Metabolic improvements associated with a reduction of abdominal visceral fat caused by a new alpha-glucosidase inhibitor, AO-128, in Zucker fatty rats.

The relationship between mesenteric fat accumulation and metabolic disorder was studied in genetically obese Zucker fatty rats. These animals had high levels of plasma glucose, triglyceride and total cholesterol as well as increased liver triglyceride in comparison with lean rats. In addition, portal free fatty acid (FFA) levels were also higher in fatty rats than in lean rats. Direct measurement of fat weight revealed a substantial increase of mesenteric as well as subcutaneous fat. The volume of mesenteric fat cells was greater than that of subcutaneous fat cells in Zucker fatty rats (1.67 +/- 0.49 nl versus 1.00 +/- 0.31 nl), although the mesenteric fat cell volume was less than half of the subcutaneous fat cell volume (0.05 +/- 0.02 nl versus 0.14 +/- 0.07 nl) in lean rats. An increase in mesenteric fat cell volume was thus more predominant than that of subcutaneous fat cells in the fatty rats. Administration of AO-128 (50 p.p.m./day), a new alpha-glucosidase inhibitor, caused a substantial reduction of mesenteric fat weight accompanied by a marked decrease in fat cell volume in Zucker fatty rats. The drug also caused a significant reduction of FFA levels in the portal vein in parallel with a marked reduction of triglyceride content in the liver. These observations indicate that the fat accumulation in the markedly enlarged mesenteric fat cells is related to the elevated levels of FFA in the portal vein, which in turn may cause metabolic disorders in the liver. A new alpha-glucosidase inhibitor improves these disorders, at least in part, by preventing an enlargement of mesenteric fat cells.