Paradoxical Increase in TAG and DAG Content Parallel the Insulin Sensitizing Effect of Unilateral DGAT1 Overexpression in Rat Skeletal Muscle

Abstract

BackgroundThe 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 FindingsThe 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/SignificanceWe 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.

Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity

“…However, we previously reported that elevated muscle DAG levels are not per se accompanied by skeletal muscle insulin resistance. That is, we showed that myocellular DGAT1 overexpression, an enzyme responsible for the conversion of DAG into inert TAG, improved skeletal muscle insulin sensitivity, yet increased muscle DAG levels (31). This phenomenon of improved insulin sensitivity coupled to increased storage of DAG in muscle was also reported in endurance-trained athletes (32).…”

“…DAG Measurement. Total lipids were extracted from frozen mouse tibialis anterior muscle and DAG content was determined as described previously (31).…”

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

“…However, our results clearly show substantial increases in both DAGs and ceramides, and yet no detriments to insulin signaling. This result is at first counterintuitive; however, other reports have found similar increases in lipotoxic species without induction of insulin resistance, including the well-known athlete's paradox (31)(32)(33)(34). Elevated DAGs have been found in endurance athletes with high insulin sensitivity (35).…”

Skeletal muscle lipid flux: running water carries no poison

“…Increasing net TG synthesis by diacylglycerol acyltransferase-1 (DGAT1) overexpression (70,106) or ATGL inactivation (34,59) promoted skeletal muscle insulin sensitivity. Conversely, isolated skeletal muscle from whole body DGAT1 knockout mice exhibited insulin resistance (70).…”