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


RESULTS
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
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.
Top Institute Food and Nutrition, Wageningen, The Netherlands.
Silvie
S
Timmers
Johan
J
de Vogel-van den Bosch
Matthijs K C
MK
Hesselink
Denis
D
van Beurden
Gert
G
Schaart
Maria Joao
MJ
Ferraz
Mario
M
Losen
Pilar
P
Martinez-Martinez
Marc H
MH
De Baets
Johannes M F G
JM
Aerts
Patrick
P
Schrauwen
D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000008:administration & dosage / Q000096:biosynthesis*; D004075:Diglycerides / Q000032:analysis* / Q000378:metabolism; D018274:Electroporation; D015870:Gene Expression; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology*; D051381:Rats; D014280:Triglycerides / Q000032:analysis* / Q000378:metabolism
C011439:1,2-diacylglycerol; D004075:Diglycerides; D007328:Insulin; D014280:Triglycerides; C494883:Dgat1 protein, rat; D051048:Diacylglycerol O-Acyltransferase
Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E99-E107
16464906
Am J Physiol. 1985 May;248(5 Pt 1):E567-74
3887942
Am J Physiol Endocrinol Metab. 2007 Apr;292(4):E1231-7
17179390
Prog Lipid Res. 2006 Jan;45(1):17-41
16384603
J Biol Chem. 2005 Dec 30;280(52):42841-7
16115879
J Clin Invest. 2007 Jun;117(6):1690-8
17510709
J Physiol. 1993 Sep;469:459-78
8271208
J Biol Chem. 2007 Apr 27;282(17):12583-9
17337731
Am J Physiol Endocrinol Metab. 2009 Mar;296(3):E445-53
19106247
Am J Physiol Regul Integr Comp Physiol. 2001 Sep;281(3):R760-9
11506990
J Lipid Res. 1964 Oct;5:600-8
14221106
Diabetes. 2006 Dec;55(12):3418-28
17130488
Am J Physiol Endocrinol Metab. 2008 May;294(5):E882-8
18319352
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4262-7
10200250
Mol Cell Biochem. 2006 Mar;284(1-2):167-73
16532261
Diabetes. 1999 Aug;48(8):1600-6
10426379
Obes Res. 2005 Aug;13(8):1321-9
16129713
J Clin Endocrinol Metab. 2001 Dec;86(12):5755-61
11739435
J Biol Chem. 1957 May;226(1):497-509
13428781
Metabolism. 1996 Aug;45(8):947-50
8769349
Metabolism. 2000 Feb;49(2):220-4
10690948
Diabetes. 2010 Jan;59(1):80-8
19833891
FASEB J. 2003 Dec;17(15):2272-4
14525936
J Lipid Res. 2005 Feb;46(2):230-6
15576838
Diabetes. 2010 Mar;59(3):572-9
20028948
Diabetes. 2001 Nov;50(11):2579-84
11679437
J Appl Physiol (1985). 2004 Jul;97(1):11-6
14978010
Cell Metab. 2008 Jan;7(1):45-56
18177724
Diabetes. 2002 Jul;51(7):2005-11
12086926
Am J Physiol Regul Integr Comp Physiol. 2009 Oct;297(4):R913-24
19692657
Biochem J. 2004 Sep 1;382(Pt 2):619-29
15193147
J Clin Invest. 2007 Jun;117(6):1679-89
17510710
Diabetes. 1997 Jun;46(6):983-8
9166669
FEBS Lett. 2006 Oct 9;580(23):5484-91
16962104
Diabetes. 2009 Nov;58(11):2516-24
19675136
Mol Endocrinol. 2008 May;22(5):1200-12
18202145
Cell Metab. 2006 May;3(5):309-19
16679289
Am J Physiol Endocrinol Metab. 2005 Mar;288(3):E519-25
15522993
Am J Physiol. 1999 Jan;276(1):E106-17
9886956
Diabetes. 2010 Oct;59(10):2453-64
20522596
Clin Exp Pharmacol Physiol. 2009 Jan;36(1):5-11
18986321
J Biol Chem. 2002 Dec 27;277(52):50230-6
12006582
Diabetes. 2001 Jul;50(7):1612-7
11423483
Diabetes. 2009 Mar;58(3):550-8
19073774
FEBS Lett. 2003 Dec 18;555(3):631-7
14675786
Arch Biochem Biophys. 2003 Nov 15;419(2):101-9
14592453
Clin Chem. 2007 Apr;53(4):742-7
17332150