Obesity-induced hypothalamic inflammation is closely associated with various metabolic complications and neurodegenerative disorders. Astrocytes, the most abundant glial cells in the central nervous system, play a crucial role in pathological hypothalamic inflammatory processes. Here, we demonstrate that hypothalamic astrocytes accumulate lipid droplets under saturated fatty acid-rich conditions, such as obese environment, and that the lipid-laden astrocytes increase astrogliosis markers and inflammatory cytokines (TNFα, IL-1β, IL-6, MCP-1) at the transcript and/or protein level. Medium conditioned by the lipid-laden astrocytes stimulate microglial chemotactic activity and upregulate transcripts of the microglia activation marker Iba-1 and inflammatory cytokines. These findings indicate that the lipid-laden astrocytes formed in free fatty acid-rich obese condition may participate in obesity-induced hypothalamic inflammation through promoting microglia migration and activation.
Obesity-induced hypothalamic inflammation is characterized by activation of microglia, which are resident macrophages of the central nervous system, and is implicated in the derangement of energy homeostasis, metabolic complications, and neurodegenerative diseases. Quercetin, a naturally occurring flavonoid, is known to protect against oxidative stress and inflammation-related metabolic complications. Here, we demonstrate that quercetin reduces obesity-induced hypothalamic inflammation by inhibiting microglia-mediated inflammatory responses, and the beneficial action of quercetin is associated with heme oxygenase (HO-1) induction. Quercetin markedly reduced the production of inflammatory mediators (monocyte chemoattractant protein (MCP)-1, interleukin (IL-6), IL-1β, nitric oxide) by microglia stimulated with saturated fatty acid palmitate and/or lipid-laden microglia-conditioned medium. Quercetin also upregulated the expression of HO-1 in palmitate-treated lipid-laden microglia, and the actions of quercetin against microglia activation accompanied by IκBα degradation were abolished by a HO-1 inhibitor. Moreover, quercetin supplementation reduced the levels of inflammatory cytokines and microglia activation markers in the hypothalamus of high fat diet (HFD)-fed obese mice, which was accompanied by upregulation of HO-1. These findings indicate that quercetin suppresses microglia-mediated inflammatory responses via the induction of HO-1, and hence protects against obesity-induced hypothalamic inflammation.
BackgroundDietary fructose can rapidly cause fatty liver in animals through de novo lipogenesis (DNL) and contribute to the development and severity of nonalcoholic fatty liver disease (NAFLD). In response to diverse cellular insults including endoplasmic reticulum (ER) and oxidative stress, phosphorylation of the eukaryotic translation initiation factor 2 alpha subunit (eIF2α) attenuates general translation initiation, allowing cells to conserve resources and initiate adaptive gene expression to restore homeostasis. The present study aimed to investigate the role of eIF2α phosphorylation in protecting against NAFLD induced by high fructose ingestion in a hepatocyte-specific eIF2α-phosphorylation-deficient mouse model.MethodsHepatocyte-specific non-phosphorylatable (S51A) eIF2α knock-in (A/A;fTg/0;Cre Hep /0, A/A Hep) mice were generated by crossing A/A;fTg/fTg mice with the floxed WT eIF2α transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre Hep /0 (S/A-Cre Hep) mice. Hepatocyte-specific eIF2α-phosphorylation-deficient 3-month-old mice or 12-month-old mice were fed a 60% high fructose diet (HFrD) for 16 or 5 wks, and the effects of eIF2α-phosphorylation deficiency on NADP/NADPH and GSSG/GSH levels, ROS-defense gene expression, oxidative damage, cell death, and fibrosis were observed.ResultsProlonged fructose feeding to mice caused dysregulation of the unfolded protein response (UPR) sensor activation and UPR gene expression, and then led to decreased expression of several ROS defense genes including glutathione biogenesis genes. Nonetheless, these changes were not sufficient to induce the death of eIF2α phosphorylation-sufficient hepatocytes. However, there was a substantial increase in hepatocyte death and liver fibrosis in fructose-fed middle-aged mice deficient in hepatocyte-specific eIF2α phosphorylation because of diminished antioxidant capacity due to reduced expression of antioxidant enzymes (GPX1 and HO-1) and lower NADPH and glutathione levels, as well as a possible increase in ROS-induced damage from infiltrating NOX2-expressing leukocytes; all this led to a vicious cycle of hepatocyte death and leukocyte infiltration.ConclusionOur findings suggest that eIF2α phosphorylation maintains NADPH and GSH levels and controls the expression of ROS-defense genes, thereby protecting hepatocytes from oxidative stresses induced by fructose metabolism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-017-0202-6) contains supplementary material, which is available to authorized users.
Abbreviations: HRP, horseradish peroxidase; iNOS, inducible nitric oxide synthase; NF-κB, nuclear factor kappa B; NO, nitric oxide; PDTC, pyrolidine dithiocarbamate
Highlights d CD38 induces TTP in the onset of acute inflammation d TTP-dependent degradation of CD38 activates Sirt1 at the onset of resolution d TTP controls the resolution of inflammation during sepsis d Carbon monoxide inhibits inflammation in sepsis by increasing TTP expression
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