Polymyxin B reduces cecal flora, TNF production and hepatic steatosis during total parenteral nutrition in the rat

Pappo, Itzhak; Becovier, Herve; Berry, Elliot M.; Freund, Herbert R.

doi:10.1016/0022-4804(91)90078-z

Cited by 109 publications

(62 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is in agreement with a two-to four-times-increased endotoxemia characterizing db/db and ob/ob mice due to an increased intestinal permeability (42). Furthermore, polymyxin B treatment, which specifically eliminates Gram-negative bacterias and further quenches LPS, diminishes hepatic steatosis (43). Our data demonstrate that in absence of CD14, a high-fat diet could not induce inflammation as reflected by the total blunting of cytokine expression augmentation in the liver and adipose depot.…”

Section: Discussionsupporting

confidence: 85%

Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

Cani

Amar

Iglesias³

et al. 2007

View full text Add to dashboard Cite

Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPScontaining microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in highfat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not wholebody, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases. Diabetes 56: [1761][1762][1763][1764][1765][1766][1767][1768][1769][1770][1771][1772] 2007 T he outbreak of a fat-enriched diet in Western countries is becoming a problem of the utmost importance. Obesity is the result of a complex interaction between genetic and environmental factors. Among the latter, changes in eating habits to increase fat intake are involved in the increased occurrence of metabolic diseases, such as obesity and diabetes, which are bearing features of the metabolic syndrome. The major metabolic consequence of a high-fat diet is that insulin action and the regulatory mechanisms of body weight are impaired through a well-described lipotoxic effect (1). In addition, it has been recently determined that obesity and insulin resistance are associated with lowgrade chronic systemic inflammation (2). In models of diet-induced and genetic obesity, the adipose tissue presents increased expression and content of proinflammatory cytokines such as tumor necrosis factor (TNF)-␣ (3,4), interleukin (IL)-1 (3,4), and IL-6 (4). This cytokine production is then deleterious for muscle insulin action; for example, TNF-␣ has been shown to cause insulin resistance by increasing serine phosphorylation on insulin receptor substrate-1 (5), leading to its inactivation. The consequent insulin resistance will favor hyperinsulinemia and excessive hepatic and adipose tissue lipid storage. However, while extensive research is dedicated to the effects of an in...

show abstract

Section: Discussionsupporting

confidence: 85%

Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

Cani

Amar

Iglesias³

et al. 2007

View full text Add to dashboard Cite

show abstract

“…In support of this, feeding a HFD to mice was found to increase gut gram-negative bacteria, which was shown to be correlated to endotoxemia and insulin resistance. Particularly, polymyxin B treatment, an antibiotic specific for gram-negative bacteria, lowered LPS levels and improved hepatic steatosis [24,25] . As gut-derived LPS is a major source of endotoxemia, which contributes to chronic low-grade inflammation, this reduction by metformin on blood LPS levels could be a novel mechanism for the metformin-mediated insulin-sensitizing effects.…”

Section: Discussionmentioning

confidence: 99%

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

et al. 2016

View full text Add to dashboard Cite

Aim: Accumulating evidence shows that lipopolysaccharides (LPS) derived from gut gram-negative bacteria can be absorbed, leading to endotoxemia that triggers systemic inflammation and insulin resistance. In this study we examined whether metformin attenuated endotoxemia, thus improving insulin signaling in high-fat diet fed mice. Methods: Mice were fed a high-fat diet for 18 weeks to induce insulin resistance. One group of the mice was treated with oral metformin (100 mg·kg -1 ·d -1 ) for 4 weeks. Another group was treated with LPS (50 μg·kg -1 ·d -1 , sc) for 5 days followed by the oral metformin for 10 d. Other two groups received a combination of antibiotics for 7 d or a combination of antibiotics for 7 d followed by the oral metformin for 4 weeks, respectively. Glucose metabolism and insulin signaling in liver and muscle were evaluated, the abundance of gut bacteria, gut permeability and serum LPS levels were measured. Results: In high-fat fed mice, metformin restored the tight junction protein occludin-1 levels in gut, reversed the elevated gut permeability and serum LPS levels, and increased the abundance of beneficial bacteria Lactobacillus and Akkermansia muciniphila. Metformin also increased PKB Ser473 and AMPK T172 phosphorylation, decreased MDA contents and redox-sensitive PTEN protein levels, activated the anti-oxidative Nrf2 system, and increased IκBα in liver and muscle of the mice. Treatment with exogenous LPS abolished the beneficial effects of metformin on glucose metabolism, insulin signaling and oxidative stress in liver and muscle of the mice. Treatment with antibiotics alone produced similar effects as metformin did. Furthermore, the beneficial effects of antibiotics were addictive to those of metformin. Conclusion: Metformin administration attenuates endotoxemia and enhances insulin signaling in high-fat fed mice, which contributes to its anti-diabetic effects.

show abstract

“…Isolation and culture of peritoneal macrophages Peritoneal macrophages were prepared as described [13] and then incubated for 18 h with or without LPS from E. coli serotype 026:B6 (50 ng/ml, Sigma). Media were collected and stored at −80°C.…”

Section: Methodsmentioning

confidence: 99%

“…Genetically obese rodents quickly develop steatohepatitis after exposure to low doses of LPS [12], while polymyxin B diminishes hepatic steatosis during total parenteral nutrition in the rat by reducing caecal flora [13]. Moreover, endotoxins exert a strong effect on liver of mice fed a high-fat diet [14].…”

Section: Introductionmentioning

confidence: 99%

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

et al. 2007

View full text Add to dashboard Cite

Aims/hypothesis Inflammation is associated with obesity and has been implicated in the development of diabetes and atherosclerosis. During gram-negative bacterial infection, lipopolysaccharide causes an inflammatory reaction via toll-like receptor 4 (TLR4), which has an essential function in the induction of innate and adaptative immunity. Our aim was to determine what role TLR4 plays in the development of metabolic phenotypes during high-fat feeding. Materials and methods We evaluated metabolic consequences of a high-fat diet in TLR4 mutant mice (C3H/HeJ) and their respective controls. Results TLR4 inactivation reduced food intake without significant modification of body weight, but with higher epididymal adipose tissue mass and adipocyte hypertrophy. It also attenuated the inflammatory response and increased glucose transport and the expression levels of adiponectin and lipogenic markers in white adipose tissue. In addition, TLR4 inactivation blunted insulin resistance induced by lipopolysaccharide in differentiated adipocytes. Increased feeding efficiency in TLR4 mutant mice was associated with lower mass and lower expression of uncoupling protein 1 gene in brown adipose tissue. Finally, TLR4 inactivation slowed the development of hepatic steatosis, reducing the liver triacylglycerol content and also expression levels of lipogenic and fibrosis markers. Conclusions/interpretation TLR4 influences white adipose tissue inflammation and insulin sensitivity, as well as liver fat storage, and is important in the regulation of metabolic phenotype during a fat-enriched diet.

show abstract

Polymyxin B reduces cecal flora, TNF production and hepatic steatosis during total parenteral nutrition in the rat

Cited by 109 publications

References 39 publications

Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

Contact Info

Product

Resources

About