Hormones Regulate Fat Mobilization

Insulin Reduces the Output of Free Fatty Acids

The rate of release of free fatty acids from adipose tissue is affected by many hormones that influence either the rate of esterification or the rate of lipolysis. Insulin inhibits the release of free fatty acids from adipose tissue, which is followed by a fall in circulating plasma free fatty acids. It enhances lipogenesis and the synthesis of acylglycerol and increases the oxidation of glucose to CO2 via the pentose phosphate pathway. All of these effects are dependent on the presence of glucose and can be explained, to a large extent, on the basis of the ability of insulin to enhance the uptake of glucose into adipose cells via the GLUT 4 transporter. Insulin also increases the activity of pyruvate dehydrogenase, acetyl-CoA carboxylase, and glycerol phosphate acyltrans-ferase, reinforcing the effects of increased glucose uptake on the enhancement of fatty acid and acylglycerol synthesis. These three enzymes are now known to be regulated in a coordinate manner by phosphorylation-dephosphorylation mechanisms.

A principal action of insulin in adipose tissue is to inhibit the activity of hormone-sensitive lipase, reducing the release not only of free fatty acids but of glycerol as well. Adipose tissue is much more sensitive to insulin than are many other tissues, which points to adipose tissue as a major site of insulin action in vivo.

Several Hormones Promote Lipolysis

Other hormones accelerate the release of free fatty acids from adipose tissue and raise the plasma free fatty acid concentration by increasing the rate of lipolysis of the triacylglycerol stores (Figure 25-8). These include epi-nephrine, norepinephrine, glucagon, adrenocorticotro-pic hormone (ACTH), a- and P-melanocyte-stimulat-ing hormones (MSH), thyroid-stimulating hormone (TSH), growth hormone (GH), and vasopressin. Many of these activate the hormone-sensitive lipase. For an optimal effect, most of these lipolytic processes require the presence of glucocorticoids and thyroid hormones. These hormones act in a facilitatory or permissive capacity with respect to other lipolytic endocrine factors.

The hormones that act rapidly in promoting lipoly-sis, ie, catecholamines, do so by stimulating the activity of adenylyl cyclase, the enzyme that converts ATP to cAMP. The mechanism is analogous to that responsible for hormonal stimulation of glycogenolysis (Chapter 18). cAMP, by stimulating cAMP-dependent protein kinase, activates hormone-sensitive lipase. Thus, processes which destroy or preserve cAMP influence lipolysis. cAMP is degraded to 5'-AMP by the enzyme cyclic 3',5'-nucleotide phosphodiesterase. This enzyme is inhibited by methylxanthines such as caffeine and theophylline. Insulin antagonizes the effect of the lipolytic hormones. Lipolysis appears to be more sensitive to changes in concentration of insulin than are glucose utilization and esterification. The antilipolytic effects of insulin, nicotinic acid, and prostaglandin E1 are accounted for by inhibition of the synthesis of cAMP at the adenylyl cyclase site, acting through a Gi protein. Insulin also stimulates phosphodiesterase and the lipase phosphatase that inactivates hormone-sensitive lipase. The effect of growth hormone in promoting lipolysis is dependent on synthesis of proteins involved in the formation of cAMP. Glucocorticoids promote lipolysis via synthesis of new lipase protein by a cAMP-independent pathway, which may be inhibited by insulin, and also by promoting transcription of genes involved in the cAMP signal cascade. These findings help to explain the role of the pituitary gland and the adrenal cortex in enhancing fat mobilization. The recently discovered body weight regulatory hormone, leptin, stimulates

Epinephrine, norepinephrine

t Insulin, prostaglandin E,, / nicotinic acid

P-Adrenergic ' "Q \ blockers n

Thyroid hormone ' v

Growth hormone ' %

Inhibitors of ■* protein synthesis

Thyroid hormone

Growth hormone ' %

Inhibitors of ■* protein synthesis

cAMP

Insulin

-ATP

cAMP

Hormone-sensitive lipase b (inactive)

Insulin

ATP

©

cAMP-

dependent

protein

kinase

Hormone-sensitive lipase b (inactive)

Insulin

Hormone-sensitive lipase a (active)

TRIACYL-GLYCEROL

^ FFA + Diacylglycerol

Hormone-sensitive lipase a (active)

Insulin

TRIACYL-GLYCEROL

^ FFA + Diacylglycerol

Hormone-sensitive lipase f

Insulin

Inhibitors of Glucocorticoids protein synthesis

2-Monoacylglycerol lipase

FFA + 2-Monoacylglycerol

FFA + glycerol

Figure 25-8. Control of adipose tissue lipolysis. (TSH, thyroid-stimulating hormone; FFA, free fatty acids.) Note the cascade sequence of reactions affording amplification at each step. The lipolytic stimulus is "switched off" by removal of the stimulating hormone; the action of lipase phosphatase; the inhibition of the lipase and adenylyl cyclase by high concentrations of FFA; the inhibition of adenylyl cyclase by adenosine; and the removal of cAMP by the action of phosphodiesterase. ACTH, TSH, and glucagon may not activate adenylyl cyclase in vivo, since the concentration of each hormone required in vitro is much higher than is found in the circulation. Positive (©) and negative (©) regulatory effects are represented by broken lines and substrate flow by solid lines.

lipolysis and inhibits lipogenesis by influencing the activity of the enzymes in the pathways for the breakdown and synthesis of fatty acids.

The sympathetic nervous system, through liberation of norepinephrine in adipose tissue, plays a central role in the mobilization of free fatty acids. Thus, the increased lipolysis caused by many of the factors described above can be reduced or abolished by denerva-tion of adipose tissue or by ganglionic blockade.

A Variety of Mechanisms Have Evolved for Fine Control of Adipose Tissue Metabolism

Human adipose tissue may not be an important site of lipogenesis. There is no significant incorporation of glucose or pyruvate into long-chain fatty acids; ATP-

citrate lyase, a key enzyme in lipogenesis, does not appear to be present, and other lipogenic enzymes—eg, glucose-6-phosphate dehydrogenase and the malic enzyme—do not undergo adaptive changes. Indeed, it has been suggested that in humans there is a "carbohydrate excess syndrome" due to a unique limitation in ability to dispose of excess carbohydrate by lipogenesis. In birds, lipogenesis is confined to the liver, where it is particularly important in providing lipids for egg formation, stimulated by estrogens. Human adipose tissue is unresponsive to most of the lipolytic hormones apart from the catecholamines.

On consideration of the profound derangement of metabolism in diabetes mellitus (due in large part to increased release of free fatty acids from the depots) and the fact that insulin to a large extent corrects the condi-

OUTSIDE

INNER MITOCHONDRIAL

INSIDE

OUTSIDE

INNER MITOCHONDRIAL

INSIDE

Fat Mobilization

Figure 25-9. Thermogenesis in brown adipose tissue. Activity of the respiratory chain produces heat in addition to translocating protons (Chapter 12). These protons dissipate more heat when returned to the inner mitochondrial compartment via thermogenin instead of generating ATP when returning via the F1 ATP synthase. The passage of H+ via thermogenin is inhibited by purine nucleotides when brown adipose tissue is unstimulated. Under the influence of norepinephrine, the inhibition is removed by the production of free fatty acids (FFA) and acyl-CoA. Note the dual role of acyl-CoA in both facilitating the action of thermogenin and supplying reducing equivalents for the respiratory chain. © and © signify positive or negative regulatory effects.

Figure 25-9. Thermogenesis in brown adipose tissue. Activity of the respiratory chain produces heat in addition to translocating protons (Chapter 12). These protons dissipate more heat when returned to the inner mitochondrial compartment via thermogenin instead of generating ATP when returning via the F1 ATP synthase. The passage of H+ via thermogenin is inhibited by purine nucleotides when brown adipose tissue is unstimulated. Under the influence of norepinephrine, the inhibition is removed by the production of free fatty acids (FFA) and acyl-CoA. Note the dual role of acyl-CoA in both facilitating the action of thermogenin and supplying reducing equivalents for the respiratory chain. © and © signify positive or negative regulatory effects.

tion, it must be concluded that insulin plays a prominent role in the regulation of adipose tissue metabolism.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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