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Paradoxical increase in TAG and DAG content parallel the insulin sensitizing effect of unilateral DGAT1 overexpression in rat skeletal muscle.

Timmers S, de Vogel-van den Bosch J, Hesselink MK, van Beurden D, Schaart G, Ferraz MJ, Losen M, Martinez-Martinez P, De Baets MH, Aerts JM, Schrauwen P - PLoS ONE (2011)

Bottom Line: The enzyme 1,2-acylCoA:diacylglyceroltransferase-1 (DGAT1) esterifies a fatty acyl-CoA on DAG to form TAG.Interestingly, markers of muscle lipolysis and mitochondrial function were also increased in DGAT1 overexpressing muscle.We conclude that unilateral DGAT1 overexpression can rescue insulin sensitivity, possibly by increasing DAG and TAG turnover in skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: Top Institute Food and Nutrition, Wageningen, The Netherlands.

ABSTRACT

Background: The involvement of muscle triacylglycerol (TAG) storage in the onset of insulin resistance is questioned and the attention has shifted towards inhibition of insulin signalling by the lipid intermediate diacylglycerol (DAG). The enzyme 1,2-acylCoA:diacylglyceroltransferase-1 (DGAT1) esterifies a fatty acyl-CoA on DAG to form TAG. Therefore, the aim of the present study was to investigate if unilateral overexpression of DGAT1 in adult rat Tibialis anterior (TA) muscle will increase conversion of the lipid intermediate DAG into TAG, thereby improving muscle insulin sensitivity.

Methodology/principal findings: The DGAT1 gene construct was injected in the left TA muscle of male rats on chow or high-fat (45% kcal) diet for three weeks, followed by application of one 800 V/cm and four 80 V/cm pulses, using the contralateral leg as sham-electroporated control. Seven days after electroporation, muscle specific insulin sensitivity was assessed with a hyperinsulinemic euglycemic clamp using 2-deoxy-[3H]glucose. Here, we provide evidence that unilateral overexpression of DGAT1 in TA muscle of male rats is associated with an increased rather than decreased DAG content. Strikingly, this increase in DAG content was accompanied by improved muscle insulin sensitivity. Interestingly, markers of muscle lipolysis and mitochondrial function were also increased in DGAT1 overexpressing muscle.

Conclusions/significance: We conclude that unilateral DGAT1 overexpression can rescue insulin sensitivity, possibly by increasing DAG and TAG turnover in skeletal muscle. In case of a proper balance between the supply and oxidation of fatty acids in skeletal muscle, the lipid intermediate DAG may not exert harmful effects on insulin signalling.

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Related in: MedlinePlus

Three weeks of high-fat feeding is associated with an increased TA DAG content compared to rats on CHOW.DGAT1 overexpression leads to an increase in TA DAG content in rats on CHOW and tended to increase DAG content in rats on HFD. Data are expressed as mean ± SEM (n = 6). *P<0.05 CHOW-DGAT1 and HFD-control vs. CHOW-control.
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pone-0014503-g002: Three weeks of high-fat feeding is associated with an increased TA DAG content compared to rats on CHOW.DGAT1 overexpression leads to an increase in TA DAG content in rats on CHOW and tended to increase DAG content in rats on HFD. Data are expressed as mean ± SEM (n = 6). *P<0.05 CHOW-DGAT1 and HFD-control vs. CHOW-control.

Mentions: To determine whether the increased IMCL content in TA muscle overexpressing DGAT1 was accompanied by a reduction of DAG, we measured the latter in the legs overexpressing DGAT1 as well as in their empty vector control legs (figure 2). Three weeks of high-fat feeding was associated with a ∼75% increase in DAG content (p = 0.039). Remarkably, overexpressing DGAT1 led to a ∼30% increase in DAG content in the HFD-DGAT1 overexpressing leg and a ∼35% increase in DAG content in CHOW-DGAT1 overexpressing leg, compared to control legs of the animals (p = 0.073, HFD-DGAT1 vs. HFD-control leg, and p = 0.045, CHOW-DGAT1 vs. CHOW-control leg).


Paradoxical increase in TAG and DAG content parallel the insulin sensitizing effect of unilateral DGAT1 overexpression in rat skeletal muscle.

Timmers S, de Vogel-van den Bosch J, Hesselink MK, van Beurden D, Schaart G, Ferraz MJ, Losen M, Martinez-Martinez P, De Baets MH, Aerts JM, Schrauwen P - PLoS ONE (2011)

Three weeks of high-fat feeding is associated with an increased TA DAG content compared to rats on CHOW.DGAT1 overexpression leads to an increase in TA DAG content in rats on CHOW and tended to increase DAG content in rats on HFD. Data are expressed as mean ± SEM (n = 6). *P<0.05 CHOW-DGAT1 and HFD-control vs. CHOW-control.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3021516&req=5

pone-0014503-g002: Three weeks of high-fat feeding is associated with an increased TA DAG content compared to rats on CHOW.DGAT1 overexpression leads to an increase in TA DAG content in rats on CHOW and tended to increase DAG content in rats on HFD. Data are expressed as mean ± SEM (n = 6). *P<0.05 CHOW-DGAT1 and HFD-control vs. CHOW-control.
Mentions: To determine whether the increased IMCL content in TA muscle overexpressing DGAT1 was accompanied by a reduction of DAG, we measured the latter in the legs overexpressing DGAT1 as well as in their empty vector control legs (figure 2). Three weeks of high-fat feeding was associated with a ∼75% increase in DAG content (p = 0.039). Remarkably, overexpressing DGAT1 led to a ∼30% increase in DAG content in the HFD-DGAT1 overexpressing leg and a ∼35% increase in DAG content in CHOW-DGAT1 overexpressing leg, compared to control legs of the animals (p = 0.073, HFD-DGAT1 vs. HFD-control leg, and p = 0.045, CHOW-DGAT1 vs. CHOW-control leg).

Bottom Line: The enzyme 1,2-acylCoA:diacylglyceroltransferase-1 (DGAT1) esterifies a fatty acyl-CoA on DAG to form TAG.Interestingly, markers of muscle lipolysis and mitochondrial function were also increased in DGAT1 overexpressing muscle.We conclude that unilateral DGAT1 overexpression can rescue insulin sensitivity, possibly by increasing DAG and TAG turnover in skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: Top Institute Food and Nutrition, Wageningen, The Netherlands.

ABSTRACT

Background: The involvement of muscle triacylglycerol (TAG) storage in the onset of insulin resistance is questioned and the attention has shifted towards inhibition of insulin signalling by the lipid intermediate diacylglycerol (DAG). The enzyme 1,2-acylCoA:diacylglyceroltransferase-1 (DGAT1) esterifies a fatty acyl-CoA on DAG to form TAG. Therefore, the aim of the present study was to investigate if unilateral overexpression of DGAT1 in adult rat Tibialis anterior (TA) muscle will increase conversion of the lipid intermediate DAG into TAG, thereby improving muscle insulin sensitivity.

Methodology/principal findings: The DGAT1 gene construct was injected in the left TA muscle of male rats on chow or high-fat (45% kcal) diet for three weeks, followed by application of one 800 V/cm and four 80 V/cm pulses, using the contralateral leg as sham-electroporated control. Seven days after electroporation, muscle specific insulin sensitivity was assessed with a hyperinsulinemic euglycemic clamp using 2-deoxy-[3H]glucose. Here, we provide evidence that unilateral overexpression of DGAT1 in TA muscle of male rats is associated with an increased rather than decreased DAG content. Strikingly, this increase in DAG content was accompanied by improved muscle insulin sensitivity. Interestingly, markers of muscle lipolysis and mitochondrial function were also increased in DGAT1 overexpressing muscle.

Conclusions/significance: We conclude that unilateral DGAT1 overexpression can rescue insulin sensitivity, possibly by increasing DAG and TAG turnover in skeletal muscle. In case of a proper balance between the supply and oxidation of fatty acids in skeletal muscle, the lipid intermediate DAG may not exert harmful effects on insulin signalling.

Show MeSH
Related in: MedlinePlus