Dysfunction of the Murine Liver with Aging and Its Improvement with the Continuous Consumption of Enterococcus faecalis EC-12.

Chronic inflammation is involved in the development of age-related diseases. Given its persistence, controlling chronic inflammation is essential for preventing age-related diseases. In this study, we investigated the effects of Enterococcus faecalis EC-12 (EC-12), which has immunomodulatory and antioxidant effects, on liver gene expression and aging phenomena in mice. Short-term EC-12 administration stimulated the expression of genes involved in lipid synthesis and metabolism in the liver. Furthermore, long-term EC-12 administration from 10 weeks to 1.5 years of age resulted in significant increases in blood interleukin (IL)-6 and IL-10 concentrations (both p < 0.05) and a significant decrease in the monocyte chemotactic protein-1 concentration (p < 0.05). These results indicated pathologic improvement, such as suppression of fat degeneration in the liver. These results suggest that continuous EC-12 intake from a young age can suppress liver function abnormalities, which is one of the aging phenomena in old age, and contribute to health in old age.

Mucus plugging on computed tomography and the sputum microbiome in patients with asthma, chronic obstructive pulmonary disease, and asthma-COPD overlap.

BACKGROUND: Despite clinical implications, the pathogenesis of mucus plugging in asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) remains unclear. We hypothesized that distinct airway microbiomes might affect mucus plugging differently among ACO, asthma, and COPD and among different extents of airway eosinophilic inflammation. METHODS: The sputum microbiome, sputum cell differential count, and mucus plug score on computed tomography were cross-sectionally evaluated in patients with chronic airflow limitation. RESULTS: Patients with ACO, asthma, or COPD were enrolled (n = 56, 10, and 25). Higher mucus plug scores were associated with a greater relative abundance of the phylum Proteobacteria (rho = 0.29) only in patients with ACO and a greater relative abundance of the phylum Actinobacteria (rho = 0.46) only in patients with COPD. In multivariable models including only patients with ACO, the presence of mucus plugs was associated with a greater relative abundance of the phylum Proteobacteria and the genus Haemophilus, independent of smoking status, airflow limitation, and emphysema severity. Moreover, the mucus score was associated with a greater relative abundance of the genus Streptococcus (rho = 0.46) in patients with a high sputum eosinophil count (n = 22) and with that of the genus Haemophilus (rho = 0.46) in those with a moderate sputum eosinophil count (n = 26). CONCLUSIONS: The associations between mucus plugging and the microbiome in ACO differed from those in COPD and asthma. Greater relative abundances of the phylum Proteobacteria and genus Haemophilus may be involved in mucus plugging in patients with ACO and moderate airway eosinophilic inflammation.

Neoplasia in captive Tsushima leopard cats (Prionailurus bengalensis euptilurus).

The Tsushima leopard cat (Prionailurus bengalensis euptilurus) is a subspecies of the mainland leopard cat that lives on the small island of Tsushima, Japan. Captive breeding has been attempted in zoos in Japan because only approximately 100 animals remain in the wild and the Tsushima leopard cat is an endangered species. There are very few reports on diseases, including tumours, of this species. We analysed the deaths of 58 Tsushima leopard cats and confirmed that nine had neoplastic disease. The average age at death of the animals with neoplasia was 14 years and tumours were the primary cause of death in all animals. Eight of the nine cases involved primary tumours of the pancreas, liver, gallbladder, tongue and salivary glands, suggesting that Tsushima leopard cats may have a predilection for digestive system tumours. This is the first report of neoplastic disease in the Tsushima leopard cat.

Edible bird's nest extract downregulates epidermal apoptosis and helps reduce damage by ultraviolet radiation in skin of hairless mice.

The purpose of the present study was to examine whether daily intake of edible bird's nest extract reduced ultraviolet-induced damage to skin. Twenty-one female HR-1/Hos mice were divided into control (C, n = 7), low-dose (2 mg/kg body weight/day of edible bird's nest extract) (L, n = 7), and high-dose (20 mg/kg body weight/day of edible bird's nest extract) (H, n = 7) groups. With their left back skin covered with aluminum sheet to prevent exposure, mice were radiated with either ultraviolet A (20 J/cm2) or ultraviolet B (40 mJ/cm2) in an alternate manner once daily for 10 weeks. They were gavaged either a solution of saline or edible bird's nest extract every day. The moisture content of the ultraviolet-exposed right back skin was significantly higher in H than in C or L. Histochemical analysis showed that the number of apoptotic epidermal cells on the ultraviolet-exposed skin was significantly lower in L and H than in C. In H, the mRNA expression of superoxide dismutase 2 was significantly higher on ultraviolet-exposed skin than on unexposed skin. Our data suggested that edible bird's nest extract enhanced superoxide dismutase 2 expression and downregulated apoptosis in their epidermis, which likely helped reduce skin damage.

Eosinophilic Leukaemia and Systemic Mycobacterium marinum Infection in an African Pygmy Hedgehog (Atelerix albiventris).

A two-year-old male African pygmy hedgehog (Atelerix albiventris) presented with lethargy and anorexia. Ultrasonographic and radiographic examinations revealed splenomegaly and pneumonia, respectively. Prominent leucocytosis, consisting mainly of large atypical eosinophils, was observed in a peripheral blood smear. Necropsy revealed a black scab on the left hindlimb, which was swollen, an enlarged left inguinal lymph node, firm oedematous lungs, splenomegaly and multiple nodules in the lung, spleen and liver. Histopathologically, infiltration of numerous eosinophils was seen in lung, spleen, liver, kidney, lymph node and adrenal medulla tissues. Necrotizing granulomatous lesions, with intralesional acid-fast bacilli, were found in the lung, spleen, liver, left inguinal lymph node and left hindlimb. Mycobacterium marinum was identified by broad-range polymerase chain reaction targeting of the bacterial 16S rRNA gene. To the best of our knowledge, this is only the second reported case of systemic M. marinum infection in any mammalian species.

Consecutive intra-gingival injections of lipopolysaccharide and butyric acid to mice induce abnormal behavior and changes in cytokine concentrations.

BACKGROUND: Periodontopathic bacteria such as Porphyromonas gingivalis produce several metabolites, including lipopolysaccharide (LPS) and n-butyric acid (BA). Past work suggested that periodontal infection may cause cognitive impairment in mice. AIMS: To elucidate the mechanisms by which metabolites such as LPS and BA, resulting from Porphyromonas gingivalis activity, induce immunological and physiological abnormalities in mice. METHODS: In the present work, 28 male ICR mice were placed in an open-field arena and the total distance (cm/600 s) they covered was recorded. Based on their moving distances, mice were divided into 4 groups (n = 7) and injected the following substances into their gingival tissues for 32 consecutive days: saline (C), 5 mmol/L of BA (B), 1 µg/mouse of LPS (L), and BA-LPS (BL) solutions. Distances covered by mice were also measured on days 14 and 21, with their habituation scores considered as "(moving distance on day 14 or 21)/(moving distance on day 0)". Afterwards, mice were dissected, and hippocampal gene expression and the concentrations of short-chain fatty acids, neurotransmitters and cytokines in their blood plasma and brains were analyzed. In addition, mouse brain and liver tissues were fixed and visually assessed for histopathological abnormalities. RESULTS: Group BL had significantly higher habituation scores than C and B on day 14. LPS induced higher habituation scores on day 21. LPS induced significant decreases in the mRNA levels of interleukin (IL)-6 and brain-derived neurotrophic factors, and an increase in neurotrophic tyrosine kinase receptor type 2. In both plasma and brain, LPS induced a significant acetate increase. Moreover, LPS significantly increased acetylcholine in brain. In plasma alone, LPS and BA significantly decreased monocyte chemoattractant protein 1 (MCP-1). However, while LPS significantly decreased tyrosine, BA significantly increased it. Lastly, LPS significantly decreased IL-6 and tumor necrosis factor in plasma. No histopathological abnormalities were detected in liver or brain tissues of mice. CONCLUSION: We showed that injections of LPS and/or BA induced mice to move seemingly tireless and that both LPS and BA injections strongly induced a reduction of MCP-1 in blood plasma. We concluded that LPS and BA may have been crucial to induce and/or aggravate abnormal behavior in mice.

Spontaneous abdominal hemangiosarcoma in a ferret.

Herein, we describe the case of a 6-year-old female ferret that died within a few days of the onset of anorexia and reduced spontaneous locomotor activity. Necropsy revealed a dark red abdominal mass of unknown origin between the right lobes of the pancreas and the proximal jejunum, with massive blood retention in the peritoneal cavity. Histopathologically, spindle-shaped or sometimes polygonal tumor cells were proliferating with irregularly shaped vascular spaces containing blood components and surrounding-tissue infiltration. In some areas, tumor cells formed distinctly dilated blood vessel-like structures. Immunohistochemically, most of the tumor cells were strongly positive for CD31, but factor VIII-related antigen immunoreactivity was confined to the area with dilated blood vessel-like structures. Based on these findings, the tumor was diagnosed as an abdominal hemangiosarcoma. Abdominal hemangiosarcoma excluding cases of the liver and spleen are rare in ferrets.

Dietary supplementation with partially hydrolyzed guar gum helps improve constipation and gut dysbiosis symptoms and behavioral irritability in children with autism spectrum disorder.

Prebiotic dietary water-soluble fiber obtained from partially hydrolyzed guar gum was added to diets of children with autism spectrum disorders who presented constipation symptoms. Supplementation with partially hydrolyzed guar gum altered gut microbiota and significantly increased the frequency of defecation per week and altered the gut microbiota. In addition, supplementation with partially hydrolyzed guar gum significantly (p<0.05) decreased and tended to decrease (p = 0.07) the concentrations of serum interleukin-1ß and tumor necrosis factor-α, respectively. More importantly, supplementation with partially hydrolyzed guar gum significantly ameliorated behavioral irritability as per the Aberrant Behavior Checklist, Japanese Version. The present study demonstrated that supplementation with partially hydrolyzed guar gum to diets of constipated autism spectrum disorders children helped improve constipation and gut dysbiosis symptoms, which in turn helped attenuate the level of serum inflammation cytokines and behavioral irritability.

Stimulation of murine cell-mediated immunity by dietary administration of a cell preparation of Enterococcus faecalis strain KH-2 and its possible activity against tumour development in mice.

It is well known that dietary lactic acid bacteria (LAB) stimulate cell-mediated immunity such as natural killer (NK) activity in mice. Here, we aimed to assay the immunomodulatory effects of a cell preparation of Enterococcus faecalis strain KH-2 (CPEF). We further evaluated the possibility of antitumour activity caused by CPEF administration, because NK cells actively participate in the prevention of tumour formation. NK cell activity and gene expression of IFN-γ and Perforin 1, which were induced most likely by a synergetic action of their cytotoxic activity, were higher in splenocytes of CPEF-administered mice than they were in control mice. Moreover, unlike those of control mice, the splenocytes of CPEF-administered mice had significantly higher CD28+CD69+/CD4+ and CD28+CD69+/CD8+ ratios that resulted in a survival rate with a tendency toward improvement after 47 days of CPEF administration (p=0.1) in Meth-A fibrosarcoma-bearing mice. In conclusion, we showed that CPEF might be effective in treating Meth-A fibrosarcoma in mice, as it helped increase their survival rate via stimulation of an immune response in splenocytes, which involved systemic cellular immunity processes such as cytotoxic activity, and active T cells.

Oral supplementation of Bifidobacterium longum strain BR-108 alters cecal microbiota by stimulating gut immune system in mice irrespectively of viability.

Effect on cecal microbiota and gene expression of various cytokines in ileal Peyer's patches and cecal tissues were compared between viable and heat-killed Bifidobacterium longum strain BR-108 (BR-108) using a mouse model. Irrespectively of viability, oral supplementation of BR-108 altered the cecal microbiota and stimulated gene expression of cytokines such as IL-6 and IL-10 in ileal Peyer's patches and cecal tissue of mice. In addition, BR-108 supplementation significantly affected the relative abundance of bacterial genera and family, Oscillospira, Bacteroides and S24-7. The abundance of these bacterial genera and family strongly correlated with gene expression induced by BR-108. This study demonstrated that the effect of heat-killed BR-108 on the mouse cecal microbiota is similar to that of viable BR-108, most likely due to stimulation of the gut immune system by both heat-killed and viable BR-108 is also similar.

Generation of anti-porcine CD69 monoclonal antibodies and their usefulness to evaluate early activation of cellular immunity by flow cytometric analysis.

T cell-mediated cellular immunity and humoral immunity are equally important for the prevention of diseases. To assess activation of human and mouse cellular immunity, early activation markers of lymphocytes are often used in flow cytometry targeting expression of CD69 molecules. Response of humoral immunity against infection or vaccination has been well investigated in pigs, but that of cellular immunity has been largely neglected due to lack of direct evaluation tools. Thus, in pig research a proper assay of antibody reacted with porcine CD69 is still unavailable. In the present study, two anti-porcine CD69 mAb-producing mouse hybridomas, 01-14-22-51 (IgG2b-κ) and 01-22-44-102 (IgG2a-κ), both showing fine reactivity with phorbol 12-myristate 13-acetate (PMA) and ionomycin-stimulated porcine peripheral blood lymphocytes in flow cytometry, were established. When porcine peripheral blood lymphocytes were activated with PMA and ionomycin and analyzed by flow cytometry, it was found that both mAbs generated in this study stained about 70% of lymphocytes. In contrast, after an identical procedure, only 5% and 13.5% of lymphocytes were stained with anti-interferon-γ mAb and anti-tumor necrosis factor-α mAb, respectively. These results indicate that evaluation of cellular immunity activation turns more sensitive after using our newly generated mAbs.

Fructo-oligosaccharide-Induced Transient Increases in Cecal Immunoglobulin A Concentrations in Rats Are Associated with Mucosal Inflammation in Response to Increased Gut Permeability.

Background: The mechanism underlying transient increases in immunoglobulin (Ig) A concentrations in the cecal contents of rats fed fructo-oligosaccharide (FOS) is unclear.Objective: This study was designed to test whether increased IgA concentrations represent one aspect of the inflammatory response to increased permeability induced by FOS in the cecum.Methods: Seven-week-old male Wistar rats were fed a fiber-free semipurified diet (FFP) with or without supplemental FOS (60 g/kg diet) for 9 or 58 d [experiment (expt.) 1], 7 d (expt. 2), or 7 or 56 d (expt. 3). In addition to measuring IgA concentrations in cecal content, we assessed gut permeability, inflammatory responses (expt. 1), the number of IgA plasma cells in the cecal lamina propria, polymeric Ig receptor (pIgR) expression in the cecal mucosa (expt. 2), and the condition of the cecal mucus layer (expt. 3).Results: The cecal IgA concentration in the FOS-fed rats was 15-fold higher than that of the rats fed FFP for 9 d (P < 0.05). Gut permeability estimated by urinary chromium-EDTA excretion, bacterial translocation to mesenteric lymph nodes, myeloperoxidase activity, and expression of inflammatory cytokine genes in the cecal mucosa was greater in the FOS-fed rats than in the rats fed FFP for 9 d. These effects were not observed in the rats fed FOS for 58 d (expt. 1). Accompanying the higher cecal IgA concentration, pIgR protein and the number of IgA plasma cells in the cecal mucosa were higher in the FOS-fed rats than in the rats fed FFP for 7 d (expt. 2). Destruction of the mucus layer on the epithelial surface, as evidenced by Alcian blue staining in the cecal sections, was evident in the rats fed FOS for 7 d, but the mucus layer appeared normal in the rats fed FOS for 56 d (expt. 3).Conclusions: These findings suggest that transient increases in cecal IgA concentrations induced by FOS in rats are associated with mucosal inflammation in response to increased gut permeability; these are presumably evoked by disruption of the cecal mucus barrier. The observed responses could contribute to the maturation of the gut immune system.

Effects of chronic mild food restriction on behavior and the hypothalamic malonyl-CoA signaling pathway.

Depression induces anorexia, leading to suppressed feeding behaviors and energy intake. Previously, we revealed that chronic social defeat induced a mild suppression of feeding in rats with elevated levels of hypothalamic malonyl-CoA which regulates feeding. Therefore, we attempted to elucidate the effects of chronic mild food restriction on behavior and on hypothalamic malonyl-CoA. The chronic mild food restricted rats were fed a restricted diet approximately 80% to 90% amount of diet compared to the control for 5 weeks. Ratios of restriction were adjusted with feed consumption in the chronic social defeat stressed rats. Chronic mild food restricted rats exhibited a suppression of body weight gain similar to that of the chronic social defeat stressed rats. Also these rats showed increased time spent in the center area of an open field (OF), prolonged immobility time in forced swim, increased phosphorylation of hypothalamic adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase and a decreased concentration of hypothalamic malonyl-CoA. Weight of the adrenal glands, locomotion in an OF, mitogen-activated protein kinase cascade and calcium/calmodulin-dependent protein kinases II in the hippocampus were not affected by chronic mild food restriction. Our findings suggest that chronic mild food restriction activates AMPK following a decreased hypothalamic malonyl-CoA.

High-sensitivity detection of short-chain fatty acids in porcine ileal, cecal, portal and abdominal blood by gas chromatography-mass spectrometry.

Short-chain fatty acids (SCFA), such as acetate, propionate and n-butyrate, are the main end-products of fermentation in the large intestine. SCFA are rapidly absorbed from the large intestinal mucosa to provide energy to the host. In this study, high-sensitivity detection of SCFA was demonstrated in blood using the gas chromatometry with mass spectrometry (GC-MS). Few studies have measured SCFA in porcine blood. Therefore, SCFA concentrations in the ileal (IV), cecal (CV), portal (PV) and abdominal (AV) vein blood, urine (Ur) and saliva (Sa) were measured by GC-MS. All body fluids were collected from four 5-month-old pigs. Cecal (CD) and ileal (ID) digesta, and cecal (CM) and ileal (IM) mucosa were also collected and their corresponding SCFA concentrations were measured using ion-exclusion high-performance liquid chromatography. GC-MS analyses were successful to determine the SCFA concentrations in the porcine body fluids. n-Butyrate concentration was surprisingly high in CV and its proportion remained higher in CV than that in CD and CM. Acetate showed a constantly high proportion in all porcine body fluids. Propionate was detected at a relatively high proportion in CV, IV and PV, but was low in AV.

The effects of oral taurine administration on behavior and hippocampal signal transduction in rats.

Taurine, 2-aminoethylsulfonic acid, is one of the most abundant amino acids in the brain. It has various important physiological functions as a neuromodulator and antioxidant. Taurine is expected to be involved in depression; however, knowledge regarding its function in relation to depression is limited. In this study, we attempted to elucidate the effects of oral taurine administration on antidepressant-like behaviors in rats and depression-related signal transduction in the hippocampus. In behavioral tests, rats fed a high taurine (HT: 45.0 mmol/kg taurine) diet for 4 weeks (HT4w) showed decreased immobility in the forced swim test (FS) compared to controls. However, rats fed a low taurine (LT: 22.5 mmol/kg taurine) diet for 4 weeks or an HT diet for 2 weeks (HT2w) did not show a significant difference in FS compared to controls. In biochemical analyses, the expression of glutamic acid decarboxylase (GAD) 65 and GAD67 in the hippocampus was not affected by taurine administration. However, the phosphorylation levels of extracellular signal-regulated kinase1/2 (ERK1/2), protein kinase B (Akt), glycogen synthase kinase3 beta (GSK3ß) and cAMP response element-binding protein (CREB) were increased in the hippocampus of HT4w and HT2w rats. Phospho-calcium/calmodulin-dependent protein kinase II (CaMKII) was increased in the hippocampus of HT4w rats only. Moreover, no significant changes in these molecules were observed in the hippocampus of rats fed an HT diet for 1 day. In conclusion, our findings suggest that taurine has an antidepressant-like effect and an ability to change depression-related signaling cascades in the hippocampus.

Improvement of bone strength and dermal thickness due to dietary edible bird's nest extract in ovariectomized rats.

Oral administration of edible bird's nest extract (EBNE) improved bone strength and calcium concentration in the femur of ovariectomized rats. Dermal thickness was also increased by EBNE supplementation, whereas EBNE administration did not affect the serum estradiol concentration. These results suggest that EBNE is effective for the improvement of bone loss and skin aging in postmenopause all women.

Oral administration of Enterococcus faecalis EC-12 cell preparation improves villous atrophy after weaning through enhancement of growth factor expression in mice.

Lactic acid bacteria, either alive or dead, can improve villous atrophy caused by weaning in both piglets and mice. In this experiment, we tried to detect the molecules involved in this phenomenon with a real-time RT-PCR array approach. Weaning pups of mice were administered either a suspension of an Enterococcus faecalis EC-12 dried cell preparation (EC-12) or saline for 11 consecutive days after weaning. The jejunal and ileal villous heights were measured histologically, and the expression levels of 86 genes were analyzed for the jejunal and ileal epithelial cells and the lamina propria (LP). EC-12 induced significantly higher villous height in the jejunum and the ileum. Interleukin (IL)-6, fibroblast growth factor (FGF)-7, -10, and -22, and the platelet-derived growth factor (PDGF) beta in the jejunal and the ileal LP were the most enhanced genes by EC-12. The possible role of these molecules in the improvement of villous atrophy is discussed.

Alpha-linked galactooligosaccharide suppresses small intestinal eosinophil infiltration and improves growth performance in weaning pigs.

A healthy pig shows significant eosinophil infiltration in the lamina propria of the small intestine. Although the exact role of these infiltrated eosinophils in healthy pigs is unclear, eosinophil infiltration is a well-known phenomenon that is frequently observed during an allergic status. Alpha-linked galactooligosaccharide (GOS) reduces eosinophil infiltration into broncho-alveolar lavage fluid of an allergic airway eosinophilia model. We evaluated the effect of GOS oral administration on the suppression of eosinophil infiltration in the small intestine of healthy weaned pigs. Nine 21-day-old pigs were purchased and divided into three groups. One group was fed the basal diet supplemented with sucrose at 0.11% (C), one group was fed the basal diet supplemented with GOS at 1.17% (GOS A) and one group was fed the basal diet supplemented with GOS at 0.03% (GOS B). Each group was fed its respective diet throughout this study (10 days). The daily body weight gain from d3 to d10 was significantly bigger in the GOS B group than in the other groups. The feed conversion ratios from d0 to d10 were two times lower in the GOS B group than in the C group. Dietary GOS suppressed eosinophil infiltration in the small intestine. However, GOS administration had no effect on the organic acid level or microbial composition in the small and large intestinal digesta.

Improved isolation methods for mucosal leukocytes from small and large intestines in rats.

We optimized the isolation protocol for intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) from the rat small intestine, and LPLs from even the rat large intestine. The major population of IELs in the small intestine was considered to be from the villus epithelia. The cytotoxicity of mucosal leukocytes was comparable among isolated fractions from both the small and large intestines, regardless of the population differences. Further analyses of the cells collected from other lymphoid tissues demonstrated that CD161(+) cells selectively accumulated in the intestinal lamina propria and did not recirculate through the lymph ducts. Our modified isolation protocol enables the collection of mucosal immune cells from the rat intestines without any deterioration of cell function and could contribute to a better understanding of dietary influences on the mucosal immune system.

Activating transcription factor 3 constitutes a negative feedback mechanism that attenuates saturated Fatty acid/toll-like receptor 4 signaling and macrophage activation in obese adipose tissue.

Obese adipose tissue is markedly infiltrated by macrophages, suggesting that they may participate in the inflammatory pathways that are activated in obese adipose tissue. Evidence has suggested that saturated fatty acids released via adipocyte lipolysis serve as a naturally occurring ligand that stimulates Toll-like receptor (TLR)4 signaling, thereby inducing the inflammatory responses in macrophages in obese adipose tissue. Through a combination of cDNA microarray analyses of saturated fatty acid-stimulated macrophages in vitro and obese adipose tissue in vivo, here we identified activating transcription factor (ATF)3, a member of the ATF/cAMP response element-binding protein family of basic leucine zipper-type transcription factors, as a target gene of saturated fatty acids/TLR4 signaling in macrophages in obese adipose tissue. Importantly, ATF3, when induced by saturated fatty acids, can transcriptionally repress tumor necrosis factor-alpha production in macrophages in vitro. Chromatin immunoprecipitation assay revealed that ATF3 is recruited to the region containing the activator protein-1 site of the endogenous tumor necrosis factor-alpha promoter. Furthermore, transgenic overexpression of ATF3 specifically in macrophages results in the marked attenuation of proinflammatory M1 macrophage activation in the adipose tissue from genetically obese KKA(y) mice fed high-fat diet. This study provides evidence that ATF3, which is induced in obese adipose tissue, acts as a transcriptional repressor of saturated fatty acids/TLR4 signaling, thereby revealing the negative feedback mechanism that attenuates obesity-induced macrophage activation. Our data also suggest that activation of ATF3 in macrophages offers a novel therapeutic strategy to prevent or treat obesity-induced adipose tissue inflammation.