Central nervous system inflammation in the context of obesity : implication of bioactive lipids and pathophysiological repercussions
(2017)
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- Authors
- Supervisors
- Muccioli, Giulio
- Abstract
- Obesity and sedentary lifestyle are on the rise and pose serious threats to people's health. Indeed, obesity is associated with a cluster of comorbidities collectively known as the metabolic syndrome and represents one of the most alarming health issues of modern times. Amongst other etiologies, a high-fat diet and cholesterol metabolism are key players in the genesis of these disorders and lead to the onset of a low-grade inflammation affecting both the periphery and the central nervous system. In this context, obesity can be considered as an inflammatory condition. We are particularly interested in the consequences of obesity on neuroinflammation and in the involvement of bioactive lipids in these processes. We first wanted to study the impact of obesity and subsequent low grade inflammation on different structures of the central nervous system. We found that the inflammatory tone during diet-induced obesity was both time-dependent and structure-dependent with, for instance, striking differences between the cerebellum (increased inflammatory markers’ expression and astrocyte activation) and the cortex (no changes) when compared after 16 weeks of high fat diet. We further interrogated the potential involvement of bioactive lipids in these inflammatory differences. We singled out four lipid families and one species as potentially exerting anti-inflammatory effects and upon ex-vivo testing on co-culture of primary astrocytes and microglia, we identified phosphatidyinositols, lysophosphatidylcholine and palmitoylethanolamide as able to decrease inflammatory markers’ expression. In another study, instead of assessing different families of bioactive lipids in the context of diet-induced inflammation, we focused on one specific family, namely the oxysterols. First, using different models of obesity, either from genetic origins or diet-induced, we measured oxysterol levels in tissues affected by the subsequent obesity-induced inflammation. We also assessed the expression of metabolic enzymes responsible for oxysterols’ synthesis and degradation. Interestingly, based on the hepatic levels of three oxysterol levels (4β-hydroxycholesterol, 27-hydroxycholesterol, and 7-hydroxycholestenone) and their hepatic synthesis enzymes’ expression (CYP3a11, CYP27a1, and CYP7a1) we were able to discriminate between a lean and an obese phenotype regardless of the experimental model used. Finally, another important finding of this study was the sustained and significant decrease of 4β-hydroxycholesterol levels, as soon as after one week of high-fat diet and until sixteen weeks, in the liver, adipose tissue, and plasma as well as decreased levels in the hypothalamus from six weeks on. Finally, we wondered what would be the potential impact of another inflammatory insult in the context of obesity. We chose to use a post-operative pain model, the hind paw incision, and devised three separate studies. The first one allowed us to identify diet-induced obesity as able to significantly increase post-operative pain. The second study enabled us to identify some mechanisms potentially explaining this prolonged pain. Indeed, the sciatic nerve inflammatory tone and more specifically macrophage recruitment and activation, glial cells activation in the dorsal horn of the spinal cord and an increased endoplasmic reticulum stress represent different mechanisms that could explain the obesity-induced prolonged post-operative pain. Finally, in an interventional study, we used a diet switch from a high-fat diet to a standard show. This dietary intervention was able to rescue the prolonged pain. We also measured bioactive lipid levels in the paw, the sciatic nerve, and the spinal cord of these animals but unfortunately we could not identify lipids potentially linked to the obesity-induced prolonged post-operative pain. This work allowed for a better comprehension of the impact of obesity on the central nervous system by nuancing it according to the different effects observed in specific structures. It also evaluated the implication of bioactive lipids involvement in the context of obesity-induced inflammation some of which were never quantified in these conditions before. Finally, we interrogated some pathophysiological implications in the context of obesity using a post-operative pain model and we demonstrated that obesity significantly prolonged post-operative pain. Taken together, this work paves the way for further studies addressing the link between bioactive lipids involvement in the context of obesity-induced inflammation and neuroinflammation.
- Affiliations
Citations
Guillemot-Legris, O. (2017). Central nervous system inflammation in the context of obesity : implication of bioactive lipids and pathophysiological repercussions. https://hdl.handle.net/2078.5/180009