Human Biochemistry Volume 1 - Murray R. 1993

Bioenergetics and Carbohydrate and Lipid Metabolism
Transport and Storage of Lipids
Metabolic Transformations in Adipose Tissue and Fat Mobilization - The Role of Hormones in Fat Mobilization

Insulin

The rate of free fatty acid release from Adipose tissue is regulated by several Hormones that affect either the rate of lipolysis or the rate of Esterification. Insulin inhibits the release of free Fatty acids from adipose tissue, resulting in a decreased concentration of free fatty acids in plasma. It enhances Lipogenesis and the Biosynthesis ofacylglycerols, as well as The oxidation of glucose to CO₂ via the Pentose Phosphate Pathway. All these effects depend on glucose concentration and can be largely explained by the ability of insulin to increase glucose uptake into adipose tissue Cells; this is achieved through the translocation of glucose transporters from the Golgi apparatus to Cell/30.html">The Plasma Membrane. It has been shown that insulin also increases The activity of Pyruvate dehydrogenase, acetyl-CoA carboxylase, and glycerolphosphate acyltransferase; against the Background of increased glucose influx into adipose tissue cells, these Enzymes promote enhanced synthesis of Fatty Acids and acylglycerols. It is known that these enzymes are coordinately regulated by covalent modification, specifically via the phosphorylation–dephosphorylation mechanism.

The primary Action of Insulin in adipose tissue is to inhibit the activity of hormone-sensitive lipase, thereby reducing the release of not only free fatty acids but also glycerol. Adipose tissue is more sensitive to insulin than many other Tissues, which indicates that in vivo, adipose tissue is the principal site of insulin action.

Hormones stimulating lipolysis (Fig. 26.9)

Several Other Hormones accelerate the release of free fatty acids from adipose tissue and increase their plasma concentration by increasing the rate of triacylglycerol lipolysis. These hormones include epinephrine, norepinephrine, Glucagon, adrenocorticotropic hormone (ACTH), alpha- and beta-melanocyte-stimulating hormone (MSH), thyroid-stimulating hormone (TSH), Growth Hormone (GH), and vasopressin. Many of these hormones are activators of hormone-sensitive lipase. The presence of glucocorticoids and THYROID HORMONES is essential for the optimal progression of most lipolytic processes. By themselves, these hormones do not have a direct effect on lipolysis, but rather act as permissive factors enhancing the action of other hormones.

Hormones that rapidly promote lipolysis, such as catecholamines, stimulate the activity of adenylate cyclase, the enzyme that catalyzes The conversion of ATP to cAMP. The MECHANISM OF ACTION in this case is analogous to the hormonal stimulation of Glycogenolysis discussed above (see Ch. 19). By stimulating a cAMP-dependent protein kinase, cAMP converts inactive hormone-sensitive triacylglycerol lipase into the active form. Lipolysis is regulated primarily by The amount of cAMP present in tissues. Consequently, processes that trigger the degradation or formation of cAMP also directly affect lipolysis. cAMP is hydrolyzed to 5'-AMP by the action of cyclic 3', 5'-nucleotide phosphodiesterase. This enzyme is inhibited by methylxanthines, such as caffeine and theophylline. Therefore, the consumption of coffee containing caffeine causes a significant and sustained increase in plasma FFA levels in humans.

Insulin acts as an antagonist to lipolysis-stimulating hormones. It is currently believed that lipolysis is more sensitive to changes in Blood insulin concentrations than glucose utilization or esterification processes. The antilipolytic action of insulin, nicotinic acid, and prostaglandin E₁ can be explained either by the inhibition of cAMP synthesis at the adenylate cyclase-catalyzed step or by The stimulation of phosphodiesterase activity. The Mechanism of Action of Thyroid hormones likely involves an increase in cAMP levels by creating more favorable conditions for signal Transduction from the receptor on the outer surface of The Cell membrane to the localization site of adenylate cyclase on the inner surface, as well as by inhibiting phosphodiesterase activity. The stimulatory effect of growth hormone on lipolysis develops slowly and is associated with the de novo synthesis of enzymes involved in cAMP production. Glucocorticoids stimulate lipolysis by accelerating lipase synthesis via a cAMP-independent pathway that is inhibited by insulin. These data help clarify The Role of the Pituitary Gland and adrenal cortex in enhancing fat mobilization.

By releasing norepinephrine within adipose tissue, the sympathetic Nervous system plays a central role in the mobilization of free fatty acids. The enhancement of lipolysis induced by many of the factors discussed above can be reduced or completely prevented by denervation of adipose tissue, ganglion blockade with hexamethonium, or the depletion of norepinephrine stores via the administration of reserpine.

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Fig. 26.9. Regulation of lipolysis in adipose tissue. TSH — thyroid-stimulating hormone; FFA — free fatty acids. Note that due to the cascade sequence, rate acceleration can occur at various stages. Lipolysis is inhibited by: 1) removal of the stimulatory hormone; 2) the action of lipase phosphatase; 3) inhibition of lipase and adenylate cyclase by high concentrations of FFAs; 4) inhibition of adenylate cyclase by adenosine; 5) phosphodiesterase-catalyzed Hydrolysis of cAMP. It is possible that ACTH, TSH, and glucagon do not activate adenylate cyclase in vivo, since the concentrations of each of these hormones required in vitro are much higher than those detected in the bloodstream. Dashed lines indicate positive (+) and negative (—) regulatory effects, while solid lines represent substrate flux.