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Loss of Toll-Like Receptor 4 Function Partially Protects against Peripheral and Cardiac Glucose Metabolic Derangements During a Long-Term High-Fat Diet.

Jackson EE, Rendina-Ruedy E, Smith BJ, Lacombe VA - PLoS ONE (2015)

Bottom Line: No significant differences in cytokine expression were observed between groups, suggesting a lack of inflammation in the heart following a HFD.Loss of TLR4 function partially restored a healthy metabolic phenotype, suggesting that TLR4 signaling is a key mechanism in HFD-induced peripheral and cardiac insulin resistance.Our data further suggest that TLR4 exerts its detrimental metabolic effects in the myocardium through a cytokine-independent pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, United States of America.

ABSTRACT
Diabetes is a chronic inflammatory disease that carries a high risk of cardiovascular disease. However, the pathophysiological link between these disorders is not well known. We hypothesize that TLR4 signaling mediates high fat diet (HFD)-induced peripheral and cardiac glucose metabolic derangements. Mice with a loss-of-function mutation in TLR4 (C3H/HeJ) and age-matched control (C57BL/6) mice were fed either a high-fat diet or normal diet for 16 weeks. Glucose tolerance and plasma insulin were measured. Protein expression of glucose transporters (GLUT), AKT (phosphorylated and total), and proinflammatory cytokines (IL-6, TNF-α and SOCS-3) were quantified in the heart using Western Blotting. Both groups fed a long-term HFD had increased body weight, blood glucose and insulin levels, as well as impaired glucose tolerance compared to mice fed a normal diet. TLR4-mutant mice were partially protected against long-term HFD-induced insulin resistance. In control mice, feeding a HFD decreased cardiac crude membrane GLUT4 protein content, which was partially rescued in TLR4-mutant mice. TLR4-mutant mice fed a HFD also had increased expression of GLUT8, a novel isoform, compared to mice fed a normal diet. GLUT8 content was positively correlated with SOCS-3 and IL-6 expression in the heart. No significant differences in cytokine expression were observed between groups, suggesting a lack of inflammation in the heart following a HFD. Loss of TLR4 function partially restored a healthy metabolic phenotype, suggesting that TLR4 signaling is a key mechanism in HFD-induced peripheral and cardiac insulin resistance. Our data further suggest that TLR4 exerts its detrimental metabolic effects in the myocardium through a cytokine-independent pathway.

No MeSH data available.


Related in: MedlinePlus

Lack of increased pro-inflammatory cytokine expression in the myocardium following a long-term high fat diet.(A) Mean ± SE of cardiac IL-6 protein content from cardiac total lysate. (B) Mean ± SE of cardiac SOCS-3 protein content from cardiac total lysate. (C) Mean ± SE of TNF-alpha protein content from cardiac total lysate. (D) Representative Western Blots of IL-6, SOCS-3, TNF-alpha and their corresponding calsequestrin (loading control). RU = relative units; HFD = high-fat diet; ND = normal diet. Values are relative to relative to control ND; n = 6–8 per group.
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pone.0142077.g003: Lack of increased pro-inflammatory cytokine expression in the myocardium following a long-term high fat diet.(A) Mean ± SE of cardiac IL-6 protein content from cardiac total lysate. (B) Mean ± SE of cardiac SOCS-3 protein content from cardiac total lysate. (C) Mean ± SE of TNF-alpha protein content from cardiac total lysate. (D) Representative Western Blots of IL-6, SOCS-3, TNF-alpha and their corresponding calsequestrin (loading control). RU = relative units; HFD = high-fat diet; ND = normal diet. Values are relative to relative to control ND; n = 6–8 per group.

Mentions: In order to investigate whether feeding a HFD for 16 weeks induces cardiac inflammation, protein expression of major pro-inflammatory cytokines was quantified as direct or indirect measure of TLR4 signaling (i.e., IL-6/TNF-α and SOCS-3, respectively). Surprisingly, no significant differences in SOCS-3, IL-6, or TNF-α expression were observed in the myocardium between groups (Fig 3). To investigate the potential interplay of glucose metabolism and inflammation in the heart, linear regression between the expression of pro-inflammatory cytokines and GLUTs were performed. Interestingly, cardiac GLUT8, but not GLUT4, protein content correlated positively (p<0.05) with both IL-6 and SOCS-3 expression (Fig 4). TNF-α protein content did not correlate with cardiac protein expression of either GLUT isoform (data not shown).


Loss of Toll-Like Receptor 4 Function Partially Protects against Peripheral and Cardiac Glucose Metabolic Derangements During a Long-Term High-Fat Diet.

Jackson EE, Rendina-Ruedy E, Smith BJ, Lacombe VA - PLoS ONE (2015)

Lack of increased pro-inflammatory cytokine expression in the myocardium following a long-term high fat diet.(A) Mean ± SE of cardiac IL-6 protein content from cardiac total lysate. (B) Mean ± SE of cardiac SOCS-3 protein content from cardiac total lysate. (C) Mean ± SE of TNF-alpha protein content from cardiac total lysate. (D) Representative Western Blots of IL-6, SOCS-3, TNF-alpha and their corresponding calsequestrin (loading control). RU = relative units; HFD = high-fat diet; ND = normal diet. Values are relative to relative to control ND; n = 6–8 per group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4634760&req=5

pone.0142077.g003: Lack of increased pro-inflammatory cytokine expression in the myocardium following a long-term high fat diet.(A) Mean ± SE of cardiac IL-6 protein content from cardiac total lysate. (B) Mean ± SE of cardiac SOCS-3 protein content from cardiac total lysate. (C) Mean ± SE of TNF-alpha protein content from cardiac total lysate. (D) Representative Western Blots of IL-6, SOCS-3, TNF-alpha and their corresponding calsequestrin (loading control). RU = relative units; HFD = high-fat diet; ND = normal diet. Values are relative to relative to control ND; n = 6–8 per group.
Mentions: In order to investigate whether feeding a HFD for 16 weeks induces cardiac inflammation, protein expression of major pro-inflammatory cytokines was quantified as direct or indirect measure of TLR4 signaling (i.e., IL-6/TNF-α and SOCS-3, respectively). Surprisingly, no significant differences in SOCS-3, IL-6, or TNF-α expression were observed in the myocardium between groups (Fig 3). To investigate the potential interplay of glucose metabolism and inflammation in the heart, linear regression between the expression of pro-inflammatory cytokines and GLUTs were performed. Interestingly, cardiac GLUT8, but not GLUT4, protein content correlated positively (p<0.05) with both IL-6 and SOCS-3 expression (Fig 4). TNF-α protein content did not correlate with cardiac protein expression of either GLUT isoform (data not shown).

Bottom Line: No significant differences in cytokine expression were observed between groups, suggesting a lack of inflammation in the heart following a HFD.Loss of TLR4 function partially restored a healthy metabolic phenotype, suggesting that TLR4 signaling is a key mechanism in HFD-induced peripheral and cardiac insulin resistance.Our data further suggest that TLR4 exerts its detrimental metabolic effects in the myocardium through a cytokine-independent pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, United States of America.

ABSTRACT
Diabetes is a chronic inflammatory disease that carries a high risk of cardiovascular disease. However, the pathophysiological link between these disorders is not well known. We hypothesize that TLR4 signaling mediates high fat diet (HFD)-induced peripheral and cardiac glucose metabolic derangements. Mice with a loss-of-function mutation in TLR4 (C3H/HeJ) and age-matched control (C57BL/6) mice were fed either a high-fat diet or normal diet for 16 weeks. Glucose tolerance and plasma insulin were measured. Protein expression of glucose transporters (GLUT), AKT (phosphorylated and total), and proinflammatory cytokines (IL-6, TNF-α and SOCS-3) were quantified in the heart using Western Blotting. Both groups fed a long-term HFD had increased body weight, blood glucose and insulin levels, as well as impaired glucose tolerance compared to mice fed a normal diet. TLR4-mutant mice were partially protected against long-term HFD-induced insulin resistance. In control mice, feeding a HFD decreased cardiac crude membrane GLUT4 protein content, which was partially rescued in TLR4-mutant mice. TLR4-mutant mice fed a HFD also had increased expression of GLUT8, a novel isoform, compared to mice fed a normal diet. GLUT8 content was positively correlated with SOCS-3 and IL-6 expression in the heart. No significant differences in cytokine expression were observed between groups, suggesting a lack of inflammation in the heart following a HFD. Loss of TLR4 function partially restored a healthy metabolic phenotype, suggesting that TLR4 signaling is a key mechanism in HFD-induced peripheral and cardiac insulin resistance. Our data further suggest that TLR4 exerts its detrimental metabolic effects in the myocardium through a cytokine-independent pathway.

No MeSH data available.


Related in: MedlinePlus