Skeletal muscle triglycerides lowering is associated with net improvement of insulin sensitivity, TNF-α reduction and GLUT4 expression enhancement

Abstract

AIMS=HYPOTHESIS:The aim of the present study was to investigate the relationship between intramyocytic triglycerides levels, muscle TNF-a and GLUT4 expression and insulin resistance. METHODS: Insulin sensitivity was studied in 14 severely obese women (BMI > 40 kg=m 2 ), before and 6 months after low-dietary intake or bariatric malabsorptive surgery (bilio-pancreatic diversion, BPD), by the euglycaemic hyperinsulinaemic clamp technique, while the amount of intramyocytic triglycerides was chemically measured in needle muscle biopsies. Using reverse transcriptase-polymerase chain reaction analysis, the muscle mRNA expression of TNF-a and GLUT4 was also investigated. RESULTS: The weight loss after surgery was 25.98 AE 5.81 kg (P < 0.001), while that obtained with the diet was 5.07 AE 5.99 kg (P ¼ NS). Marked decrease in TNF-a mRNA levels (76.67 AE 12.59 to 14.01 AE 5.21 AU, P < 0.001) were observed in comparison with pre-treatment, whereas GLUT4 was significantly increased (62.25 AE 11.77 -124.25 AE 21.01 AU, P < 0.001) only in BPD patients. Increased glucose uptake (M) was accompanied by a significant decrease of TNF-a mRNA (76.67 AE 12.59 -14.01 AE 5.21 AU, P < 0.01) and an increase of GLUT4. The amounts of TNF-a mRNAs in skeletal muscle correlated inversely with GLUT4 mRNAs and directly with intramyocytic triglycerides levels. In a step-down regression analysis (r 2 ¼ 0.95) TNFa mRNA (P ¼ 0.0014), muscular TG levels (P ¼ 0.018), and GLUT4 mRNA (P ¼ 0.028) resulted to be the most powerful independent variables for predicting M values. CONCLUSION=INTERPRETATION: These findings suggest that insulin resistance in morbidly obese patients is positively associated to the intramyocytic triglycerides content and to TNF-a gene expression and inversely correlated to GLUT4 expression.

Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity?

“…The large increase in MFN2 mRNA levels was associated with the net improvement of insulin-dependent whole-body glucose We have previously demonstrated that insulin resistance in morbidly obese patients is positively associated with the IMTG content and with TNF-α expression and inversely correlated to SLC2A4 expression [16]. In agreement with this previous observation [16], whole-body glucose uptake was found to be a linear function of SLC2A4 expression in skeletal muscle.…”

Diet but not aerobic exercise training reduces skeletal muscle TNF-a in overweight humans

“…In a previous study skeletal muscle TNF-α mRNA levels and fasting plasma insulin were reduced after malabsorptive surgery causing substantial weight loss (~26 kg) in severely obese women (BMI >40 kg/m 2 ) [8]. In this previous study, GLUT4 mRNA levels were elevated, correlating inversely with the reduction in skeletal muscle TNF-α mRNA.…”

“…Skeletal muscle, however, is less well studied. Recently it was shown that massive weight loss through malabsorptive surgery can reduce TNF-α mRNA levels in skeletal muscle [8]. In the same study, the more moderate weight loss associated with energy restriction had no effect.…”

“…In human and animal adipocyte cell cultures, TNF-α down-regulated GLUT4 transcription [2,30,31], while GLUT4 protein levels were correspondingly reduced [32]. Thus with severe weight loss [8], an increase in GLUT4 levels and increased insulin receptor sensitivity are likely to contribute to enhanced glucose metabolism. The same study also found that a low-energy diet inducing a weight reduction of 5 kg over 6 months did not influence insulin levels or skeletal muscle TNF-α mRNA levels, but compliance with the diet was poor [8].…”

“…Thus with severe weight loss [8], an increase in GLUT4 levels and increased insulin receptor sensitivity are likely to contribute to enhanced glucose metabolism. The same study also found that a low-energy diet inducing a weight reduction of 5 kg over 6 months did not influence insulin levels or skeletal muscle TNF-α mRNA levels, but compliance with the diet was poor [8]. In contrast to this previous study, which focused on energy restriction, the current data indicate that with a diet that is low in saturated fats, high in fibre and complex carbohydrates, and has a low glycaemic index, the reduction of skeletal muscle TNF-α may contribute to risk factor reduction.…”