Glucagon lipolysis

Otfier fiormones accelerate tfie release of free fatty acids from adipose tissue and raise tfie plasma free fatty acid concentration by increasing the rate of lipolysis of the triacylglycerol stores (Figure 25—8). These include epinephrine, norepinephrine, glucagon, adrenocorticotropic 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 hpase. 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. 

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. ACTFI,TSFI, 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.

Gs Glucagon, 3-adrenergics T Adenylyl cyclase T Cardiac Ca +, CL, and Na+ channels Gluconeogenesis, lipolysis, glycogenolysis... 

The regulation of fat metabolism is relatively simple. During fasting, the rising glucagon levels inactivate fatty acid synthesis at the level of acetyl-CoA carboxylase and induce the lipolysis of triglycerides in the adipose tissue by stimulation of a hormone-sensitive lipase. This hormone-sensitive lipase is activated by glucagon and epinephrine (via a cAMP mechanism). This releases fatty acids into the blood. These are transported to the various tissues, where they are used. 

Hormones can modify the concentration of precursors, particularly the lipolytic hormones (growth hormone, glucagon, adrenaline) and cortisol. The lipolytic hormones stimulate lipolysis in adipose tissue so that they increase glycerol release and the glycerol is then available for gluconeogenesis. Cortisol increases protein degradation in muscle, which increases the release of amino acids (especially glutamine and alanine) from muscle (Chapter 18). 

Changes in hormone levels in starvation can extend the control provided by the cycle. The levels of glucagon and growth hormone are increased, which stimulates lipolysis, and the level of insnUn is decreased, which decreases rates of glncose nptake bnt increases lipolysis and hence fatty acid mobilisation (Fignres 16.3 and 16.4). 

Figure 16.4 Effect of several hormones on the glucose/fatty acid cycle. Catecholamines, glucagon and growth hormone stimulate lipolysis in adipose tissue and hence antagonise the effects of insulin.

In fat cells epinephrine stimulation of cyclic AMP accumulation and lipolysis is markedly reduced in hypothyroidism but enhanced in hyperthyroidism (see Ref. 79). Similar effects of altered thyroid status on the response to two other lipolytic hormones, ACTH and glucagon, have been reported suggesting that thyroid hormones regulate similarly either the different receptors of the various lipolytic hormones and/or a common step of the lipolytic pathway [80],... 

Situations in which the blood insulin/glucagon ratio is higher than normal lead to fatty acid and cholesterol biosynthesis, whereas low insulin/glucagon ratios are characterized by lipolysis, increased activity of the /3-oxidation pathway, and a low level of cholesterol biosynthetic activity. Enzymes that are either activated by insulin or derepressed by low glucagon levels are lipoprotein lipase, which... 

Because insulin normally inhibits lipolysis, a diabetic has an extensive lipolytic activity in the adipose tissue. As is seen in Table 21.4, plasma fatty acid concentrations become remarkably high. /3-Oxidation activity in the liver increases because of a low insulin/glucagon ratio, acetyl-CoA carboxylase is relatively inactive and acyl-CoA-camitine acyltransferase is derepressed. /3-Oxidation produces acetyl-CoA which in turn generates ketone bodies. Ketosis is perhaps the most prominent feature of diabetes mellitus. Table 21.5 compares ketone body production and utilization in fasting and in diabetic individuals. It may be seen that, whereas in the fasting state ketone body production is roughly equal to excretion plus utilization, in diabetes this is not so. Ketone bodies therefore accumulate in diabetic blood. 

Fatty acids increase in the bloodstream in a lipolysis environment, when blood glucagon levels are increased. 

In the -in vivo situation, the ketogenic action of glucagon is most prominent in states of insulin deficiency. This can be explained because insulin normally suppresses the effect of glucagon on hepatic cAMP levels [170] and inhibits the action of the hormone on lipolysis, i.e., fatty acid release in adipose tissue [171]. 

Inhibits Glucagon-, Cortisol-, Epinephrine- Dibutyryl cAMP-induced adipocyte lipolysis]... 

The initial event in the utilization of fat as an energy source is the hydrolysis of triacylglycerols by lipases, an event referred to as lipolysis. The lipase of adipose tissue are activated on treatment of these cells with the hormones epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone. In adipose cells, these hormones trigger 7TM receptors that activate adenylate cyclase (Section 15,1.3 ). The increased level of cyclic AMP then stimulates protein kinase A, -which activates the lipases by phosphorylating them. Thus, epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone induce lipolysis (Figure 22.6). In contrast, insulin inhibits lipolysis. The released fatty acids are not soluble in blood plasma, and so, on release, serum albumin binds the fatty acids and serves as a carrier. By these means, free fatty acids are made accessible as a fuel in other tissues. 

Ketogenesis is an important metabolic function in the liver. It is the result of an increase in lipolysis in the fatty tissue, with a rise in fatty acids. Insulin inhibits ketogenesis, whereas it is accelerated by fasting as well as by glucagons and insulin deficiency. Ketones (acetacetate, 3-hydroxybutyrate, acetone) are synthesized by means of P-oxidation from acetyl-CoA, assuming the production of this substance exceeds the amount required by the hepa-tocytes (and glucose metabolism is simultaneously reduced). The liver itself does not require any ketones acetone is expired, whereas 3-hydroxybutyrate and acetacetate serve as a source of energy. Ketonaemia can lead to metabolic acidosis and electrolyte shifts. 

Starvation —> Low Blood Glucose —> Insulin Low, Glucagon High —> (+) Lipolysis (free fatty acids for liver). 

Glucagon, which is elevated during fasting, stimulates lipolysis. 

C. VLDL levels are elevated because the decreased insulin and increased glucagon cause lipolysis of adipose triacylglycerols. The fatty acids and glycerol are repackaged in VLDL, which are secreted by the liver. Therefore, both triacylglycerols and cholesterol are elevated in the blood. Lipoprotein lipase is decreased because its synthesis and secretion by adipose tissue are stimulated by insulin. 

Withdrawal of most, or all, caloric intake has been used to treat certain cases of obesity. Such withdrawal provokes many metabolic responses. The body attempts to conserve protein at the expense of other sources of energy, such as fat. The blood glucose concentration decreases by as much as ISmg/dL (1 mmol/L) within the first 3 days of the start of a fast in spite of the body s attempts to maintain glucose production. Insulin secretion is greatly reduced, whereas glucagon secretion may double in an attempt to maintain normal glucose concentration. Lipolysis and hepatic keto-... 

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