Adipose-Tissue Metabolism

Lipogenesis

Lipogenesis is the deposition of fat.  This process occurs in adipose tissue and in the liver at cytoplasmic and mitochondrial sites (Figure 2). 

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Energy ingested as fat beyond that needed for current energy demands is stored in adipose tissue.  In addition, carbohydrate and protein consumed in the diet can be converted to fat.  Energy ingested as carbohydrate can be stored as glycogen in the liver and muscle. Carbohydrate can also be converted to triglycerides primarily in the liver and transferred to adipose tissue for storage.  Amino acids from ingested proteins are used for new protein synthesis or they can be converted to carbohydrate and fat.

Fatty acids, in the form of triglycerides or free fatty acids bound to albumin, are ingested in the diet or synthesized by the liver (described above).  Very little synthesis of free fatty acids occurs in the adipocytes.  Triglycerides are the most significant source of fatty acids, because this is the form in which dietary lipids are assembled by the gut and liver.  Triglycerides made up of long chain fatty acids, in the form of chylomicrons (from intestinal absorption) or lipoproteins (from hepatic synthesis), are hydrolyzed to glycerol and free fatty acids by an enzyme called lipoprotein lipase (LPL).  Lipoprotein lipase is synthesized in adipocytes and secreted into adjacent endothelial cells.  Chylomicrons and lipoproteins (very low density lipoproteins) contain C-ll apoprotein, which activates LPL.  Free fatty acids are taken up by adipocytes in a concentration-dependent manner by a transmembrane transport protein.  Once inside the adipocyte, fatty acids enter a common pool made up of both incoming and outgoing fatty acids.  Fatty acids that are stored in the adipose tissue must first combine with coenzyme A to form a thioester and then they are re-esterified in a stepwise manner to triglycerides.  Glucose is the primary source of glycerol for this re-esterification process.  Only a small amount of glycerol released, when triglycerides are hydrolyzed by LPL, can be reused by adipocytes to form alpha glycerol phosphate to be used for trigyceride assembly.  Most glycerol is returned to the circulation.

Insulin, a hormone secreted by the beta cells of the pancreas, plays a predominant role in the lipogenic process.  The net effect of insulin is to enhance storage and block mobilization and oxidation of fatty acids.  Insulin exerts its effect by stimulating LPL formation, so that circulating triglycerides are hydrolyzed and free fatty acids can enter the adipocyte.  Insulin is also required for the transport of glucose, which is needed for re-esterification of the triglycerides once inside the adipocyte.  Finally, the conversion of glucose to fatty acids is accomplished by insulin's activation of several enzymes.

Lipolysis

Lipolysis is the chemical decomposition and release of fat from adipose tissue.   This process predominates over lipogenesis when additional energy is required (Figure 2).  The triglycerides within the adipocyte are acted upon by a multi-enzyme complex called hormone sensitive lipase (HSL), which hydrolyzes the triglyceride into free fatty acids and glycerol.  These lipases act consecutively on triglycerides, diglycerides, and monoglycerides.  Triglyceride lipase regulates the rate of lipolysis, because its activity is low.

Once triglycerides are hydrolyzed to fatty acids and glycerol, fatty acids enter the common free fatty acid pool where they may be re-esterified, undergo beta-oxidation (metabolic degradation), or be released into the circulation as substrates for skeletal muscle, cardiac muscle, and liver.  If the fatty acids are to undergo beta-oxidation for ATP production, fatty acids move from the adipocytes into the blood and are carried to the tissues that can use them as an energy source.  Long-chain fatty acids enter the cells of these tissues by passive diffusion, and their rate of uptake is proportional to their difference in concentration inside and outside of the cell.  Once inside the cells, beta-oxidation begins with "activation", that is, the formation of thioesters with coenzyme A.  This activation step converts the fatty acids to a form that is more amenable to the successive biochemical changes that ultimately result in ATP formation.

Insulin reduces mobilization of fatty acids from adipose tissue by inhibiting triglyceride lipase.  The mechanism of this inhibition may be through a decrease in cyclic AMP which in turn results in an inhibition of cyclic-AMP-dependent protein kinase.  This suppression of lipolysis lowers the rate of fatty acid delivery to the liver and to peripheral tissues.  The consequence of fewer fatty acids to the liver is a reduction in the formation of ketoacids (e.g., ketones).  Insulin also stimulates the use of ketoacids by peripheral tissues, preventing an accumulation of these acids in the blood.