scholarly journals CD226 knockout alleviates high-fat diet induced obesity by suppressing proinflammatory macrophage phenotype

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jingchang Ma ◽  
Wei Hu ◽  
Dongliang Zhang ◽  
Jiangang Xie ◽  
Chujun Duan ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Costimulatory Molecule ◽  
Low Grade ◽  
Macrophage Phenotype ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Ppar Γ ◽  
M1 Polarization

AbstractObesity is associated with chronic low-grade inflammation, contributing to an increasing prevalence of chronic metabolic diseases, such as insulin resistance, non-alcoholic fatty liver disease (NALFD), and steatohepatitis. Macrophages are the predominant immune cells in adipose tissues. Adipose tissue macrophages (ATMs) would switch to pro-inflammatory M1 state during obesity, causing local and systemic inflammation. However, the regulatory mechanism of ATMs has not yet been well described within this process. Using a high-fat diet (HFD)–induced mouse obesity model, we found that the costimulatory molecule CD226 was highly expressed on ATMs and knockout (KO) of CD226 alleviated obesity caused by HFD. Loss of CD226 reduced the accumulation of ATMs and hindered macrophage M1 polarization, with lower serum proinflammatory cytokine levels. Furthermore, deficiency of CD226 on ATMs decreased the phosphorylation levels of VAV1, AKT, and FOXO1 and thereby upregulated PPAR-γ. Further administration of PPAR-γ inhibitor restored M1 phenotype in CD226KO ATMs. In summary, loss of CD226 alleviates the HFD-induced obesity and systemic inflammation through inhibition of the accumulation and M1 polarization of ATMs in which PPAR-γ-dependent signaling pathway is involved, suggesting that CD226 may be identified as a potential molecular target for the clinical treatment of obesity.

scholarly journals Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

2020 ◽  
Vol 295 (31) ◽  
pp. 10842-10856 ◽  
Author(s):  
Wen Liu ◽  
Ye Yin ◽  
Meijing Wang ◽  
Ting Fan ◽  
Yuyu Zhu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Low Grade ◽  
High Fat ◽  
Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

scholarly journals Sex differences in gut microbiome in high-fat-diet fed rats.

2020 ◽  
Author(s):  
Ying Shi ◽  
Fangzhi Yue ◽  
Lin Xing ◽  
Shanyu Wu ◽  
Lin Wei ◽  
...  
Keyword(s):  
Sex Differences ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Normal Diet ◽  
Female Rats ◽  
Male Rats ◽  
High Fat ◽  
Alcoholic Fatty Liver

Abstract Background Sex differences in obesity and related metabolic diseases are well recognized, however, the mechanism has not been elucidated. Gut microbiota and its metabolites may play a vital role in the development of obesity and metabolic diseases. The aim of the present study was to investigate sex differences in gut microbiota and its metabolites in a high-fat-diet (HFD) obesity rats and identify microbiota genera potentially contributing to such differences in obesity and non-alcoholic fatty liver disease (NAFLD) susceptibility. Results Sprague–Dawley rats were divided into the following groups (seven animals per group): (1) male rats on a normal diet (MND), (2) male rats on HFD (MHFD), (3) female rats on a normal diet (FND), and (4) female rats on HFD (FHFD). HFD induced more body weight gain and fat storage in female rats, however, lower hepatic steatosis in FHFD than in MHFD rats was observed. When considering gut microbiota composition, FHFD rats had lower microbiome diversity than MHFD. A significant increase of Firmicutes phylum and Bilophila genus was detected in MHFD rats, as compared with FHFD, which showed increased relative abundance of Murimonas and Roseburia . Moreover, propionic and lauric acid levels were higher in FHFD than those in MHFD rats. Conclusion HFD induced sex-related alterations in gut microbiome and fatty acids. Furthermore, the genus Bilophila and Roseburia might contribute to sex differences observed in obesity and NAFLD susceptibility.

scholarly journals Gallic Acid Ameliorated Impaired Lipid Homeostasis in a Mouse Model of High-Fat Diet—and Streptozotocin-Induced NAFLD and Diabetes through Improvement of β-oxidation and Ketogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Jung Chao ◽  
Hao-Yuan Cheng ◽  
Ming-Ling Chang ◽  
Shyh-Shyun Huang ◽  
Jiunn-Wang Liao ◽  
...  
Keyword(s):  
Mouse Model ◽  
Gallic Acid ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Pathological Condition ◽  
Underlying Mechanism ◽  
High Fat ◽  
High Blood Glucose ◽  
Alcoholic Fatty Liver ◽  
Liver Histopathology

Gallic acid (GA) is a simple polyphenol found in food and traditional Chinese medicine. Here, we determined the effects of GA administration in a combined mouse model of high-fat diet (HFD)-induced obesity and low-dose streptozotocin (STZ)-induced hyperglycemia, which mimics the concurrent non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes pathological condition. By combining the results of physiological assessments, pathological examinations, metabolomic studies of blood, urine, liver, and muscle, and measurements of gene expression, we attempted to elucidate the efficacy of GA and the underlying mechanism of action of GA in hyperglycemic and dyslipidemic mice. HFD and STZ induced severe diabetes, NAFLD, and other metabolic disorders in mice. However, the results of liver histopathology and serum biochemical examinations indicated that daily GA treatment alleviated the high blood glucose levels in the mice and decelerated the progression of NAFLD. In addition, our results show that the hepatoprotective effect of GA in diabetic mice occurs in part through a partially preventing disordered metabolic pathway related to glucose, lipids, amino acids, purines, and pyrimidines. Specifically, the mechanism responsible for alleviation of lipid accumulation is related to the upregulation of β-oxidation and ketogenesis. These findings indicate that GA alleviates metabolic diseases through novel mechanisms.

scholarly journals High Fat Diet-Induced CD8+ T Cells in Adipose Tissue Mediate Macrophages to Sustain Low-Grade Chronic Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Sonia Kiran ◽  
Vijay Kumar ◽  
E. Angela Murphy ◽  
Reilly T. Enos ◽  
Udai P. Singh
Keyword(s):  
T Cells ◽  
Adipose Tissue ◽  
Chronic Inflammation ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Killer Cell ◽  
The United States ◽  
Low Grade ◽  
High Fat ◽  
Activated T Cells

Obesity in the United States and worldwide reached epidemic proportions within the last 20 years. Obesity is a very powerful health determinant or indicator that facilitates the development and progression of several metabolic diseases, insulin resistance, and low-grade chronic inflammation. Low-grade chronic inflammation in adipose tissue (AT) is marked by the accumulation of T cells, macrophages, and other immune cells and increased production of proinflammatory cytokines. During the onset of obesity but before the influx of macrophages, the AT is infiltrated by T cells that are strongly implicated in the initiation of obesity-associated inflammation. In comparing mice fed a high-fat diet (HFD) with those fed a normal diet (ND), we observed in HFD epididymal AT induction and infiltration of activated T cells, an accumulation and polarization of macrophages, and an increase in populations of activated CD4+ T cells and CD8+ T cells that express CXCR3 or killer cell lectin-like receptor subfamily G member 1 (KLRG1). Levels of inflammatory cytokines and leptin and the results of in vitro co-culture experiments revealed interactions among HFD- and ND-induced CD8+ T cells, macrophages, and adipocytes. Our findings suggest that obese tissues activate and induce both CD4+ and CD8+ CD69+ T cells and augment the expression of CXCR3 receptors, which promotes the recruitment and numbers of pro-inflammatory M1 macrophages to maintain low-grade chronic inflammation. The results support the hypothesis that CXCR3-expressing CD8+T cells play an essential role in the initiation and maintenance of adipose tissue inflammation.

scholarly journals Folic Acid Attenuates High-Fat Diet-Induced Osteoporosis Through the AMPK Signaling Pathway

2022 ◽  
Vol 9 ◽  
Author(s):  
Haiting He ◽  
Yaxi Zhang ◽  
Yue Sun ◽  
Yanwei Zhang ◽  
Jingjing Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Folic Acid ◽  
Lipid Metabolism ◽  
Signaling Pathway ◽  
Systemic Inflammation ◽  
High Fat Diet ◽  
Water Soluble ◽  
Low Grade ◽  
High Fat ◽  
Ampk Signaling

Objective: Obesity caused by a high-fat diet (HFD) will expand adipose tissue and cause chronic low-grade systemic inflammation, leading to osteoporosis. Folic acid (FA) is a water-soluble vitamin that plays an essential role in regulating blood lipids and antioxidants. However, the effects and underlying mechanisms of FA in osteoporosis induced by an HFD remain poorly understood. This study aimed to investigate the effect of FA on bone health by using HFD-induced osteoporosis mice.Materials and Methods: Mice were fed a normal diet, HFD or an HFD supplemented with FA (20 μg/ml in drinking water) for 16 weeks. Throughout the 16 weeks study period, the rats were weighed once every week. GTT, ITT and lipid indexes were detected to evaluate the effects of FA on lipid metabolism in the HFD-fed mice. Morphological and structural changes of the femur and tibial bone were observed using micro-CT, HE staining and bone conversion parameters. The expression of MDA, SOD and inflammatory factors were detected to evaluate the effects of FA on oxidative stress and inflammatory response in the HFD-fed mice. Quantitative real-time PCR and Western blot (WB) were used to investigate the AMPK signaling pathway.Results: After the intervention of FA, the body fat rate of obese mice was reduced, and related metabolic disorders such as insulin resistance, hyperlipidemia, and systemic inflammation were alleviated. In correlation with those modifications, FA attenuated bone loss and improved bone microarchitecture, accompanied the number of osteoclasts and adipocytes decreased. Furthermore, FA promoted the phosphorylation of AMPK, thereby promoting the expression of Carnitine palmitoyltransferase 1 (CPT1), nuclear factor erythroid-2 related factor 2 (Nrf2) and antioxidant enzymes.Conclusion: These findings suggest that FA may modulate lipid metabolism and oxidative stress responses activating the AMPK signaling pathway, thereby alleviating HFD-induced osteoporosis. The results from our study provide experimental evidence to prevent HFD-induced osteoporosis.

scholarly journals Phytosterol esters attenuate hepatic steatosis in rats with non-alcoholic fatty liver disease rats fed a high-fat diet

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Lihua Song ◽  
Dan Qu ◽  
Qing Zhang ◽  
Jing jiang ◽  
Haiyue Zhou ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Hepatic Tissue ◽  
High Dose ◽  
Chow Diet ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Inflammatory Stress ◽  
Beneficial Effects ◽  
Ppar Γ ◽  
Phytosterol Esters

Abstract Given the adverse effects of drugs used for NAFLD treatment, identifying novel and effective natural compound to prevent NAFLD is urgently needed. In the present study, the effects of phytosterol esters (PSEs) on NAFLD were explored. Adult SD rats were randomized into five groups: normal chow diet (NC), high-fat diet (HF), low-, medium- and high-dose PSE treatment plus high-fat diet groups (PSEL, PSEM, and PSEH). Our results showed that the levels of LDL-C in the PSEL group and hepatic TG, TC, and FFA in the three PSEs groups were significantly decreased. Notably, the uric acid (UA) level was significantly decreased by PSEs intervention. The hepatic inflammatory stress was ameliorated via the inhibition of the cytokines, including TGF-β, IL-6, IL-10 and CRP in the PSEs intervention groups. Further, the oxidative status was improved by PSE treatment through adjusting the enzyme activity (SOD and XOD) and decreasing the MDA level. These beneficial effects of PSE may have been partly due to its regulation on the expression of TGF-β1, TGF-β2, TNF-α, UCP-2, PPAR-α and PPAR-γ in hepatic tissue at both mRNA and protein level. The results of this study suggest that PSEs may be used as therapeutic agents for the prevention and progression of NAFLD and that hyperuricemia is induced by high-fat diet consumption.

scholarly journals Extract of Wax Gourd Peel Prevents High-Fat Diet-Induced Hyperlipidemia in C57BL/6 Mice via the Inhibition of the PPARγPathway

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Ming Gu ◽  
Shengjie Fan ◽  
Gaigai Liu ◽  
Lu Guo ◽  
Xiaobo Ding ◽  
...  
Keyword(s):  
Blood Glucose ◽  
High Fat Diet ◽  
Target Genes ◽  
Metabolic Diseases ◽  
Body Weight Gain ◽  
Fasting Blood Glucose ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
High Fat ◽  
Wax Gourd

Wax gourd is a popular vegetable in East Asia. In traditional Chinese medicine, wax gourd peel is used to prevent and treat metabolic diseases such as hyperlipidemia, hyperglycemia, obesity, and cardiovascular disease. However, there is no experimental evidence to support these applications. Here, we examined the effect of the extract of wax gourd peel (EWGP) on metabolic disorders in diet-induced C57BL/6 obese mice. In the preventive experiment, EWGP blocked body weight gain and lowered serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), liver TG and TC contents, and fasting blood glucose in mice fed with a high-fat diet. In the therapeutic study, we induced obesity in the mice and treated with EWGP for two weeks. We found that EWGP treatment reduced serum and liver triglyceride (TG) contents and fasting blood glucose and improved glucose tolerance in the mice. Reporter assay and gene expression analysis showed that EWGP could inhibit peroxisome proliferator-activated receptorγ(PPARγ) transactivities and could decrease mRNA levels of PPARγand its target genes. We also found that HMG-CoA reductase (HMGCR) was downregulated in the mouse liver by EWGP. Our data suggest that EWGP lowers hyperlipidemia of C57BL/6 mice induced by high-fat diet via the inhibition of PPARγand HMGCR signaling.

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