Increased intraabdominal adipose tissue mass in fructose fed rats: correction by metformin

Summary. The aim of the present study was to investigate the effect of metformin on insulin sensitivity, adipose tissue mass and sympathetic nervous system (SNS) activity in fructose fed rats. Male Sprague-Dawley rats were fed for six weeks either on a standard diet (C group) or on a high-fructose diet (F group, 10% in drinking water). In each group, half of the animals received metformin in drinking water for the last 4 weeks (500 mg/kg x day, C+M and F+M). Hyperinsulinemic-euglycemic clamps (6 mU insulin/kg.min) were performed on awake unrestrained rats to test insulin resistance. Six-week fructose diet induced a reproducible insulin resistance (31.1 +/- 1.9 C vs 22.5 +/- 3.2 mg glucose/kg.min F, p<0.05). Metformin treatment prevented insulin resistance (31.1 +/- 1.9 C vs 30,2 +/- 1.8 mg glucose/kg x min F+M, ns). To measure SNS activity, rats received, ten minutes before sacrifice, an i.p. injection of NSD (m-hydroxybenzylhydrazine, inhibitor of DOPA decarboxylase, 100 mg/kg). DOPA accumulation was used as an index of SNS activity and measured in superior cervical, coeliac ganglias, retroperitoneal and epidydimal adipose tissues. SNS activity was increased in F group only in coeliac ganglia (16.8 +/- 1.1 C vs 22.6 +/- 2.2 ng DOPA/ganglia, F group, p<0.05) and not in superior cervical ganglia (8.4 +/- 0.7 C vs 8.6 +/- 0.7 ng DOPA/ganglia, F group, ns). Metformin had no effect on SNS activity in coeliac ganglia of control animals (15.9 +/- 1.7 C+M vs 16.8 +/- 1.1 ng DOPA/coeliac ganglia C, ns) but prevented the increase in SNS activity in fructose fed animals (22.6 +/- 2.2 F vs 16.3 +/- 2.8 ng DOPA/coeliac ganglia F + M). In fructose fed rats, metformin significantly increased sympathetic activity in retroperitoneal white adipose tissue (RPWAT) resulting in a marked decrease in depot mass but had no effect on epidydimal WAT. In conclusion, our results demonstrate that fructose diet caused a selective increase of SNS activity in coeliac ganglia. Metformin increased SNS activity in RPWAT resulting in a significant reduction in RPWAT mass, lowered SNS activity in coeliac ganglia to control values and restore whole body insulin sensitivity.