scholarly journals Depletion of adipocyte sphingosine kinase 1 leads to cell hypertrophy, impaired lipolysis, and nonalcoholic fatty liver disease

2020 ◽  
Vol 61 (10) ◽  
pp. 1328-1340 ◽  
Author(s):  
Andrea K. Anderson ◽  
Johana M. Lambert ◽  
David J. Montefusco ◽  
Bao Ngan Tran ◽  
Patrick Roddy ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Inflammatory Cytokines ◽  
Systemic Inflammation ◽  
Lipolytic Activity ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Nonalcoholic Fatty Liver ◽  
Triacylglycerol Accumulation ◽  
Pro Inflammatory Cytokines

Sphingolipids have become established participants in the pathogenesis of obesity and its associated maladies. Sphingosine kinase 1 (SPHK1), which generates S1P, has been shown to increase in liver and adipose of obese humans and mice and to regulate inflammation in hepatocytes and adipose tissue, insulin resistance, and systemic inflammation in mouse models of obesity. Previous studies by us and others have demonstrated that global sphingosine kinase 1 KO mice are protected from diet-induced obesity, insulin resistance, systemic inflammation, and NAFLD, suggesting that SPHK1 may mediate pathological outcomes of obesity. As adipose tissue dysfunction has gained recognition as a central instigator of obesity-induced metabolic disease, we hypothesized that SPHK1 intrinsic to adipocytes may contribute to HFD-induced metabolic pathology. To test this, we depleted Sphk1 from adipocytes in mice (SK1fatKO) and placed them on a HFD. In contrast to our initial hypothesis, SK1fatKO mice displayed greater weight gain on HFD and exacerbated impairment in glucose clearance. Pro-inflammatory cytokines and neutrophil content of adipose tissue were similar, as were levels of circulating leptin and adiponectin. However, SPHK1-null adipocytes were hypertrophied and had lower basal lipolytic activity. Interestingly, hepatocyte triacylglycerol accumulation and expression of pro-inflammatory cytokines and collagen 1a1 were exacerbated in SK1fatKO mice on a HFD, implicating a specific role for adipocyte SPHK1 in adipocyte function and inter-organ cross-talk that maintains overall metabolic homeostasis in obesity. Thus, SPHK1 serves a previously unidentified essential homeostatic role in adipocytes that protects from obesity-associated pathology. These findings may have implications for pharmacological targeting of the SPHK1/S1P signaling axis.

Abstract 1123: Critical Role Of Adipose Senescence In Insulin Resistance And Vascular Dysfunction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Masayuki Orimo ◽  
Tohru Minamino ◽  
Hideyuki Miyauchi ◽  
Kaoru Tateno ◽  
Sho Okada ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Inflammatory Cytokines ◽  
Cellular Senescence ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Serum Levels ◽  
P53 Expression ◽  
Deficient Mice ◽  
Pro Inflammatory Cytokines

Cellular senescence is originally described as the finite replicative lifespan of human somatic cells in culture. As a consequence of semi-conservative DNA replication, the extreme terminals of the chromosomes are not duplicated completely, resulting in successive shortening of telomeres with each cell division. Telomerase is a ribonucleoprotein that adds telomeres to the ends of chromosomes. Critically short telomeres are thought to trigger DNA damage response, thereby inducing cellular senescence. Accumulating evidence has suggested that senescent cells promote aging phenotypes or age-related pathologies. Here we show that adipose senescence is critically involved in the regulation of insulin resistance that underlies age-associated cardiovascular disease. The later generation of telomerase-deficient mice with short telomeres exhibited insulin resistance and vascular dysfunction when fed on a high-calorie diet. Adipose tissue of these mice revealed senescence-like phenotypes such as an increase in neutral β galactosidase activity and upregulation of p53 and pro-inflammatory cytokines. Serum levels of pro-inflammatory cytokines were markedly elevated in telomerase-deficient mice and treatment of these mice with a neutralizing antibody against TNF-α significantly improved insulin and glucose intolerance. Removal of senescent adipose tissue reduced serum levels of pro-inflammatory cytokines and thereby improved insulin resistance in telomerase-deficient mice. Conversely, implantation of senescent adipose tissue to wild-type mice impaired insulin sensitivity and glucose tolerance in recipients. Introduction of telomere dysfunction to young adipose tissue markedly upregulated p53 expression and increased the production of pro-inflammatory cytokines. Inhibition of p53 activity significantly improved senescence-like phenotypes of adipose tissue, insulin resistance, and vascular dysfunction in telomerase-deficient mice. These results disclose a novel mechanism of insulin resistance and suggest that adipose senescence is a potential therapeutic target for the treatment of diabetes and diabetic vasculopathy.

TNF-related apoptosis-inducing ligand significantly attenuates metabolic abnormalities in high-fat-fed mice reducing adiposity and systemic inflammation

2012 ◽  
Vol 123 (9) ◽  
pp. 547-555 ◽  
Author(s):  
Stella Bernardi ◽  
Giorgio Zauli ◽  
Christos Tikellis ◽  
Riccardo Candido ◽  
Bruno Fabris ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Inflammatory Cytokines ◽  
Systemic Inflammation ◽  
Tolerance Test ◽  
Metabolic Abnormalities ◽  
High Fat ◽  
Adipose Tissue Gene Expression ◽  
Tissue Gene Expression ◽  
Pro Inflammatory Cytokines

TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] has recently been shown to ameliorate the natural history of DM (diabetes mellitus). It has not been determined yet whether systemic TRAIL delivery would prevent the metabolic abnormalities due to an HFD [HF (high-fat) diet]. For this purpose, 27 male C57bl6 mice aged 8 weeks were randomly fed on a standard diet, HFD or HFD+TRAIL for 12 weeks. TRAIL was delivered weekly by intraperitoneal injection. Body composition was evaluated; indirect calorimetry studies, GTT (glucose tolerance test) and ITT (insulin tolerance test) were performed. Pro-inflammatory cytokines, together with adipose tissue gene expression and apoptosis, were measured. TRAIL treatment reduced significantly the increased adiposity associated with an HFD. Moreover, it reduced significantly hyperglycaemia and hyperinsulinaemia during a GTT and it improved significantly the peripheral response to insulin. TRAIL reversed the changes in substrate utilization induced by the HFD and ameliorated skeletal muscle non-esterified fatty acids oxidation rate. This was associated with a significant reduction of pro-inflammatory cytokines together with a modulation of adipose tissue gene expression and apoptosis. These findings shed light on the possible anti-adipogenic and anti-inflammatory effects of TRAIL and open new therapeutic possibilities against obesity, systemic inflammation and T2DM (Type 2 DM).

scholarly journals Sphingosine kinase 1 regulates adipose proinflammatory responses and insulin resistance

2014 ◽  
Vol 306 (7) ◽  
pp. E756-E768 ◽  
Author(s):  
Jing Wang ◽  
Leylla Badeanlou ◽  
Jacek Bielawski ◽  
Theodore P. Ciaraldi ◽  
Fahumiya Samad
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Molecular Mechanisms ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Tissue Macrophage ◽  
Proinflammatory Responses ◽  
Sphingosine 1 Phosphate ◽  
Adipose Inflammation

Adipose dysfunction resulting from chronic inflammation and impaired adipogenesis has increasingly been recognized as a major contributor to obesity-mediated insulin resistance, but the molecular mechanisms that maintain healthy adipocytes and limit adipose inflammation remain unclear. Here, we used genetic and pharmacological approaches to delineate a novel role for sphingosine kinase 1 (SK1) in metabolic disorders associated with obesity. SK1 phosphorylates sphingosine to form sphingosine 1 phosphate (S1P), a bioactive sphingolipid with numerous roles in inflammation. SK1 mRNA expression was increased in adipose tissue of diet-induced obese (DIO) mice and obese type 2 diabetic humans. In DIO mice, SK1 deficiency increased markers of adipogenesis and adipose gene expression of the anti-inflammatory molecules IL-10 and adiponectin and reduced adipose tissue macrophage (ATM) recruitment and proinflammatory molecules TNFα and IL-6. These changes were associated with enhanced insulin signaling in adipose and muscle and improved systemic insulin sensitivity and glucose tolerance in SK1−/− mice. Specific pharmacological inhibition of SK1 in WT DIO mice also reduced adipocyte and ATM inflammation and improved overall glucose homeostasis. These data suggest that the SK1-S1P axis could be an attractive target for the development of treatments to ameliorate adipose inflammation and insulin resistance associated with obesity and type 2 diabetes.

scholarly journals My D88-Dependent Interplay Between Myeloid and Endothelial Cells in the Initiation and Progression of Obesity-Associated Inflammatory Diseases

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-44-SCI-44
Author(s):  
Xiaoxia Li
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Adipose Tissue ◽  
Systemic Inflammation ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Low Grade

Abstract Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor-MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet-induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases. Disclosures No relevant conflicts of interest to declare.

scholarly journals The effect of adipocyte–macrophage crosstalk in obesity-related breast cancer

2019 ◽  
Vol 62 (3) ◽  
pp. R201-R222 ◽  
Author(s):  
Ayse Basak Engin ◽  
Atilla Engin ◽  
Ipek Isik Gonul
Keyword(s):  
Breast Cancer ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Cancer Cells ◽  
Inflammatory Cytokines ◽  
Breast Cancer Cells ◽  
Sirtuin 1 ◽  
Aromatase Activity ◽  
Breast Adipose Tissue ◽  
Mtorc1 Signaling

Adipose tissue is the primary source of many pro-inflammatory cytokines in obesity. Macrophage numbers and pro-inflammatory gene expression are positively associated with adipocyte size. Free fatty acid and tumor necrosis factor-α involve in a vicious cycle between adipocytes and macrophages aggravating inflammatory changes. Thereby, M1 macrophages form a characteristic ‘crown-like structure (CLS)’ around necrotic adipocytes in obese adipose tissue. In obese women, CLSs of breast adipose tissue are responsible for both increase in local aromatase activity and aggressive behavior of breast cancer cells. Interlinked molecular mechanisms between adipocyte–macrophage–breast cancer cells in obesity involve seven consecutive processes: Excessive release of adipocyte- and macrophage-derived inflammatory cytokines, TSC1–TSC2 complex–mTOR crosstalk, insulin resistance, endoplasmic reticulum (ER) stress and excessive oxidative stress generation, uncoupled respiration and hypoxia, SIRT1 controversy, the increased levels of aromatase activity and estrogen production. Considering elevated risks of estrogen receptor (E2R)-positive postmenopausal breast cancer growth in obesity, adipocyte–macrophage crosstalk is important in the aforementioned issues. Increased mTORC1 signaling in obesity ensures the strong activation of oncogenic signaling in E2Rα-positive breast cancer cells. Since insulin and insulin-like growth factors have been identified as tumor promoters, hyperinsulinemia is an independent risk factor for poor prognosis in breast cancer despite peripheral insulin resistance. The unpredictable effects of adipocyte-derived leptin–estrogen–macrophage axis, and sirtuin 1 (SIRT1)–adipose-resident macrophage axis in obese postmenopausal patients with breast cancer are unresolved mechanistic gaps in the molecular links between the tumor growth and adipocytokines.

scholarly journals Effect of Curcumin on Growth Performance, Inflammation, Insulin level, and Lipid Metabolism in Weaned Piglets with IUGR

Animals ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 1098 ◽  
Author(s):  
Yu Niu ◽  
Jintian He ◽  
Yongwei Zhao ◽  
Mingming Shen ◽  
Lili Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Slow Growth ◽  
Hepatic Glycogen ◽  
Lipid Levels ◽  
Weaned Piglets ◽  
Hepatic Lipid ◽  
Pro Inflammatory Cytokines

The possible causes of intrauterine growth retardation (IUGR) might stem from placental insufficiency, maternal malnutrition, inflammation in utero, and other causes. IUGR has had an adverse influence on human health and animal production. Forty weaned piglets with normal birth weights (NBWs) or IUGR were randomly divided into four treatments groups: NBW, NC (NBW with curcumin supplementation), IUGR, and IC (IUGR with curcumin supplementation) from 26 to 50 d. Levels of cytokines, glucose, and lipid metabolism were evaluated. IUGR piglets showed slow growth during the experiment. Piglets with IUGR showed higher levels of serum pro-inflammatory cytokines, insulin resistance, and hepatic lipid accumulation. Curcumin supplementation reduced the production of serum pro-inflammatory cytokines, attenuated insulin resistance and hepatic triglyceride, and enhanced the hepatic glycogen concentrations and lipase activities of IUGR piglets. The hepatic mRNA expressions of the insulin-signaling pathway and lipogenic pathway were influenced by IUGR and were positively attenuated by diets supplemented with curcumin. In conclusion, IUGR caused slow growth, insulin resistance, and increased hepatic lipid levels. Diets supplemented with curcumin improved growth, attenuated insulin resistance, and reduced lipid levels in the liver by regulating the hepatic gene expressions of the related signaling pathway in IUGR piglets.

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