scholarly journals An impaired gut immune response to a high‐fat diet is associated with visceral adipose inflammation and peripheral insulin resistance in leptin‐deficient mice

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Sin Hoa Gieng ◽  
Aria Eshraghi ◽  
Elizabeth Hawley ◽  
Patrick Sanger ◽  
Julia Menshenina ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Immune Response ◽  
High Fat Diet ◽  
High Fat ◽  
Peripheral Insulin Resistance ◽  
Adipose Inflammation ◽  
Visceral Adipose ◽  
Deficient Mice

scholarly journals Estrogens Protect against High-Fat Diet-Induced Insulin Resistance and Glucose Intolerance in Mice

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2109-2117 ◽  
Author(s):  
Elodie Riant ◽  
Aurélie Waget ◽  
Haude Cogo ◽  
Jean-François Arnal ◽  
Rémy Burcelin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Chow Diet ◽  
High Fat ◽  
Normal Chow ◽  
Visceral Adipose ◽  
Deficient Mice ◽  
Normal Chow Diet

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor α (ERα), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17β-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERα-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-α) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERα-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERα pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

scholarly journals 12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response

2012 ◽  
Vol 302 (6) ◽  
pp. E654-E665 ◽  
Author(s):  
Banumathi K. Cole ◽  
Norine S. Kuhn ◽  
Shamina M. Green-Mitchell ◽  
Kendall A. Leone ◽  
Rebekah M. Raab ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Pancreatic Islets ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Stress Markers ◽  
Deficient Mice

Central obesity is associated with chronic inflammation, insulin resistance, β-cell dysfunction, and endoplasmic reticulum (ER) stress. The 12/15-lipoxygenase enzyme (12/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12/15-LO is expressed in adipose tissue, we determined whether 12/15-LO could mediate ER stress signals. Addition of 12/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1α. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12/15-LO activation. Addition of a 12/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12/15-LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12/15-LO-deficient mice fed a high-fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12/15-LO-deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12/15-LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity.

scholarly journals CXCL12-CXCR4 pathway activates brown adipocytes and induces insulin resistance in CXCR4-deficient mice under high-fat diet

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kenichi Kurita ◽  
Ko Ishikawa ◽  
Kenji Takeda ◽  
Masanori Fujimoto ◽  
Hiraku Ono ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
High Fat ◽  
Brown Adipocytes ◽  
Deficient Mice

scholarly journals Effects of Maternal Resveratrol on Maternal High-Fat Diet/Obesity with or without Postnatal High-Fat Diet

2020 ◽  
Vol 21 (10) ◽  
pp. 3428 ◽  
Author(s):  
Mei-Hsin Hsu ◽  
Jiunn-Ming Sheen ◽  
I-Chun Lin ◽  
Hong-Ren Yu ◽  
Mao-Meng Tiao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Cognitive Impairment ◽  
Adult Male ◽  
High Fat Diet ◽  
Dorsal Hippocampus ◽  
Fetal Brain ◽  
Male Offspring ◽  
High Fat ◽  
Peripheral Insulin Resistance

To examine the effects of maternal resveratrol in rats borne to dams with gestational high-fat diet (HFD)/obesity with or without postnatal high-fat diet. We first tested the effects of maternal resveratrol intake on placenta and male fetus brain in rats borne to dams with gestational HFD/obesity. Then, we assessed the possible priming effect of a subsequent insult, male offspring were weaned onto either a rat chow or a HFD. Spatial learning and memory were assessed by Morris water maze test. Blood pressure and peripheral insulin resistance were examined. Maternal HFD/obesity decreased adiponectin, phosphorylation alpha serine/threonine-protein kinase (pAKT), sirtuin 1 (SIRT1), and brain-derived neurotrophic factor (BDNF) in rat placenta, male fetal brain, and adult male offspring dorsal hippocampus. Maternal resveratrol treatment restored adiponectin, pAKT, and BDNF in fetal brain. It also reduced body weight, peripheral insulin resistance, increased blood pressure, and alleviated cognitive impairment in adult male offspring with combined maternal HFD and postnatal HFD. Maternal resveratrol treatment restored hippocampal pAKT and BDNF in rats with combined maternal HFD and postnatal HFD in adult male offspring dorsal hippocampus. Maternal resveratrol intake protects the fetal brain in the context of maternal HFD/obesity. It effectively reduced the synergistic effects of maternal HFD/obesity and postnatal HFD on metabolic disturbances and cognitive impairment in adult male offspring. Our data suggest that maternal resveratrol intake may serve as an effective therapeutic strategy in the context of maternal HFD/obesity.

Impaired Insulin Resistance in IF1-Deficient Mice Subjected to a High-Fat Diet with Reduced-Fat Mass and Skeletal Muscle Lipid Accumulation

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1748-P ◽  
Author(s):  
FENGYUAN HUANG ◽  
KEVIN YANG ◽  
KAMALAMMA SAJA ◽  
YICHENG HUANG ◽  
QINGQIANG LONG ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
High Fat ◽  
Muscle Lipid ◽  
Reduced Fat ◽  
Impaired Insulin ◽  
Skeletal Muscle Lipid ◽  
Deficient Mice

scholarly journals Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor

2014 ◽  
Vol 307 (3) ◽  
pp. E305-E315 ◽  
Author(s):  
Chongben Zhang ◽  
Daniel E. Cooper ◽  
Trisha J. Grevengoed ◽  
Lei O. Li ◽  
Eric L. Klett ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Glycogen Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
Lipid Signal ◽  
Mouse Hepatocytes ◽  
Triacylglycerol Accumulation ◽  
Deficient Mice

Glycerol-3-phosphate acyltransferase (GPAT) activity is highly induced in obese individuals with insulin resistance, suggesting a correlation between GPAT function, triacylglycerol accumulation, and insulin resistance. We asked whether microsomal GPAT4, an isoform regulated by insulin, might contribute to the development of hepatic insulin resistance. Compared with control mice fed a high fat diet, Gpat4 −/− mice were more glucose tolerant and were protected from insulin resistance. Overexpression of GPAT4 in mouse hepatocytes impaired insulin-suppressed gluconeogenesis and insulin-stimulated glycogen synthesis. Impaired glucose homeostasis was coupled to inhibited insulin-stimulated phosphorylation of Akt(Ser473) and Akt(Thr308). GPAT4 overexpression inhibited rictor's association with the mammalian target of rapamycin (mTOR), and mTOR complex 2 (mTORC2) activity. Compared with overexpressed GPAT3 in mouse hepatocytes, GPAT4 overexpression increased phosphatidic acid (PA), especially di16:0-PA. Conversely, in Gpat4 −/− hepatocytes, both mTOR/rictor association and mTORC2 activity increased, and the content of PA in Gpat4 −/− hepatocytes was lower than in controls, with the greatest decrease in 16:0-PA species. Compared with controls, liver and skeletal muscle from Gpat4 −/−-deficient mice fed a high-fat diet were more insulin sensitive and had a lower hepatic content of di16:0-PA. Taken together, these data demonstrate that a GPAT4-derived lipid signal, likely di16:0-PA, impairs insulin signaling in mouse liver and contributes to hepatic insulin resistance.

scholarly journals Role of Muscle c-Jun NH2-Terminal Kinase 1 in Obesity-Induced Insulin Resistance

2009 ◽  
Vol 30 (1) ◽  
pp. 106-115 ◽  
Author(s):  
Guadalupe Sabio ◽  
Norman J. Kennedy ◽  
Julie Cavanagh-Kyros ◽  
Dae Young Jung ◽  
Hwi Jin Ko ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Akt Activation ◽  
Peripheral Insulin Resistance ◽  
Diet Induced Obesity

ABSTRACT Obesity caused by feeding of a high-fat diet (HFD) is associated with an increased activation of c-Jun NH2-terminal kinase 1 (JNK1). Activated JNK1 is implicated in the mechanism of obesity-induced insulin resistance and the development of metabolic syndrome and type 2 diabetes. Significantly, Jnk1 − / − mice are protected against HFD-induced obesity and insulin resistance. Here we show that an ablation of the Jnk1 gene in skeletal muscle does not influence HFD-induced obesity. However, muscle-specific JNK1-deficient (MKO) mice exhibit improved insulin sensitivity compared with control wild-type (MWT) mice. Thus, insulin-stimulated AKT activation is suppressed in muscle, liver, and adipose tissue of HFD-fed MWT mice but is suppressed only in the liver and adipose tissue of MKO mice. These data demonstrate that JNK1 in muscle contributes to peripheral insulin resistance in response to diet-induced obesity.

scholarly journals Endothelin-1 Receptor A Blockade Attenuates Metabolic and Proinflammatory Profile in Mice Fed a High Fat Diet

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A41-A42
Author(s):  
Osvaldo Rivera-Gonzalez ◽  
Erin Taylor ◽  
Joshua S Speed
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
High Fat Diet ◽  
Immune Cell ◽  
Ppar Gamma ◽  
High Fat ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Visceral Adipose

Abstract Endothelin-1 (ET-1) is elevated in patients with obesity; however, its contribution to the pathophysiology related to obesity is not fully understood. Obesity is associated with dyslipidemia and insulin resistance, which may in part be mediated by inflammation and alterations to immune cell subsets within the adipose tissue. ET-1 promotes inflammation via the ET-1 type A (ETA) receptor, and blockade of ETA receptors improves dyslipidemia in patients with chronic kidney disease. We hypothesized that ET-1 causes dyslipidemia and inflammation within the adipose tissue of obese mice. To test this hypothesis, C57BL/6J mice were fed either normal diet (NMD) or high fat diet (HFD) for 8 weeks followed by 2 weeks of treatment with either vehicle or atrasentan (ETA receptor antagonist, 10mg/kg/day). HFD mice had significantly higher fat mass than NMD mice, with no significant effect of treatment with atrasentan. HFD mice had significantly higher circulating non-esterified free fatty acids, an effect that was ameliorated in mice treated with atrasentran (1.03±0.07 vs 0.58±0.02 mEq/L, p<0.05). Atrasentan-treated mice had significantly attenuated increase in liver triglycerides compared to non-treated HFD mice (3.8±0.7 vs 7.5±1.3mg/dL respectively, p<0.05). Mice treated with atrasentan had significantly improved glucose tolerance (10150±1031 vs 6563±975 AUC, p<0.05) and insulin tolerance (-2796±386 vs -9825±319 AUC, p<0.05) compared to non-treated insulin-resistant HFD mice. Plasma adiponectin, an insulin sensitizing adipokine that is inversely associated with adiposity and insulin resistance, was significantly increased in atrasentan-treated mice compared to non-treated HFD (4.8±0.1326 vs 6.5±0.3 µg/ml, p<0.05), with no differences in plasma insulin levels. Gene expression analysis of visceral fat showed improved expression of genes negatively associated with insulin resistance that were downregulated in non-treated HFD mice vs. NMD (IRS-1, PPAR-gamma, GLUT4, and adiponectin). Flow cytometric analyses of visceral adipose tissue indicated that HFD mice had a significantly higher number of both CD4+ and CD8+ T cells compared to NMD mice, which was attenuated by treatment with atrasentan. Further, eosinophils, which are important in maintaining adipose tissue health and reducing inflammation, were significantly decreased in HFD mice compared to NMD. Atrasentan treatment abolished the decrease in eosinophils. Taken together, these data indicate that ETA receptor blockade improves peripheral glucose homeostasis, dyslipidemia, and liver triglyceride levels, and also attenuates the proinflammatory immune profile in visceral adipose tissue. These data suggest a potential use for ETA receptor blockers in the treatment of obesity-associated dyslipidemia and insulin resistance.

scholarly journals Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet

Diabetologia ◽  
2010 ◽  
Vol 53 (8) ◽  
pp. 1795-1806 ◽  
Author(s):  
J. A. Ehses ◽  
D. T. Meier ◽  
S. Wueest ◽  
J. Rytka ◽  
S. Boller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Beta Cell ◽  
High Fat Diet ◽  
Beta Cell Dysfunction ◽  
Toll Like Receptor ◽  
High Fat ◽  
Cell Dysfunction ◽  
Toll Like Receptor 2 ◽  
Deficient Mice
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