Local activation of the IκK-NF-κB pathway in muscle does not cause insulin resistance

Polkinghorne, Emma; Lau, Quintin; Cooney, Gregory J.; Kraegen, Edward W.; Cleasby, Mark E.

doi:10.1152/ajpendo.00537.2007

Cited by 21 publications

(21 citation statements)

References 52 publications

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“…Second, we were able to increase the activity of CPT1 in a skeletal muscle to levels seen with physiological interventions such as exercise training (29). Of note, we have consistently reported a transfection efficiency of ϳ50% in the tibialis anterior muscle (25,26). We did not determine transfection efficiency of the CPT1 plasmid, but based on our previous reports (25,26), we expect that 40 -50% of fibers would be overexpressing CPT1.…”

Section: Discussionmentioning

confidence: 89%

“…Of note, we have consistently reported a transfection efficiency of ϳ50% in the tibialis anterior muscle (25,26). We did not determine transfection efficiency of the CPT1 plasmid, but based on our previous reports (25,26), we expect that 40 -50% of fibers would be overexpressing CPT1. However, given that CPT1 protein was only increased by ϳ40%, it is possible that the transfection efficiency of CPT1 was lower than in our previous studies, or it may indicate that CPT1 protein has a rapid turnover rate when overexpressed.…”

Section: Discussionmentioning

confidence: 96%

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Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet–Induced Insulin Resistance

et al. 2009

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OBJECTIVE-Skeletal muscle insulin resistance is associated with lipid accumulation, but whether insulin resistance is due to reduced or enhanced flux of long-chain fatty acids into the mitochondria is both controversial and unclear. We hypothesized that skeletal muscle-specific overexpression of the muscle isoform of carnitine palmitoyltransferase 1 (CPT1), the enzyme that controls the entry of long-chain fatty acyl CoA into mitochondria, would enhance rates of fatty acid oxidation and improve insulin action in muscle in high-fat diet insulin-resistant rats. RESEARCH DESIGN AND METHODS-Ratswere fed a standard (chow) or high-fat diet for 4 weeks. After 3 weeks, in vivo electrotransfer was used to overexpress the muscle isoform of CPT1 in the distal hindlimb muscles (tibialis anterior and extensor digitorum longus [EDL]). Skeletal muscle insulin action was examined in vivo during a hyperinsulinemic-euglycemic clamp.RESULTS-In vivo electrotransfer produced a physiologically relevant increase of ϳ20% in enzyme activity; and although the high-fat diet produced insulin resistance in the sham-treated muscle, insulin action was improved in the CPT1-overexpressing muscle. This improvement was associated with a reduction in triacylglycerol content, the membrane-to-cytosolic ratio of diacylglycerol, and protein kinase C activity. Importantly, overexpression of CPT1 did not affect markers of mitochondrial capacity or function, nor did it alter skeletal muscle acylcarnitine profiles irrespective of diet. CONCLUSIONS-Our data provide clear evidence that a physiological increase in the capacity of long-chain fatty acyl CoA entry into mitochondria is sufficient to ameliorate lipid-induced insulin resistance in muscle. Diabetes 58:550-558, 2009

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 96%

Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet–Induced Insulin Resistance

et al. 2009

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“…Findings from several studies performed in cell culture systems and insulin-resistant rodents suggest that the NF-B pathway plays a role in insulin resistance (3,4,32,50,56). However, results from other studies in which IKK was either knocked down (46) or overexpressed (42) in rodents do not support the concept that the NF-B pathway negatively affects insulin sensitivity. Using a primary human muscle cell culture system, Austin et al (4) demonstrated recently that silencing IKK via siRNA prevents TNF␣-induced insulin resistance.…”

Section: Discussionmentioning

confidence: 98%

NF-κB activity in muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions

Tantiwong

Shanmugasundaram²,

Monroy

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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NF-κB is a transcription factor that controls the gene expression of several proinflammatory proteins. Cell culture and animal studies have implicated increased NF-κB activity in the pathogenesis of insulin resistance and muscle atrophy. However, it is unclear whether insulin-resistant human subjects have abnormal NF-κB activity in muscle. The effect that exercise has on NF-κB activity/signaling also is not clear. We measured NF-κB DNA-binding activity and the mRNA level of putative NF-κB-regulated myokines interleukin (IL)-6 and monocyte chemotactic protein-1 (MCP-1) in muscle samples from T2DM, obese, and lean subjects immediately before, during (40 min), and after (210 min) a bout of moderate-intensity cycle exercise. At baseline, NF-κB activity was elevated 2.1- and 2.7-fold in obese nondiabetic and T2DM subjects, respectively. NF-κB activity was increased significantly at 210 min following exercise in lean (1.9-fold) and obese (2.6-fold) subjects, but NF-κB activity did not change in T2DM. Exercise increased MCP-1 mRNA levels significantly in the three groups, whereas IL-6 gene expression increased significantly only in lean and obese subjects. MCP-1 and IL-6 gene expression peaked at the 40-min exercise time point. We conclude that insulin-resistant subjects have increased basal NF-κB activity in muscle. Acute exercise stimulates NF-κB in muscle from nondiabetic subjects. In T2DM subjects, exercise had no effect on NF-κB activity, which could be explained by the already elevated NF-κB activity at baseline. Exercise-induced MCP-1 and IL-6 gene expression precedes increases in NF-κB activity, suggesting that other factors promote gene expression of these cytokines during exercise.

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“…Our data, demonstrating that the inhibition of TLR2 expression rescues the tissues from the activation of IKK and MAPK8 and from the insulin resistance, suggest that TLR2 is a key modulator in the crosstalk between inflammatory and metabolic pathways. However, the fact that the activation of IKK leads to the insulin resistance is not uniformly observed (Polkinghorne et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of toll-like receptor 2 expression improves insulin sensitivity and signaling in muscle and white adipose tissue of mice fed a high-fat diet

Caricilli¹,

Nascimento²,

Pauli³

et al. 2008

Journal of Endocrinology

120

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The aims of the present study were to investigate the expression of toll-like receptor 2 (TLR2) in muscle and white adipose tissue (WAT) of diet-induced obesity (DIO) mice, and also the effects of its inhibition, with the use of TLR2 antisense oligonucleotide (ASON), on insulin sensitivity and signaling. The expression of TLR2 was increased in muscle and WAT of DIO mice, compared with those that received standard chow. Inhibition of TLR2 in DIO mice, by TLR2 ASON, improved insulin sensitivity and signaling in muscle and WAT. In addition, data show that the inhibition of TLR2 expression prevents the activation of IKBKB, MAPK8, and serine phosphorylation of IRS1 in DIO mice, suggesting that TLR2 is a key modulator of the crosstalk between inflammatory and metabolic pathways. We, therefore, suggest that a selective interference with TLR2 presents an attractive opportunity for the treatment of insulin resistance in obesity and type 2 diabetes.

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Local activation of the IκK-NF-κB pathway in muscle does not cause insulin resistance

Cited by 21 publications

References 52 publications

Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet–Induced Insulin Resistance

Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet–Induced Insulin Resistance

NF-κB activity in muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions

Inhibition of toll-like receptor 2 expression improves insulin sensitivity and signaling in muscle and white adipose tissue of mice fed a high-fat diet

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