miR-146a regulates insulin sensitivity via NPR3

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.

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TLR4/AP-1-Targeted Anti-Inflammatory Intervention Attenuates Insulin Sensitivity and Liver Steatosis

Mediators of Inflammation ◽

10.1155/2020/2960517 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Xiang Hu ◽

Jing Zhou ◽

Sha-sha Song ◽

Wen Kong ◽

Yan-Chuan Shi ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Signaling Pathway ◽

High Fat Diet ◽

Macrophage Polarization ◽

Liver Steatosis ◽

Lipid Deposition ◽

Sirna Transfection ◽

High Fat ◽

Metabolic Inflammation

Insulin resistance has been shown to be the common pathogenesis of many metabolic diseases. Metainflammation is one of the important characteristics of insulin resistance. Macrophage polarization mediates the production and development of metainflammation. Toll-like receptor 4 (TLR4) mediates macrophage activity and is probably the intersection of immunity and metabolism, but the detailed mechanism is probably not fully understood. Activated protein 1 (AP1) signaling pathway is very important in macrophage activation-mediated inflammation. However, it is unclear whether AP1 signaling pathway mediates metabolic inflammation in the liver. We aimed to investigate the effects of macrophage TLR4-AP1 signaling pathway on hepatocyte metabolic inflammation, insulin sensitivity, and lipid deposition, as well as to explore the potential of TLR4-AP1 as new intervention targets of insulin resistance and liver steatosis. TLR4 and AP1 were silenced in the RAW264.7 cells by lentiviral siRNA transfection. In vivo transduction of lentivirus was administered in mice fed with high-fat diet. Insulin sensitivity and inflammation were evaluated in the treated cells or animals. Our results indicated that TLR4/AP-1 siRNA transfection alleviated high-fat diet-induced systemic and hepatic inflammation, obesity, and insulin resistance in mice. Additionally, TLR4/AP-1 siRNA transfection mitigated palmitic acid- (PA-) induced inflammation in RAW264.7 cells and metabolic abnormalities in cocultured AML hepatocytes. Herein, we propose that TLR4-AP1 signaling pathway activation plays a crucial role in high fat- or PA-induced metabolic inflammation and insulin resistance in hepatocytes. Intervention of the TLR4 expression regulates macrophage polarization and metabolic inflammation and further alleviates insulin resistance and lipid deposition in hepatocytes.

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4-Hydroxyisoleucine Alleviates Macrophage-Related Chronic Inflammation and Metabolic Syndrome in Mice Fed a High-Fat Diet

Frontiers in Pharmacology ◽

10.3389/fphar.2020.606514 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jiali Yang ◽

Yunhui Ran ◽

Yonghui Yang ◽

Shuyi Song ◽

Yahong Wu ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Chronic Inflammation ◽

Immune Cells ◽

High Fat Diet ◽

Liver Steatosis ◽

High Fat ◽

Protein Amino Acid

In obesity, macrophages and other immune cells accumulate in organs affected by insulin, leading to chronic inflammation and insulin resistance. 4-Hydroxyisoleucine (4-HIL) is a non-protein amino acid found in fenugreek seeds. 4-HIL enhances insulin sensitivity, but its mechanism is still unclear. In this study, 4-HIL intervention reduced weight gain, liver steatosis, and dyslipidemia; moreover, it increased systemic insulin sensitivity and improved insulin resistance in mice. Importantly, after administration, the accumulation of M1 like CD11c+ macrophages and inflammation in the liver and adipose tissue were reduced in the mice. 4-HIL also reduced the proportion of CD11c+ macrophages among bone marrow-derived macrophages, which were induced in vitro. These observations demonstrate a new role of 4-HIL in insulin resistance in hepatocytes and adipocytes. 4-HIL inhibits obesity-related insulin resistance by reducing inflammation and regulating the state of M1/M2 macrophages.

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Dietary Glycotoxins Impair Hepatic Lipidemic Profile in Diet-Induced Obese Rats Causing Hepatic Oxidative Stress and Insulin Resistance

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6362910 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

C. Neves ◽

T. Rodrigues ◽

J. Sereno ◽

C. Simões ◽

J. Castelhano ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Fatty Acid ◽

High Fat Diet ◽

De Novo ◽

Liver Lipid ◽

Lipid Fraction ◽

De Novo Lipogenesis ◽

High Fat ◽

Obese Rats

Nonalcoholic fatty liver disease (NAFLD) is caused by excessive liver lipid accumulation, but insulin resistance is specifically associated with impaired lipid saturation, oxidation, and storage (esterification), besides increased de novo lipogenesis. We hypothesized that dietary glycotoxins could impair hepatic lipid metabolism in obesity contributing to lipotoxicity-driven insulin resistance and thus to the onset of nonalcoholic steatohepatitis (NASH). In diet-induced obese rats with methylglyoxal-induced glycation, magnetic resonance spectroscopy, mass spectrometry, and gas chromatography were used to assess liver composition in fatty acyl chains and phospholipids. High-fat diet-induced obesity increased liver lipid fraction and suppressed de novo lipogenesis but did not change fatty acid esterification and saturation or insulin sensitivity. Despite a similar increase in total lipid fraction when supplementing the high-fat diet with dietary glycotoxins, impairment in the suppression of de novo lipogenesis and decreased fatty acid unsaturation and esterification were observed. Moreover, glycotoxins also decreased polyunsaturated cardiolipins and caused oxidative stress, portal inflammation, and insulin resistance in high-fat diet-induced obese rats. Dietary glycated products do not change total lipid levels in the liver of obese rats but dramatically modify the lipidemic profile, leading to oxidative stress, hepatic lipotoxicity, and insulin resistance in obesity and thus contribute to the onset of NASH.

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Beneficial effects of rosuvastatin on insulin resistance, adiposity, inflammatory markers and non-alcoholic fatty liver disease in mice fed on a high-fat diet

Clinical Science ◽

10.1042/cs20110373 ◽

2012 ◽

Vol 123 (4) ◽

pp. 259-270 ◽

Cited By ~ 45

Author(s):

Julio Cesar Fraulob ◽

Vanessa Souza-Mello ◽

Marcia Barbosa Aguila ◽

Carlos Alberto Mandarim-de-Lacerda

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

High Fat Diet ◽

Plasma Cholesterol ◽

Regulatory Element ◽

Liver Steatosis ◽

Resistance Index ◽

Model Assessment ◽

High Fat ◽

Alcoholic Fatty Liver

The aim of the present study was to evaluate the effects of ST (rosuvastatin) and GZ (rosiglitazone) on IR (insulin resistance) and on liver as well as adipose tissue in mice fed on an HF (high-fat) diet. Our data show that treatment with ST resulted in a marked improvement in insulin sensitivity characterized by enhanced glucose clearance during the insulin tolerance test and a 70% decrease in the HOMA-IR (homoeostasis model assessment of insulin resistance) index level (P=0.0008). The ST-treated mice exhibited lower gains in BM (body mass; −8%; P<0.01) and visceral fat pad thickness (−60%; P<0.01) compared with the untreated HF group. In comparison with HF-diet-fed mice, HF+ST-treated mice showed a significant reduction in hepatomegaly and liver steatosis (−6%, P<0.05; and −21%, P<0.01 respectively). In HF+ST-treated mice, the hepatic TAG (triacylglycerol) levels were reduced by 58% compared with the HF group (P<0.01). In addition, the expression of SREBP-1c (sterol-regulatory-element-binding protein-1c) was decreased by 50% in the livers of HF+ST-treated mice (P<0.01) relative to the HF-diet-fed mice. The levels of resistin were lower in the HF+ST-treated group compared with the HF group (44% less, P< 0.01). In conclusion, we demonstrated that ST treatment improved insulin sensitivity and decreased liver steatosis in mice fed on an HF diet. Furthermore, ST reduced BM gains, improved the circulating levels of plasma cholesterol and TAG, and reduced hepatic TAG, which was concomitant with lower resistin levels.

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TNFSF14-Derived Molecules as a Novel Treatment for Obesity and Type 2 Diabetes

International Journal of Molecular Sciences ◽

10.3390/ijms221910647 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10647

Author(s):

Mark Agostino ◽

Jennifer Rooney ◽

Lakshini Herat ◽

Jennifer Matthews ◽

Allyson Simonds ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Glucose Intolerance ◽

High Fat Diet ◽

Metabolic Diseases ◽

Liver Steatosis ◽

Western World ◽

Acid Oxidation ◽

High Fat

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with glucose intolerance and insulin resistance, often culminating in Type 2 diabetes (T2D). Importantly, our team has recently shown that the TNF superfamily (TNFSF) member protein, TNFSF14, has been reported to protect against high fat diet induced obesity and pre-diabetes. We hypothesized that mimics of TNFSF14 may therefore be valuable as anti-diabetic agents. In this study, we use in silico approaches to identify key regions of TNFSF14 responsible for binding to the Herpes virus entry mediator and Lymphotoxin β receptor. In vitro evaluation of a selection of optimised peptides identified six potentially therapeutic TNFSF14 peptides. We report that these peptides increased insulin and fatty acid oxidation signalling in skeletal muscle cells. We then selected one of these promising peptides to determine the efficacy to promote metabolic benefits in vivo. Importantly, the TNFSF14 peptide 7 reduced high fat diet-induced glucose intolerance, insulin resistance and hyperinsulinemia in a mouse model of obesity. In addition, we highlight that the TNFSF14 peptide 7 resulted in a marked reduction in liver steatosis and a concomitant increase in phospho-AMPK signalling. We conclude that TNFSF14-derived molecules positively regulate glucose homeostasis and lipid metabolism and may therefore open a completely novel therapeutic pathway for treating obesity and T2D.

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Amelioration of Hepatic Steatosis in Mice through Bacteroides uniformis CBA7346-Mediated Regulation of High-Fat Diet-Induced Insulin Resistance and Lipogenesis

Nutrients ◽

10.3390/nu13092989 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2989

Author(s):

Hye-Bin Lee ◽

Moon-Ho Do ◽

Hyunjhung Jhun ◽

Sang-Keun Ha ◽

Hye-Seon Song ◽

...

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

High Fat Diet ◽

Fatty Liver Disease ◽

De Novo ◽

De Novo Lipogenesis ◽

Model Assessment ◽

High Fat ◽

Alcoholic Fatty Liver

Dietary habits and gut microbiota play an essential role in non-alcoholic fatty liver disease (NAFLD) and related factors such as insulin resistance and de novo lipogenesis. In this study, we investigated the protective effects of Bacteroides uniformis CBA7346, isolated from the gut of healthy Koreans, on mice with high-fat diet (HFD)-induced NAFLD. Administration of B. uniformis CBA7346 reduced body and liver weight gain, serum alanine aminotransferase and aspartate aminotransferase levels, liver steatosis, and liver triglyceride levels in mice on an HFD; the strain also decreased homeostatic model assessment for insulin resistance values, as well as serum cholesterol, triglyceride, lipopolysaccharide, leptin, and adiponectin levels in mice on an HFD. Moreover, B. uniformis CBA7346 controlled fatty liver disease by attenuating steatosis and inflammation and regulating de novo lipogenesis-related proteins in mice on an HFD. Taken together, these findings suggest that B. uniformis CBA7346 ameliorates HFD-induced NAFLD by reducing insulin resistance and regulating de novo lipogenesis in obese mice.

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Impaired adipose expansion caused by liver X receptor activation is associated with insulin resistance in mice fed a high-fat diet

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0196 ◽

2017 ◽

Vol 58 (3) ◽

pp. 141-154 ◽

Cited By ~ 5

Author(s):

Yueting Dong ◽

Zhiye Xu ◽

Ziyi Zhang ◽

Xueyao Yin ◽

Xihua Lin ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

High Fat Diet ◽

Insulin Response ◽

Receptor Activation ◽

Metabolic Effects ◽

Whole Body ◽

High Fat ◽

Epididymal Fat

Liver X receptors (LXR) are deemed as potential drug targets for atherosclerosis, whereas a role in adipose tissue expansion and its relation to insulin sensitivity remains unclear. To assess the metabolic effects of LXR activation by the dual LXRα/β agonist T0901317, C57BL/6 mice fed a high-fat diet (HFD) were treated with T0901317 (30 mg/kg once daily by intraperitoneal injection) for 3 weeks. Differentiated 3T3-L1 adipocytes were used for analysing the effect of T0901317 on glucose uptake. The following results were obtained from this study. T0901317 reduced fat mass, accompanied by a massive fatty liver and lower serum adipokine levels in HFD mice. Increased adipocyte apoptosis was found in epididymal fat of T0901317-treated HFD mice. In addition, T0901317 treatment promoted basal lipolysis, but blunted the anti-lipolytic action of insulin. Furthermore, LXR activation antagonised PPARγ target genes in epididymal fat and PPARγ-PPRE-binding activity in 3T3-L1 adipocytes. Although the glucose tolerance was comparable to that in HFD mice, the insulin response during IPGTT was significantly higher and the insulin tolerance was significantly impaired in T0901317-treated HFD mice, indicating decreased insulin sensitivity by T0901317 administration, and which was further supported by impaired insulin signalling found in epididymal fat and decreased insulin-induced glucose uptake in 3T3-L1 adipocytes by T0901317 administration. In conclusion, these findings reveal that LXR activation impairs adipose expansion by increasing adipocyte apoptosis, lipolysis and antagonising PPARγ-mediated transcriptional activity, which contributes to decreased insulin sensitivity in whole body. The potential of LXR activation being a therapeutic target for atherosclerosis might be limited by the possibility of exacerbating insulin resistance.

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Time course of insulin resistance associated with feeding dogs a high-fat diet

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.272.1.e147 ◽

1997 ◽

Vol 272 (1) ◽

pp. E147-E154 ◽

Cited By ~ 13

Author(s):

A. P. Rocchini ◽

P. Marker ◽

T. Cervenka

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Glucose Uptake ◽

Dose Response ◽

High Fat Diet ◽

Time Course ◽

Rapid Development ◽

Diet Group ◽

Whole Body ◽

High Fat

The current study evaluated both the time course of insulin resistance associated with feeding dogs a high-fat diet and the relationship between the development of insulin resistance and the increase in blood pressure that also occurs. Twelve adult mongrel dogs were chronically instrumented and randomly assigned to either a control diet group (n = 4) or a high-fat diet group (n = 8). Insulin resistance was assessed by a weekly, single-dose (2 mU.kg-1.min-1) euglycemic-hyperinsulinemic clamp on all dogs. Feeding dogs a high-fat diet was associated with a 3.7 +/- 0.5 kg increase in body weight, a 20 +/- 4 mmHg increase in mean blood pressure, a reduction in insulin-mediated glucose uptake [(in mumol-kg-1.min-1) decreasing from 72 +/- 6 before to 49 +/- 7 at 1 wk, 29 +/- 3 at 3 wk, and 30 +/- 2 at 6 wk of the high-fat diet, P < 0.01]. and a reduced insulin-mediated increase in cardiac output. In eight dogs (4 high fat and 4 control), the dose-response relationship of insulin-induced glucose uptake also was studied. The whole body glucose uptake dose-response curve was shifted to the right, and the rate of maximal whole body glucose uptake was significantly decreased (P < 0.001). Finally, we observed a direct relationship between the high-fat diet-induced weekly increase in mean arterial pressure and the degree to which insulin resistance developed. In summary, the current study documents that feeding dogs a high-fat diet causes the rapid development of insulin resistance that is the result of both a reduced sensitivity and a reduced responsiveness to insulin.

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Black rice anthocyanins alleviate hyperlipidemia, liver steatosis and insulin resistance by regulating lipid metabolism and gut microbiota in obese mice

Food & Function ◽

10.1039/d1fo01394g ◽

2021 ◽

Author(s):

Haizhao Song ◽

Xinchun Shen ◽

Yang Zhou ◽

Xiaodong Zheng

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Gut Microbiota ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Liver Steatosis ◽

Obese Mice ◽

Black Rice ◽

High Fat ◽

Diet Induced Obesity

Supplementation of black rice anthocyanins (BRAN) alleviated high fat diet-induced obesity, insulin resistance and hepatic steatosis by improvement of lipid metabolism and modification of the gut microbiota.

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Abstract 15813: Loss-of-Function Mutation in Toll-Like Receptor 4 Partially Protects Against Peripheral and Cardiac Insulin Resistance During a Long-Term High-Fat Diet

Circulation ◽

10.1161/circ.130.suppl_2.15813 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Ellen Jackson ◽

Elizabeth Rendina-Ruedy ◽

Matt Priest ◽

Brenda Smith ◽

Veronique Lacombe

Keyword(s):

Insulin Resistance ◽

Protein Content ◽

Glucose Transport ◽

High Fat Diet ◽

Whole Body ◽

Toll Like Receptor ◽

Loss Of Function ◽

High Fat ◽

The Face ◽

Tlr4 Activation

Diabetes mellitus is an epidemic disease characterized by alterations in glucose transport, which is tightly regulated by a family of specialized proteins called the glucose transporters (GLUTs). Although diabetic cardiomyopathy is a common complication in diabetic patients, its pathogenesis is still not well understood. Toll-like receptor (TLR) 4, which plays a central role in pathogen recognition by the innate immune system, may also play a critical role in linking inflammation and metabolic disease. We hypothesized that TLR4 activation triggers cardiac insulin resistance. We used mice with a loss-of function mutation in TLR4 (C3H/HeJ) and age-matched wild-type (WT, C57BL/6N) mice (n=8/group) to investigate how feeding a high-fat diet (HFD, 60% kcal from fat) for 16 weeks affected whole-body and cardiac glucose metabolism. After 16 weeks, WT mice fed a HFD were obese and developed hyperglycemia and insulin resistance compared to WT mice on a control diet (10% kcal from fat). The C3H/HeJ mice were partially protected against HFD-induced obesity and insulin resistance. In the heart, WT mice fed a HFD had a 30% decrease (P<0.05) in GLUT4 protein content as measured by Western Blot of cardiac crude membrane protein extracts. In contrast, the loss-of-function point mutation in TLR4 partially rescued cardiac GLUT4 content in the face of a HFD. Interestingly, there was a 40% increase (P<0.05) in the novel GLUT isoform, GLUT8, in the heart when mice of either genotype were fed a HFD. Additionally, GLUT4 protein content was negatively (P<0.05) correlated with GLUT8 content in the myocardium, suggesting that GLUT8 may act as a compensatory mechanism in the face of HFD-induced GLUT4 downregulation. Phosphorylated Akt, a key protein of the insulin signaling pathway, was positively (P<0.05) correlated with GLUT4 content, while the basal/inactive form was negatively correlated. In conclusion, these data suggest that activation of TLR4 activation during diabetes and obesity alters glucose transport by an Akt mechanism, and as such is a pathogenic factor during peripheral and cardiac insulin resistance. Overall, TLR4 appears to be a key modulator in the cross-talk between inflammatory and metabolic pathways, as well as a potential therapeutic target for diabetes.

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