scholarly journals The antagonist of CXCR1 and CXCR2 protects db/db mice from metabolic diseases through modulating inflammation

2019 ◽  
Vol 317 (6) ◽  
pp. E1205-E1217 ◽  
Author(s):  
Siyuan Cui ◽  
Lu Qiao ◽  
Shanshan Yu ◽  
Lili Men ◽  
Yu Li ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Immune Cell ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Signal Pathways ◽  
Therapeutic Effects ◽  
Obesity And Diabetes ◽  
Phosphorylated Akt

Interleukin-8 (IL-8, also named CXCL8) binds to its receptors (CXCR1 and CXCR2) with subsequent recruitment of neutrophils and enhancement of their infiltration into inflamed sites, which exaggerates inflammation in many diseases. Recent studies have proposed that metabolic disorders can be attenuated by counteracting certain inflammatory signal pathways. In this study, we examined whether intervention with G31P, an antagonist of CXCL8, could attenuate tissue inflammation and development of metabolic disorders in db/db mice. The db/m and db/db mice were subcutaneously injected with G31P or equivalent normal saline once a day for 6 wk. The physical and metabolic parameters, glucose tolerance, insulin sensitivity, hepatic lipid accumulation, and inflammation markers were measured. G31P improved hepatic insulin sensitivity by modulating expression of genes related to gluconeogenesis and phosphorylated Akt levels. The expressions of several genes encoding proteins involved in de novo lipogenesis were decreased in G31P-treated db/db mice. Meanwhile, immune cell infiltration and cytokine release were attenuated in db/db mice with G31P treatment. G31P also improved the ratio of proinflammatory M1 and anti-inflammatory M2 macrophages. Furthermore, G31P ameliorates metabolic disturbances via inhibition of CXCR1 and CXCR2 pathways in db/db mice. These data suggest that the selective inhibition of CXC chemokines may have therapeutic effects on symptoms associated with obesity and diabetes.

scholarly journals miR-146a regulates insulin sensitivity via NPR3

2020 ◽  
Author(s):  
Julian Roos ◽  
Meike Dahlhaus ◽  
Jan-Bernd Funcke ◽  
Monika Kustermann ◽  
Gudrun Strauss ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
De Novo ◽  
Liver Steatosis ◽  
De Novo Lipogenesis ◽  
Loss Of Function ◽  
High Fat

AbstractThe pathogenesis of obesity-related metabolic diseases has been linked to the inflammation of white adipose tissue (WAT), but the molecular interconnections are still not fully understood. MiR-146a controls inflammatory processes by suppressing pro-inflammatory signaling pathways. The aim of this study was to characterize the role of miR-146a in obesity and insulin resistance. MiR-146a−/− mice were subjected to a high-fat diet followed by metabolic tests and WAT transcriptomics. Gain- and loss-of-function studies were performed using human Simpson–Golabi–Behmel syndrome (SGBS) adipocytes. Compared to controls, miR-146a−/− mice gained significantly more body weight on a high-fat diet with increased fat mass and adipocyte hypertrophy. This was accompanied by exacerbated liver steatosis, insulin resistance, and glucose intolerance. Likewise, adipocytes transfected with an inhibitor of miR-146a displayed a decrease in insulin-stimulated glucose uptake, while transfecting miR-146a mimics caused the opposite effect. Natriuretic peptide receptor 3 (NPR3) was identified as a direct target gene of miR-146a in adipocytes and CRISPR/Cas9-mediated knockout of NPR3 increased insulin-stimulated glucose uptake and enhanced de novo lipogenesis. In summary, miR-146a regulates systemic and adipocyte insulin sensitivity via downregulation of NPR3.

The outer membrane protein Amuc_1100 of Akkermansia muciniphila promotes intestinal 5-HT biosynthesis and extracellular availability through TLR2 signalling

2021 ◽  
Author(s):  
Junchao Wang ◽  
Wenjuan Xu ◽  
Rongjuan Wang ◽  
Rongrong Cheng ◽  
Zhengquan Tang ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Outer Membrane ◽  
Outer Membrane Protein ◽  
Metabolic Disorders ◽  
Therapeutic Effects ◽  
Akkermansia Muciniphila ◽  
Intestinal Mucus ◽  
Obesity And Diabetes

Akkermansia muciniphila is a probiotic inhabiting host intestinal mucus layers and displays evident easing or therapeutic effects on host enteritis and metabolic disorders such as obesity and diabetes. The outer...

scholarly journals Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver

Metabolomics ◽  
2020 ◽  
Vol 16 (1) ◽  
Author(s):  
David Balgoma ◽  
Sofia Zelleroth ◽  
Alfhild Grönbladh ◽  
Mathias Hallberg ◽  
Curt Pettersson ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Metabolic Diseases ◽  
De Novo ◽  
High Resolution Mass Spectrometry ◽  
De Novo Lipogenesis ◽  
Anabolic Androgenic Steroids ◽  
Lipid Profiling ◽  
Testosterone Undecanoate ◽  
Androgenic Steroids

Abstract Introduction The abuse of anabolic androgenic steroids (AASs) is a source of public concern because of their adverse effects. Supratherapeutic doses of AASs are known to be hepatotoxic and regulate the lipoproteins in plasma by modifying the metabolism of lipids in the liver, which is associated with metabolic diseases. However, the effect of AASs on the profile of lipids in plasma is unknown. Objectives To describe the changes in the plasma lipidome exerted by AASs and to discuss these changes in the light of previous research about AASs and de novo lipogenesis in the liver. Methods We treated male Wistar rats with supratherapeutic doses of nandrolone decanoate and testosterone undecanoate. Subsequently, we isolated the blood plasma and performed lipidomics analysis by liquid chromatography-high resolution mass spectrometry. Results Lipid profiling revealed a decrease of sphingolipids and glycerolipids with palmitic, palmitoleic, stearic, and oleic acids. In addition, lipid profiling revealed an increase in free fatty acids and glycerophospholipids with odd-numbered chain fatty acids and/or arachidonic acid. Conclusion The lipid profile presented herein reports the imprint of AASs on the plasma lipidome, which mirrors the downregulation of de novo lipogenesis in the liver. In a broader perspective, this profile will help to understand the influence of androgens on the lipid metabolism in future studies of diseases with dysregulated lipogenesis (e.g. type 2 diabetes, fatty liver disease, and hepatocellular carcinoma).

scholarly journals Risk of diabetes associated with fatty acids in the de novo lipogenesis pathway is independent of insulin sensitivity and response: the Insulin Resistance Atherosclerosis Study (IRAS)

2019 ◽  
Vol 7 (1) ◽  
pp. e000691 ◽  
Author(s):  
Waqas Qureshi ◽  
Ingrid D Santaren ◽  
Anthony J Hanley ◽  
Steven M Watkins ◽  
Carlos Lorenzo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Palmitic Acid ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Diabetes Incidence ◽  
Incident Type ◽  
Insulin Resistance Atherosclerosis Study

ObjectiveTo examine the associations of fatty acids in the de novo lipogenesis (DNL) pathway, specifically myristic acid (14:0), palmitic acid (16:0),cis-palmitoleic acid (c16:1 n-7),cis-myristoleic acid (c14:1n5), stearic acid (18:0) andcis-oleic acid (c18:1 n-9), with 5-year risk of type 2 diabetes. We hypothesized that DNL fatty acids are associated with risk of type 2 diabetes independent of insulin sensitivity.Research design and methodsWe evaluated 719 (mean age 55.1±8.5 years, 44.2% men, 42.3% Caucasians) participants from the Insulin Resistance Atherosclerosis Study. Multivariable logistic regression models with and without adjustment of insulin sensitivity were used to assess prospective associations of DNL fatty acids with incident type 2 diabetes.ResultsType 2 diabetes incidence was 20.3% over 5 years. In multivariable regression models, palmitic, palmitoleic, myristic, myristoleic and oleic acids were associated with increased risk of type 2 diabetes (p<0.05). Palmitic acid had the strongest association (OR per standard unit of palmitic acid 1.46; 95% CI 1.23 to 1.76; p<0.001), which remained similar with addition of insulin sensitivity and acute insulin response (AIR) to the model (OR 1.36; 95% CI 1.09 to 1.70, p=0.01). Oleic and palmitoleic acids were also independently associated with incident type 2 diabetes. In multivariable models, ratios of fatty acids corresponding to stearoyl CoA desaturase-1 and Elovl6 enzymatic activity were significantly associated with risk of type 2 diabetes independent of insulin sensitivity and AIR.ConclusionsWe observed associations of DNL fatty acids with type 2 diabetes incidence independent of insulin sensitivity.

scholarly journals Role of Pterostilbene in Metabolic Diseases through SIRT1 pathway- A Review

2022 ◽  
Vol 9 (sp) ◽  
pp. 2581-2586
Author(s):  
Rashmi Patil ◽  
Urmila Aswar
Keyword(s):  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Uncoupling Protein ◽  
Glucose Disposal ◽  
Therapeutic Effects ◽  
Grape Skin ◽  
Red Grape ◽  
Diabetes And Obesity ◽  
Sirt1 Activator

Pterostilbene (PTE) (3-5 dimethoxy-4-hydroxy-trans-stilbenes) is an analogue of resveratrol. It is extracted and isolated from a natural source of the heartwood of Pterocarpus marsupium Roxb., red grape skin, and blueberries (Vaccinium spp.). Substantial evidence suggested that PTE displayed numerous preventive and therapeutic properties in many metabolic disorders such as diabetes and obesity. Metabolic diseases result in Insulin resistance (IR) which advances to impaired sensitivity to insulin-mediated glucose disposal. The prominent role of SIRT (silent information regulator proteins) is now getting emphasized in metabolic disorders. SIRT1 represses Uncoupling protein 2 (UCP2) expressions which are further responsible for improving synthesis of ATP from glucose. This results in improving glucose utilization and insulin secretion, thus preventing IR. SIRT1 also exhibits prominent role in facilitating fatty acid mobilization thereby inhibiting adiposity. Metabolic disorders are therefore the consequences of SIRT1 downregulation. Pterostilbene, being a SIRT1 activator, increases insulin sensitivity reduces adiposity, therefore can prove to be beneficial in diabetes as well as obesity. The review summarizes therapeutic effects portrayed by Pterostilbene via the SIRT1 pathway in metabolic diseases.

scholarly journals Glucose-6 Phosphate, a Central Hub for Liver Carbohydrate Metabolism

Metabolites ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 282 ◽  
Author(s):  
Fabienne Rajas ◽  
Amandine Gautier-Stein ◽  
Gilles Mithieux
Keyword(s):  
Glucose Metabolism ◽  
Metabolic Diseases ◽  
De Novo ◽  
Glycogen Synthesis ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Type I ◽  
Alcoholic Fatty Liver ◽  
Hexosamine Pathway

Cells efficiently adjust their metabolism according to the abundance of nutrients and energy. The ability to switch cellular metabolism between anabolic and catabolic processes is critical for cell growth. Glucose-6 phosphate is the first intermediate of glucose metabolism and plays a central role in the energy metabolism of the liver. It acts as a hub to metabolically connect glycolysis, the pentose phosphate pathway, glycogen synthesis, de novo lipogenesis, and the hexosamine pathway. In this review, we describe the metabolic fate of glucose-6 phosphate in a healthy liver and the metabolic reprogramming occurring in two pathologies characterized by a deregulation of glucose homeostasis, namely type 2 diabetes, which is characterized by fasting hyperglycemia; and glycogen storage disease type I, where patients develop severe hypoglycemia during short fasting periods. In these two conditions, dysfunction of glucose metabolism results in non-alcoholic fatty liver disease, which may possibly lead to the development of hepatic tumors. Moreover, we also emphasize the role of the transcription factor carbohydrate response element-binding protein (ChREBP), known to link glucose and lipid metabolisms. In this regard, comparing these two metabolic diseases is a fruitful approach to better understand the key role of glucose-6 phosphate in liver metabolism in health and disease.

Cefdinir Microsphere Modulated Microflora and Liver Immunological Response to Diet Induced Diabetes in Mice

2019 ◽  
Vol 19 (3) ◽  
pp. 349-357 ◽  
Author(s):  
Sweta Patel ◽  
Dipeeka Mandaliya ◽  
Bhumika Prajapati ◽  
Sunny Kumar ◽  
Sriram Seshadri
Keyword(s):  
Insulin Sensitivity ◽  
Metabolic Disorders ◽  
Immune Cell ◽  
Immunological Response ◽  
Cell Types ◽  
Treg Cells ◽  
Liver Trauma ◽  
Mice Model ◽  
Gut Flora ◽  
Diabetes In Mice

Objective: Gut microbiota is currently targeted for various diseases especially metabolic disorders such as diabetes. Our strategy is to alter gut microflora via specific antibiotic to reduce load of inflammation in the liver that increases as a result of high carbohydrate diet. Th1, Th17 and Treg are important immune cell types which decide the type of inflammatory response. Liver is tolerogenic in nature with low Th17/Treg ratio. In diabetics, this ratio decreases even more, and can cause liver trauma. Method: The present study tries to find relationship between gut flora and immune cells such as Th1/Th17/Treg and their role in liver metabolism using diet induced diabetic mice model. Result: Upon alteration of flora using Cefdinir in different forms, one could help lower the level of Treg cells thus increasing the ratio. Gut flora is strongly associated with the immunity in the liver. Targeted alteration of gut flora helps us to restore insulin sensitivity. Conclusion: Colon targeted Cefdinir gives more promising results, opens colonic bacteria as target for improving gut, liver inflammation and insulin sensitivity.

155 Low Insulin Sensitivity Is Associated with Increased Body Fat and Changes in Gene Expression of Lipogenic Enzymes in the Adipose Tissue of Finishing Pigs

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 83-84
Author(s):  
Hector H Salgado ◽  
Marie-France Palin ◽  
Hélène Lapierre ◽  
Aline Remus ◽  
Marie-Pierre Letourneau-Montminy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Body Fat ◽  
De Novo ◽  
Mrna Abundance ◽  
De Novo Lipogenesis ◽  
Peroxisome Proliferator ◽  
Lipogenic Enzymes ◽  
Glucose Ingestion

Abstract Variations in body fat (BF) among pigs can be associated with differences in insulin sensitivity given the insulin anabolic effect in lipid synthesis. The study objectives were to characterize this association and compare the relative mRNA abundance of genes associated with insulin resistance and de novo lipogenesis in the adipose tissue of fat and lean pigs. Thirty 95 kg pigs, catheterized in the jugular vein, received an oral dose of 1.75 g glucose/kg of BW after 18 hours of fasting. Blood samples were collected at -20, -10, 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300 and 360 minutes following glucose ingestion. Insulin sensitivity indexes were calculated and analyzed. The BF (%) was estimated by dual X-ray densitometry. The 8 fattest (22 % BF) and the 8 leanest pigs (17.2 % BF) were used to determine the relative mRNA abundance of studied genes using real-time qPCR analyses. Insulin sensitivity was determined using QUICKI and Matsuda indexes, respectively, and their association with body fat was studied with Spearman correlations. Differences in gene expression and insulin sensitivity between fat and lean pigs were studied with a one-way ANOVA. The QUICKI and Matsuda indexes negatively correlated with BF (r = -0.67 and r = -0.59; P &lt; 0.001). Fat pigs had reduced insulin sensitivity and higher relative mRNA abundance of lipogenic enzymes (ACACA, ACLY, FASN; P &lt; 0.05) than lean pigs. The higher expression level of glucose-6-phosphate dehydrogenase (G6PD) combined with the trend (P &lt; 0.10) of lower expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in fat pigs may explain part of their reduced insulin sensitivity. These results suggest that an increased BF is associated with reduced insulin sensitivity and greater expression of lipogenic enzymes in pig adipose tissue.

scholarly journals Fatty Acid Synthase: Association with Insulin Resistance, Type 2 Diabetes, and Cancer

2009 ◽  
Vol 55 (3) ◽  
pp. 425-438 ◽  
Author(s):  
Javier A Menendez ◽  
Alejandro Vazquez-Martin ◽  
Francisco Jose Ortega ◽  
Jose Manuel Fernandez-Real
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Synthase ◽  
Metabolic Diseases ◽  
De Novo ◽  
Genetic Alterations ◽  
Insulin Resistant

Abstract Background: An emerging paradigm supports the notion that deregulation of fatty acid synthase (FASN)-catalyzed de novo FA biogenesis could play a central role in the pathogenesis of metabolic diseases sharing the hallmark of insulin-resistance. Content: We reviewed pharmacological and genetic alterations of FASN activity that have been shown to significantly influence energy expenditure rates, fat mass, insulin sensitivity, and cancer risk. This new paradigm proposes that insulin-resistant conditions such as obesity, type 2 diabetes, and cancer arise from a common FASN-driven “lipogenic state”. An important question then is whether the development or the progression of insulin-related metabolic disorders can be prevented or reversed by the modulation of FASN status. If we accept the paradigm of FASN dysfunction as a previously unrecognized link between insulin resistance, type 2 diabetes, and cancer, the use of insulin sensitizers in parallel with forthcoming FASN inhibitors should be a valuable therapeutic approach that, in association with lifestyle interventions, would concurrently improve energy-flux status, ameliorate insulin sensitivity, and alleviate the risk of lipogenic carcinomas. Conclusions: Although the picture is currently incomplete and researchers in the field have plenty of work ahead, the latest clinical and experimental evidence that we discuss illuminates a functional and drug-modifiable link that connects FASN-driven endogenous FA biosynthesis, insulin action, and glucose homeostasis in the natural history of insulin-resistant pathologies.

scholarly journals Targeted Lipidomics Reveals Associations Between Serum Sphingolipids and Insulin Sensitivity Measured by the Hyperinsulinemic-euglycemic Clamp

2020 ◽  
Author(s):  
Jingya Ye ◽  
Xuan Ye ◽  
Wanzi Jiang ◽  
Chenyan Lu ◽  
Xiaomei Geng ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Metabolic Diseases ◽  
Roc Curves ◽  
Diagnostic Value ◽  
Ionization Mass ◽  
Euglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp ◽  
Obesity And Diabetes ◽  
Insight Into

Abstract BackgroundSPs are a group of ubiquitously produced lipids that are structurally involved in cell membranes and include SMs, ceramides, GM3s, etc. Sphingolipids and their substrates and constituents, FAs, are implicated in the pathogenesis of various metabolic diseases associated with obesity, diabetes, and atherosclerosis. Decreased insulin sensitivity or insulin secretion is a multifactorial condition related to obesity and diabetes. Therefore, it is likely that perturbations in serum SPs are associated with diseases. Identifying these associations may reveal useful predictors or give perceptive insight into disease processes. This study aimed to systematically investigate the associations between serum sphingolipids and insulin sensitivity as well as insulin secretion. This study also aimed to reveal potential predictors for insulin sensitivity or give perceptive insight into disease processes.MethodsWe conducted a lipidomics evaluation of molecularly distinct SPs in the serum of 86 consecutive Chinese adults with or without obesity and diabetes using electrospray ionization mass spectrometry coupled with liquid chromatography. The GIR30 was measured under steady conditions to assess insulin sensitivity by the gold standard hyperinsulinemic-euglycemic clamp, and FPIR was measured to evaluate insulin secretion by the IVGTT. We created the ROC curves to detect the serum SMs diagnostic value and establish the diagnosis of insulin sensitivity based on GIR30 derived from the glucose clamp, which is the standard method, and the cutoff point of GIR30 was set as 5.1 mg/(kg *min).ResultsDifferential correlation network analysis illustrated correlations amongst lipids, insulin sensitivity, insulin secretion and other clinical indexes. Total and subspecies of serum SMs and globotriaosylceramides (Gb3s) were positively related to GIR30, free FAs (FFA 16:1, FFA20:4), some long chain GM3 and complex ceramide GluCers showed strong negative correlations with GIR30. We also found that higher concentrations of serum free FAs (FFA 22:6, FFA 22:5, FFA 18:2, FFA 18:1) were associated with a higher risk of decreased insulin secretion. Notably, ROC curves showed that SM/Cer and SM d18:0/26:0 may be good serum lipid predictors of diagnostic indicators of insulin sensitivity close to conventional clinical indexes such as 1/HOMA-IR (all areas under the curve >0.80) based on GIR30 as standard diagnostic criteria. ConclusionsThese results provide novel associations between serum sphingolipid between insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. This suggests that the balance of SMs metabolism, rather than ceramide is correlated with the pathology of insulin resistance, obesity and T2DM. We further identify two specific SPs that may represent prognostic biomarkers for insulin sensitivity.

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