Diet-induced obesity attenuates cytokine production following an immune challenge

Abstract

Obesity increases susceptibility for numerous diseases and neurological disorders including cardiovascular disease, metabolic syndrome, and dementia. One factor that may contribute to the increased risk for these conditions is the development of chronic inflammation. The current study evaluated whether diet-induced obesity (DIO) affects cognitive performance by increasing neuroinflammation and prolonging the behavioral and inflammatory response to an immune challenge. Adult male C57BL/6J mice were fed a high-fat (60% fat) or control diet (10% fat) for 2 or 5 months. After consuming their respective diets for two months, sickness associated behaviors were assessed 4 and 24 hours after a lipopolysaccharide (LPS) or saline injection. In a separate experiment, DIO and control mice were tested for spatial learning in the water maze and challenged with LPS one month later. Peripheral cytokine production was assessed in adipose and spleen samples and the neuroinflammatory response was assessed in hippocampal, cortical, and brain samples. DIO impaired acquisition of a spatial learning task relative to control mice. However, these deficits are unlikely to be related to inflammation as DIO showed no changes in basal cytokine levels within the periphery or brain. Further, in response to LPS DIO mice showed comparable or attenuated levels of the proinflammatory cytokines interleukin-1β and interleukin-6 relative to control mice. DIO also reduced hippocampal expression of brain-derived neurotrophic factor and the pre-synaptic marker synaptophysin. Presently, the data indicate that DIO suppresses aspects of the immune response and that cognitive deficits associated with DIO may be related to reduced neurotrophic support rather than inflammation.

Diet-induced obesity attenuates endotoxin-induced cognitive deficits

“…To date, the existing literature on the effects of DIO on the behavioral response to an immune challenge has been limited to sickness behavior and has shown mixed results. DIO was reported to prolong the LPS-induced suppression of social behavior in rats, but had no effect on the LPS-induced reductions in locomotor behavior [17, 22]. In agreement we found that LPS administration reduced swim speed on day 1 of testing in both the DIO and control diet mice.…”

“…In addition, macrophages from DIO animals show reduced interleukin-1β (IL-1β), TNF-α, nuclear factor-κB (NF-κB), Toll-like receptor-4 (TLR-4) and inducible nitric oxide synthase (iNOS) levels following an immune challenge when compared to macrophages from control diet animals [13–16]. In addition, we found attenuated levels of IL-6 in the cortex of DIO males mice following LPS administration [17]. Presently, the reason for these divergent findings is unknown, but variations in the experimental procedure including differences in the animal’s age, species, timing of tissue sampling, as well as the type and duration of the diet, among other factors, likely contribute to these differences.…”

“…For example, Pohl et al [22] report that rats fed a high-fat diet showed prolonged suppression of social behavior following LPS administration. However, DIO has no effect on LPS-induced reductions in locomotor behavior, as DIO animals show a similar reduction and recovery rate when compared to control animals [17, 22]. Alterations in the fever response have also been observed, as some report an enhanced fever in DIO animals following an immune challenge [3, 22].…”

“…Similar to sickness behavior, these cognitive deficits result from proinflammatory cytokines acting within the brain, as cytokine administration mimics the deficits induced by LPS and inhibition of IL-1β and IL-6 have been shown to block memory deficits following infection [28–32]. There has been some suggestion that the cognitive deficits associated with DIO may reflect basal increases in inflammation, however, this has not been consistently reported and may depend on the age of the animal [17, 33, 34]. While data exists on how DIO may alter the sickness behavior response to an immune challenge, whether DIO alters the development of cytokine-induced cognitive deficits is presently unknown.…”

Well-being and immune response: a multi-system perspective

“…The effect of obesity in modulating the response to infection has been mostly studied in rodent models and has been recently reviewed [44 ]. Despite some studies reporting a decrease or no change in LPS-induced fever, peripheral inflammatory response or behavioral manifestations in obese rodents in comparison to their lean controls [45], a majority of the reports suggest an increase and/or prolongation of the immune response induced by LPS [46 ,47 ]. In addition, the few studies that have been conducted in humans using ex vivo protocols also suggest obesity to be associated with an intensified response to an inflammatory challenge.…”