Lipid mediators of insulin resistance: ceramide signalling down-regulates GLUT4 gene transcription in 3T3-L1 adipocytes

Long, Sheree D.; Pekala, Phillip H.

doi:10.1042/bj3190179

Cited by 118 publications

(86 citation statements)

References 48 publications

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“…One prevailing theory is that impaired skeletal muscle fatty acid oxidation (FAO) (1)(2)(3)(4) leads to cytosolic accumulation of lipotoxic intermediates that are directly linked to defects in insulin signaling (5)(6)(7)(8)(9)(10)(11). Recent findings counter this premise because they have shown that models of insulin resistance consistently exhibit enhanced (not reduced) FAO, as demonstrated by elevated incomplete β-oxidation and accumulation of excess lipid-derived acylcarnitines (12,13).…”

mentioning

confidence: 81%

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Wicks

Vandanmagsar

Haynie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

134

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The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity.carnitine palmitoyltransferase | muscle | fatty acid | lipid | carbohydrate C onsiderable evidence suggests that when oversupply of dietary fat exceeds the storage capacity of adipose tissue, ectopic lipids accumulate in skeletal muscle, leading to "metabolic stress" that induces insulin resistance. One prevailing theory is that impaired skeletal muscle fatty acid oxidation (FAO) (1-4) leads to cytosolic accumulation of lipotoxic intermediates that are directly linked to defects in insulin signaling (5-11). Recent findings counter this premise because they have shown that models of insulin resistance consistently exhibit enhanced (not reduced) FAO, as demonstrated by elevated incomplete β-oxidation and accumulation of excess lipid-derived acylcarnitines (12, 13). Supporting evidence was obtained using a whole-body genetic approach to elevate levels of the endogenous carnitine palmitoyltransferase-1 (Cpt1) inhibitor, malonyl-CoA (12). These studies have led to the contrasting theory that lipid overload and incomplete FAO within the mitochondria accelerate the progression of insulin resistance (14). Faced with a plethora of studies supporting both hypotheses, a crucial question remains: "Is inhibition of mitochondrial FAO in skeletal muscle sufficient to initiate development of insulin resistance?" Cpt1 is essential for long-chain acyl-CoA transport into the mitochondria, and lies at the nexus of both the lipotoxicity and the mitochondrial overload hypotheses. If decreased FAO is a root cause of lipotoxicity, then muscle-specific ablation of Cpt1b activity should lead to impaired FAO, intramyocellular lipid (IMCL) accumulation, and insulin resistance. In stark contrast, the mitochondrial overload hypothesis suggests that decreased Cpt1b activity would preserve insulin sensitivity by preventing unbalanced overfueling of β-oxidation. Characterization of the rare genetic disorders o...

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mentioning

confidence: 81%

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Wicks

Vandanmagsar

Haynie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

134

View full text Add to dashboard Cite

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“…Long & Pekala (44) have reported that ceramide can downregulate GLUT4 mRNA in 3T3-L1 adipocytes. It is well established that SFAs induce insulin resistance through the ceramide-dependent pathway (45).…”

Section: Discussionmentioning

confidence: 99%

Differential effects of dietary saturated and trans-fatty acids on expression of genes associated with insulin sensitivity in rat adipose tissue

et al. 2005

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Objective: Trans-fatty acids (TFAs) are formed during partial hydrogenation of vegetable oils and are shown to be more atherogenic than saturated fatty acids (SFAs). Our previous study showed that dietary TFAs decrease adipose tissue insulin sensitivity to a greater extent than SFAs in rats. We hypothesized that the effects of these fatty acids on insulin sensitivity could be mediated through an alteration in gene expression. In the current study we have investigated the effects of dietary TFAs or SFAs on expression of genes associated with insulin sensitivity in rat adipose tissue. Design and methods: Male weanling Wistar/NIN rats were divided into four groups and fed one of the following diets containing 10% fat (g/100 g diet) differing only in the fatty acid composition for 3 months: control diet (3.7% linoleic acid (LA)), SFA diet (5% SFA), TFA diet 1 (1.5% TFA þ 1% LA) and TFA diet 2 (1.5% TFA þ 2% LA). The mRNA expression of peroxisome proliferator-activated receptor g (PPARg), lipoprotein lipase (LPL), glucose transporter-4 (GLUT4), resistin and adiponectin was analyzed in epididymal fat using RT-PCR. The effects of TFA were studied at two levels of LA to understand the beneficial effects of LA over the effects of TFA. Results: Both dietary SFA and TFA upregulated the mRNA levels of resistin. Dietary SFA downregulated adiponectin and GLUT4 and upregulated LPL, while TFA downregulated PPARg and LPL. The effects of dietary TFA on PPARg and resistin were not counteracted by increased LA (TFA diet 2). Conclusion: The effects of SFAs on the aforementioned genes except PPARg could be extrapolated towards decreased insulin sensitivity, while only the alteration in the mRNA levels of PPARg and resistin could be associated with insulin resistance in TFA-fed rats. These findings suggest that dietary SFAs and TFAs alter the expression of different genes associated with insulin sensitivity in adipose tissue. European Journal of Endocrinology 153 159-165

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“…Diacylglycerol levels are elevated in many models of insulin resistance [28] and directly activate protein kinase C [29][30][31][32]. Ceramides activate a protein phosphatase that dephosphorylates AKT/protein kinase B, resulting in inhibition of GLUT4 translocation and glycogen synthesis [33,34]. Thus, strong evidence suggests that intramuscular long-chain CoA accumulation is detrimental to insulin signalling.…”

Section: Discussionmentioning

confidence: 99%

Carnitine revisited: potential use as adjunctive treatment in diabetes

et al. 2007

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Aims/hypothesis This study examined the efficacy of supplemental L-carnitine as an adjunctive diabetes therapy in mouse models of metabolic disease. We hypothesised that carnitine would facilitate fatty acid export from tissues in the form of acyl-carnitines, thereby alleviating lipidinduced insulin resistance. Materials and methods Obese mice with genetic or dietinduced forms of insulin resistance were fed rodent chow ± 0.5% L-carnitine for a period of 1-8 weeks. Metabolic outcomes included insulin tolerance tests, indirect calorimetry and mass spectrometry-based profiling of acyl-carnitine esters in tissues and plasma.Results Carnitine supplementation improved insulin-stimulated glucose disposal in genetically diabetic mice and wild-type mice fed a high-fat diet, without altering body weight or food intake. In severely diabetic mice, carnitine supplementation increased average daily respiratory exchange ratio from 0.886±0.01 to 0.914±0.01 (p<0.01), reflecting a marked increase in systemic carbohydrate oxidation. Similarly, under insulin-stimulated conditions, carbohydrate oxidation was higher and total energy expenditure increased from 172±10 to 210±9 kJ kg fatfree mass −1 h −1 in the carnitine-supplemented compared with control animals. These metabolic improvements corresponded with a 2.3-fold rise in circulating levels of acetyl-carnitine, which accounts for 86 and 88% of the total acyl-carnitine pool in plasma and skeletal muscle, respectively. Carnitine supplementation also increased several medium-and long-chain acyl-carnitine species in both plasma and tissues. Conclusions/interpretation These findings suggest that carnitine supplementation relieves lipid overload and glucose intolerance in obese rodents by enhancing mitochondrial efflux of excess acyl groups from insulin-responsive tissues. Carefully controlled clinical trials should be considered.

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Lipid mediators of insulin resistance: ceramide signalling down-regulates GLUT4 gene transcription in 3T3-L1 adipocytes

Cited by 118 publications

References 48 publications

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Differential effects of dietary saturated and trans-fatty acids on expression of genes associated with insulin sensitivity in rat adipose tissue

Carnitine revisited: potential use as adjunctive treatment in diabetes

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