Abstract
Diets high in fat (HFD) are known to cause an immune response in the periphery as well as the central nervous system. In peripheral adipose tissue, this immune response is primarily mediated by macrophages that are recruited to the tissue. Similarly, reactivity of microglia, the innate immune cells of the brain, has been shown to occur in the hypothalamus of mice fed a high-fat diet. To characterize the nature of the microglial response to diets high in fat in a temporal fashion, we studied the phenotypic spectrum of hypothalamic microglia of mice fed high-fat diet for 3 days and 8 weeks by assessing their tissue reaction and inflammatory signature. While we observed a significant increase in Iba1+ myeloid cells and a reaction of GFAP+ astrocytes in the hypothalamus after 8 weeks of HFD feeding, we found the hypothalamic myeloid cell reaction to be limited to endogenous microglia and not mediated by infiltrating myeloid cells. Moreover, obese humans were found to present with signs of hypothalamic gliosis and exacerbated microglia dystrophy, suggesting a targeted microglia response to diet in humans as well. Notably, the glial reaction occurring in the mouse hypothalamus was not accompanied by an increase in pro-inflammatory cytokines, but rather by an anti-inflammatory reaction. Gene expression analyses of isolated microglia not only confirmed this observation, but also revealed a downregulation of microglia genes important for sensing signals in the microenvironment. Finally, we demonstrate that long-term exposure of microglia to HFD in vivo does not impair the cell’s ability to respond to additional stimuli, like lipopolysaccharide. Taken together, our findings support the notion that microglia react to diets high in fat in a region-specific manner in rodents as well as in humans; however, this response changes over time as it is not exclusively pro-inflammatory nor does exposure to HFD prime microglia in the hypothalamus.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1595-4) contains supplementary material, which is available to authorized users.
Highlights
Obesity is a disease affecting millions of people worldwide [6, 7]
To determine if a similar glial response occurs in the brains of obese humans as was observed in the brains of high-fat diet (HFD)-fed mice, we analyzed postmortem hypothalamic and cortical brain tissue from normal weight individuals with body mass index (BMI) < 25 and obese individuals with BMI > 30, which was collected under very strict exclusion criteria
Recent studies have reported an early increase in the number of microglia cells in the hypothalamus upon HFD that is accompanied by an upregulation in the expression of markers of microglia activation [17, 36]
Summary
Past research has focused heavily on the effects of diets high in fat content on peripheral organs, such as adipose tissue, where obesity leads to a chronic low-level inflammation that is central to peripheral metabolic disease [19]. This inflammation is mediated by macrophages, which infiltrate the expanding adipose tissue, and results in insulin resistance [20, 39]. (1) n = 5 (Chow) n = 5 (3 days HFD) n = 3 (4 weeks HFD) n = 7 (8 weeks HFD).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
