scholarly journals Muscle-Specific Pten Deletion Protects against Insulin Resistance and Diabetes

2005 ◽  
Vol 25 (3) ◽  
pp. 1135-1145 ◽  
Author(s):  
Nadeeja Wijesekara ◽  
Daniel Konrad ◽  
Mohamed Eweida ◽  
Craig Jefferies ◽  
Nicole Liadis ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Negative Regulator ◽  
Whole Body ◽  
High Fat ◽  
Akt Phosphorylation ◽  
Dual Specificity ◽  
Pten Deletion ◽  
Insulin Dependent ◽  
Phosphoinositide 3 Kinase ◽  
Fat Feeding

ABSTRACT Pten (phosphatase with tensin homology), a dual-specificity phosphatase, is a negative regulator of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Pten regulates a vast array of biological functions including growth, metabolism, and longevity. Although the PI3K/Akt pathway is a key determinant of the insulin-dependent increase in glucose uptake into muscle and adipose cells, the contribution of this pathway in muscle to whole-body glucose homeostasis is unclear. Here we show that muscle-specific deletion of Pten protected mice from insulin resistance and diabetes caused by high-fat feeding. Deletion of muscle Pten resulted in enhanced insulin-stimulated 2-deoxyglucose uptake and Akt phosphorylation in soleus but, surprisingly, not in extensor digitorum longus muscle compared to littermate controls upon high-fat feeding, and these mice were spared from developing hyperinsulinemia and islet hyperplasia. Muscle Pten may be a potential target for treatment or prevention of insulin resistance and diabetes.

scholarly journals Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα-deficient mice

2010 ◽  
Vol 298 (2) ◽  
pp. E304-E319 ◽  
Author(s):  
Vicent Ribas ◽  
M. T. Audrey Nguyen ◽  
Darren C. Henstridge ◽  
Anh-Khoi Nguyen ◽  
Simon W. Beaven ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Whole Body ◽  
High Fat ◽  
Estrogen Action ◽  
Skeletal Muscle Insulin Resistance ◽  
The Metabolic Syndrome ◽  
Normal Chow ◽  
Fat Feeding ◽  
Deficient Mice ◽  
Pai 1

Impaired estrogen action is associated with the metabolic syndrome in humans. We sought to determine whether impaired estrogen action in female C57Bl6 mice, produced by whole body Esr1 ablation, could recapitulate aspects of this syndrome, including inflammation, insulin resistance, and obesity. Indeed, we found that global knockout (KO) of the estrogen receptor (ER)α leads to reduced oxygen uptake and caloric expenditure compared with wild-type (WT) mice. In addition, fasting insulin, leptin, and PAI-1 levels were markedly elevated, whereas adiponectin levels were reduced in normal chow-fed KO. Furthermore, ERα-KO mice exhibited impaired glucose tolerance and marked skeletal muscle insulin resistance that was accompanied by the accumulation of bioactive lipid intermediates, inflammation, and diminished PPARα, PPARδ, and UCP2 transcript levels. Although the relative glucose intolerance and insulin resistance phenotype in KO mice became more severe with high-fat feeding, WT mice were refractory to these dietary-induced effects, and this protection coincided with a marked increase in circulating adiponectin and heat shock protein 72 levels in muscle, liver, and fat. These data indicate that ERα is critical for the maintenance of whole body insulin action and protection against tissue inflammation during both normal chow and high-fat feeding.

Analysis of the liver lipidome reveals insights into the protective effect of exercise on high-fat diet-induced hepatosteatosis in mice

2015 ◽  
Vol 308 (9) ◽  
pp. E778-E791 ◽  
Author(s):  
Andreas B. Jordy ◽  
Michael J. Kraakman ◽  
Tim Gardner ◽  
Emma Estevez ◽  
Helene L. Kammoun ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Membrane Integrity ◽  
Treadmill Running ◽  
Whole Body ◽  
Oral Glucose ◽  
High Fat ◽  
Lipid Species ◽  
Fat Feeding

The accumulation of lipid at ectopic sites, including the skeletal muscle and liver, is a common consequence of obesity and is associated with tissue-specific and whole body insulin resistance. Exercise is well known to improve insulin resistance by mechanisms not completely understood. We performed lipidomic profiling via mass spectrometry in liver and skeletal muscle samples from exercise-trained mice to decipher the lipid changes associated with exercise-induced improvements in whole body glucose metabolism. Obesity and insulin resistance were induced in C57BL/6J mice by high-fat feeding for 4 wk. Mice then underwent an exercise training program (treadmill running) 5 days/wk (Ex) for 4 wk or remained sedentary (Sed). Compared with Sed, Ex displayed improved ( P < 0.01) whole body metabolism as measured via an oral glucose tolerance test. Deleterious lipid species such as diacylglycerol ( P < 0.05) and cholesterol esters ( P < 0.01) that accumulate with high-fat feeding were decreased in the liver of trained mice. Furthermore, the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) (the PC/PE ratio), which is associated with membrane integrity and linked to hepatic disease progression, was increased by training ( P < 0.05). These findings occurred without corresponding changes in the skeletal muscle lipidome. A concomitant decrease ( P < 0.05) was observed for the fatty acid transporters CD36 and FATP4 in the liver, suggesting that exercise stimulates a coordinated reduction in fatty acid entry into hepatocytes. Given the important role of the liver in the regulation of whole body glucose homeostasis, hepatic lipid regression may be a key component by which exercise can improve metabolism.

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

1997 ◽  
Vol 272 (1) ◽  
pp. E147-E154 ◽  
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.

High-fat Feeding Causes Inflammation and Insulin Resistance in the Ventral Tegmental Area in Mice

Neuroscience ◽  
2021 ◽  
Vol 461 ◽  
pp. 72-79
Author(s):  
Akira Mizoguchi ◽  
Ryoichi Banno ◽  
Runan Sun ◽  
Hiroshi Yaginuma ◽  
Keigo Taki ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Ventral Tegmental Area ◽  
High Fat ◽  
Ventral Tegmental ◽  
Fat Feeding

scholarly journals Na+-sensitive elevation in blood pressure is ENaC independent in diet-induced obesity and insulin resistance

2016 ◽  
Vol 310 (9) ◽  
pp. F812-F820 ◽  
Author(s):  
Jonathan M. Nizar ◽  
Wuxing Dong ◽  
Robert B. McClellan ◽  
Mariana Labarca ◽  
Yuehan Zhou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Elevated Blood Pressure ◽  
Elevated Blood ◽  
High Fat ◽  
Electrolyte Excretion ◽  
Diet Induced Obesity ◽  
Collecting Ducts ◽  
Fat Feeding

The majority of patients with obesity, insulin resistance, and metabolic syndrome have hypertension, but the mechanisms of hypertension are poorly understood. In these patients, impaired sodium excretion is critical for the genesis of Na+-sensitive hypertension, and prior studies have proposed a role for the epithelial Na+ channel (ENaC) in this syndrome. We characterized high fat-fed mice as a model in which to study the contribution of ENaC-mediated Na+ reabsorption in obesity and insulin resistance. High fat-fed mice demonstrated impaired Na+ excretion and elevated blood pressure, which was significantly higher on a high-Na+ diet compared with low fat-fed control mice. However, high fat-fed mice had no increase in ENaC activity as measured by Na+ transport across microperfused cortical collecting ducts, electrolyte excretion, or blood pressure. In addition, we found no difference in endogenous urinary aldosterone excretion between groups on a normal or high-Na+ diet. High fat-fed mice provide a model of metabolic syndrome, recapitulating obesity, insulin resistance, impaired natriuresis, and a Na+-sensitive elevation in blood pressure. Surprisingly, in contrast to previous studies, our data demonstrate that high fat feeding of mice impairs natriuresis and produces elevated blood pressure that is independent of ENaC activity and likely caused by increased Na+ reabsorption upstream of the aldosterone-sensitive distal nephron.

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 ◽  
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.

scholarly journals Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention

2011 ◽  
Vol 43 (8) ◽  
pp. 408-416 ◽  
Author(s):  
Isabel Rubio-Aliaga ◽  
Baukje de Roos ◽  
Manuela Sailer ◽  
Gerard A. McLoughlin ◽  
Mark V. Boekschoten ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Carbon Metabolism ◽  
Dietary Intervention ◽  
Liver Steatosis ◽  
Oxidative Capacity ◽  
Blood Cholesterol ◽  
High Fat ◽  
One Carbon Metabolism ◽  
Fat Feeding

Obesity frequently leads to insulin resistance and the development of hepatic steatosis. To characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics, and metabolomics technologies were applied to liver samples from C57BL/6J mice obtained from two independent intervention trials. After 12 wk of high-fat feeding the animals became obese, hyperglycemic, and insulin resistant, had elevated levels of blood cholesterol and VLDL, and developed hepatic steatosis. Nutrigenomic analysis revealed alterations of key metabolites and enzyme transcript levels of hepatic one-carbon metabolism and related pathways. The hepatic oxidative capacity and the lipid milieu were significantly altered, which may play a key role in the development of insulin resistance. Additionally, high choline levels were observed after the high-fat diet. Previous studies have linked choline levels with insulin resistance and hepatic steatosis in conjunction with changes of certain metabolites and enzyme levels of one-carbon metabolism. The present results suggest that the coupling of high levels of choline and low levels of methionine plays an important role in the development of insulin resistance and liver steatosis. In conclusion, the complexities of the alterations induced by high-fat feeding are multifactorial, indicating that the interplay between several metabolic pathways is responsible for the pathological consequences.

scholarly journals Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

2014 ◽  
Vol 35 (1) ◽  
pp. 26-40 ◽  
Author(s):  
Ahmed Lawan ◽  
Lei Zhang ◽  
Florian Gatzke ◽  
Kisuk Min ◽  
Michael J. Jurczak ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Energy Homeostasis ◽  
Mitogen Activated Protein Kinase ◽  
Hepatic Insulin Resistance ◽  
Fibroblast Growth Factor 21 ◽  
High Fat ◽  
Mitogen Activated Protein ◽  
Fat Feeding

The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.

Prevention of skeletal muscle insulin resistance by dietary cod protein in high fat-fed rats

2001 ◽  
Vol 281 (1) ◽  
pp. E62-E71 ◽  
Author(s):  
Charles Lavigne ◽  
Frédéric Tremblay ◽  
Geneviève Asselin ◽  
Hélène Jacques ◽  
André Marette
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Amino Acids ◽  
Glucose Uptake ◽  
Soy Protein ◽  
Whole Body ◽  
Glucose Disposal ◽  
High Fat ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance

In the present study, we tested the hypothesis that fish protein may represent a key constituent of fish with glucoregulatory activity. Three groups of rats were fed a high-fat diet in which the protein source was casein, fish (cod) protein, or soy protein; these groups were compared with a group of chow-fed controls. High-fat feeding led to severe whole body and skeletal muscle insulin resistance in casein- or soy protein-fed rats, as assessed by the euglycemic clamp technique coupled with measurements of 2-deoxy-d-[3H]glucose uptake rates by individual tissues. However, feeding cod protein fully prevented the development of insulin resistance in high fat-fed rats. These animals exhibited higher rates of insulin-mediated muscle glucose disposal that were comparable to those of chow-fed rats. The beneficial effects of cod protein occurred without any reductions in body weight gain, adipose tissue accretion, or expression of tumor necrosis factor-α in fat and muscle. Moreover, L6 myocytes exposed to cod protein-derived amino acids showed greater rates of insulin-stimulated glucose uptake compared with cells incubated with casein- or soy protein-derived amino acids. These data demonstrate that feeding cod protein prevents obesity-induced muscle insulin resistance in high fat-fed obese rats at least in part through a direct action of amino acids on insulin-stimulated glucose uptake in skeletal muscle cells.

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