SYNTHESIS OF TRIGLYCERIDES (TAG) Liver and adipose tissue are the major sites of triacylglycerol (TAG) synthesis. The TAG synthesis in adipose tissue is for storage of energy whereas in liver it is mainly secreted as VLDL and is transpoed to peripheral tissues. The TAG is synthesised by esterification of fatty acyl CoA with either glycerol-3-phosphate or dihydroxyacetone phosphate (DHAP).The glycerol pa of the fat is derived from the metabolism of glucose. DHAP is an intermediate of glycolysis. Glycerol-3-phosphate may be formed by phosphorylation of glycerol or by reduction of dihydroxyacetone phosphate (DHAP). In adipose tissue, glycerol kinase is deficient and the major source is DHAP derived from glycolysis. However, in liver glycerol kinase is active. The fatty acyl CoA molecules transfer the fatty acid to the hydroxyl groups of glycerol by specific acyltransferases. In addition to these two pathways, in the intestinal mucosal cells the TAG synthesis occurs by the MAG pathway. The 2-MAG absorbed is re-esterified with fatty acyl CoA to form TAG (Fig. 11.4). Esterification of fatty acyl CoA with glycerol phosphate to form triacylglycerol occurs at a rapid rate during the fed state. Under conditions of fasting, it is seen that synthesis of triacylglycerol occurs side by side with lipolysis since the free fatty acid level is high in plasma. The glycerol phosphate is derived from the metabolism of glucose in the fed state by channeling dihydroxyacetone phosphate, an intermediate of glycolysis. In the fasting state, the glycerol phosphate is derived from dihydroxyacetone phosphate formed during gluconeogenesis (neoglycerogenesis). The activity of the enzyme PEPCK is enhanced in liver and adipose tissue during conditions of fasting so that glycerol phosphate is available to esterify and store the excess fatty acid mobilized.METABOLISM OF ADIPOSE TISSUE The adipose tissue serves as a storage site for excess calories ingested. The triglycerides stored in the adipose tissue are not ine. They undergo a daily turnover with new triacylglycerol molecules being synthesized and a definite fraction being broken down. 1. Adipose Tissue in Well-fed Condition i. Under well-fed conditions, active lipogenesis occurs in the adipose tissue. ii. The dietary triglycerides transpoed by chylomicrons and the endogenously synthesised triglycerides from liver brought by VLDL are both taken up by adipose tissue and esterified and stored as TAG. The lipoprotein molecules are broken down by the lipoprotein lipase present on the capillary wall. iii. In well-fed condition, glucose and insulin levels are increased. GluT4 in adipose tissue is insulin dependent. Insulin increases the activity of key glycolytic enzymes as well as pyruvate dehydrogenase, acetyl CoA carboxylase, and glycerol phosphate acyltransferase. The stimulant effect of insulin on the uptake of glucose by adipose tissue, on the glycolysis and on the utilisation of glucose by the HMP pathway also enhances lipogenesis. iv. Insulin also causes inhibition of hormone-sensitive lipase, and so lipolysis is decreased2. Adipose Tissue in Fasting Condition i. The metabolic pattern totally changes under conditions of fasting. TAG from the adipose tissue is mobilized under the effect of the hormones, glucagon and epinephrine. ii. The cyclic AMP-mediated activation cascade enhances the intracellular hormone sensitive lipase.The phosphorylated form of the enzyme is active which acts on TAG and liberates fatty acids. iii. Under conditions of starvation, a high glucagon, ACTH, glucocoicoids, and thyroxine have lipolytic effect. The released free fatty acids (FFA) are taken up by peripheral tissues as a fuel.3. Adipose Tissue and Diabetes Mellitus Lipolysis is enhanced and high FFA level in plasma is noticed in diabetes mellitus. The insulin acts through receptors on the cell surface of adipocytes. These receptors are decreased, leading to insulin insensitivity in diabetes. In type 2 diabetes mellitus, there is insulin resistance and the different insulin signaling pathways are affected differently. Hepatic gluconeogenesis occurs uninhibited leading to hyperglycemia. However, increased mobilization of fatty acids from adipose tissue and the persistently high free fatty acid levels in the presence of hyperinsulinemia stimulate synthesis of triacylglycerol. The overproduction of TAG leads to increased release of VLDL from liver causing hyperiglyceridemia. The excess deposition of TAG in adipose tissue accounts for the obesity prevalent in type 2 diabetes patients. 4. Adipose Tissue and Obesity The fat content of the adipose tissue can increase to unlimited amounts, depending on the amount of excess calories taken in. This leads to obesity. Plasma insulin level is high. But the insulin receptors are decreased, and there is peripheral resistance against insulin action. When fat droplets are overloaded, the nucleus of adipose tissue cell is degraded, cell is destroyed, and TAG becomes extracellular. Such TAG cannot be metabolically reutilized and forms the dead bulk in obese individuals.Ref: DM Vasudevan - Textbook of Biochemistry, 8th edition, page no: 139-141