Excessive portal venous supply of long-chain free fatty acids to the liver, leading to hypothalamus-pituitary-adrenal-axis and sympathetic activation as a key to the development of syndrome X. A proposed concept for the induction of syndrome X.

Abstract

Insulin resistance and hypertension are two major symptoms of Syndrome X. A distinct relation between these symptoms and weight maintenance has been observed. Weight gain decreases insulin sensitivity and glucose tolerance and increases blood pressure, while loss of excessive weight normalizes these symptoms.1,2 Epidemiological studies show that upper-body obesity is associated with a higher incidence of the symptoms of Syndrome X than is lower-body obesity.3,4 This is primarily related to the amount of visceral fat rather than to the amount of subcutaneous fat.3,5 The causal relationship between visceral obesity and Syndrome X, however, is still unknown. A clue to this relation may be found in the metabolic characteristics and anatomical location of visceral adipose tissue. Visceral adipose tissue, especially the omental and mesenteric fat pads, which are drained by the portal circulation, has metabolic characteristics that are unique in comparison with other adipose tissues. The fat cells from these regions are metabolically more active,6 they have increased 3-adrenoceptor sensitivity,7 and they have a higher lipolytic activity5 than do other adipocytes. Moreover, the inhibitory action of insulin on fatty acid release from visceral adipocytes is lower than in subcutaneous fat cells.8 It has subsequently been demonstrated that visceral obesity is associated with increased fatty acid release and turnover9 and with an elevated fasting plasma fatty acid concentration.10 Normally, the liver will not be exposed to an exuberant supply of long-chain fatty acids, because long-chain fatty acids absorbed from the gut are mainly transported as triglycerides incorporated in chylomicrons by the lymphatic system, thus bypassing the liver. Primary metabolism of chylomicrons takes place in fat and muscle; the chylomicron remnants are subsequently taken up and metabolized by the liver. The increased lipolytic rate in visceral adipocytes in upper-body obesity and the direct drainage to the portal vein create a situation in which the liver directly will be ex-