Abstract
BackgroundConsecutive peripheral immune challenges can modulate the responses of brain resident microglia to stimuli. High-fat diet (HFD) intake has been reported to stimulate the activation of astrocytes and microglia in the arcuate nucleus (ARC) of the hypothalamus in obese rodents and humans. However, it is unknown whether intermittent exposure to additional peripheral immune challenge can modify HFD-induced hypothalamic glial activation in obese individuals.MethodsIn this study, we administered 1 mg/kg LPS (or saline) by intraperitoneal (i.p.) injection to 8-week-old male mice after 1, 2, or 8 weeks of a regular diet (show) or HFD. The level of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) expression in the plasma and hypothalamic tissue was analyzed 24 h after each LPS injection. The behaviors of the animals in the four groups (the chow-saline, chow-LPS, HFD-saline, and HFD-LPS groups) were examined 5 months after exposure to chow or a HFD. Morphological examination of microglia in related brain regions was also conducted.ResultsThe plasma levels and hypothalamic mRNA levels of IL-1β and TNF-α were significantly upregulated 24 h after the first injection of LPS but not after the second or third injection of LPS. Chow-LPS mice displayed increased exploratory behavior 5 months after feeding. However, this LPS-induced abnormal exploratory behavior was inhibited in HFD-fed mice. Chronic HFD feeding for 5 months induced apparent increases in the number and cell body size of microglia, mainly in the ARC, and also increased the size of microglia in the nucleus accumbens (NAc) and insula. Moreover, microglial activation in the ARC, anterior cingulate cortex (ACC), insula, and basolateral amygdala (BLA) was observed in chow-LPS mice. However, microglial activation in the analyzed brain regions was suppressed in HFD-LPS mice.ConclusionsAltogether, the results indicate that intermittent peripheral challenge with LPS might prime microglia in the ARC and NAc to modify their response to chronic HFD feeding. Alternatively, chronic HFD feeding might mediate microglia in LPS-affected brain regions and subsequently suppress LPS-induced atypical exploratory behavior. Our findings suggest that the interaction of intermittent acute peripheral immune challenges with chronic HFD intake can drive microglia to amend the microenvironment and further modify animal behaviors in the later life.
Highlights
Consecutive peripheral immune challenges can modulate the responses of brain resident microglia to stimuli
Compared to that detected in the chow-saline and High-fat diet (HFD)-saline groups, the mRNA expression of tumor necrosis factor-α (TNF-α) and IL-1β in the hypothalamus of chow- and HFD-fed mice was significantly upregulated by the first LPS injection (Fig. 3a)
The second LPS injection resulted in a reduction in the plasma level of IL-1β in chow- and HFD-fed mice when compared to the relative control group (Fig. 2a)
Summary
Consecutive peripheral immune challenges can modulate the responses of brain resident microglia to stimuli. It is unknown whether intermittent exposure to additional peripheral immune challenge can modify HFD-induced hypothalamic glial activation in obese individuals. Microglial activation is associated with neuroinflammation in human brain neurological diseases (such as Alzheimer’s disease and Parkinson’s disease), traumatic CNS injuries (such as stroke and spinal cord injury), and neuropsychiatric disorders [2]. Peripheral inflammation has been demonstrated to be a trigger for microglial activation and sickness behavior in humans and animals [4, 5]. Astrocytes, abundant glial cells that constitute approximately 40% of brain cells, participate in homeostasis in the healthy CNS and neuropathogenesis induced by CNS injury or peripheral inflammation [6, 7]. The two glial cell types are involved in metabolic disorder-linked neuroinflammation [8]
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