the CNS remain to be determined, and the reported relationships between BBB breakdown, microglial activation, and cognitive deficits remain correlative at present. 4,5,28 We used the selective PKCb inhibitor LY-317615 (Enzastaurin) to re-seal the BBB in mice with genetic diabetes and obesity (db/db mice). This approach reversed BBB leakiness based on cellular and functional measures and normalized hippocampal synaptic plasticity.…”

Neonatal vaccination with bacille Calmette-Guérin promotes the dendritic development of hippocampal neurons

“…60 The gene gun bullets were prepared according to a previously described method. 59 Briefly, 8 mg of gold particles (1.0mm in diameter, Sigma-Aldrich, USA) were mixed with 2 mg of DiI (CM-DiI, Sigma-Aldrich, USA) and dissolved in 300 ml methylene chloride.…”

Assessment of serum interleukin-1receptor antagonist (IL-1RN) levels in overweight-obese women and its relation to the cardiovascular risk using Framingham score

“…1,2 Interleukin 1 receptor antagonist (IL1RN) is an acute-phase protein that blocks the interleukin-1A and 1B receptors and thereby exerting anti-inflammatory effect. 3 It is produced by activated monocytes and tissue macrophages and other cells.…”