Obesity Elicits Interleukin 1-Mediated Deficits in Hippocampal Synaptic Plasticity

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
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
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.
treadmill training evokes broad responses not
limited to the immune system, we next assessed whether directly
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
This pattern supports a central role for
IL1-mediated neuroinflammation as a mechanism for cognitive deficits in
obesity and

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