Glucagon lipolysis stimulation

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.

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],... 

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. 

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. 

Triacylglycerols can be mobilized by the hydrolytic action of lipases that are under hormonal control. Glucagon and epinephrine stimulate triacylglycerol breakdown by activating the lipase. Insulin, in contrast, inhibits lipolysis. Fatty acids are activated to acyl CoAs, transported across the inner mitochondrial membrane by carnitine, and degraded... 

The answer is h. (Murray, pp 123—148. Scriver, pp 2367—2424. Sack, pp 159-175. Wilson, pp 287-317.) The regulatory enzyme of lipolysis is hormone-sensitive lipase. It is a triacylglyceride lipase of adipose cells regulated by hormones. The hormones that stimulate release of fatty acids into the blood are glucagon, epinephrine, and norepinephrine, all of which activate adipocyte membrane adenylate cyclase. This produces an increased level of cyclic AMP, which activates a protein lipase that, in turn, phosphorylates and activates the sensitive lipase. In contrast, insulin causes dephosphorylation and inhibition, thereby shutting down lipolysis and the release of fatty acids into the bloodstream. 

Some hormones inhibit adenylate cyclase activity. Such molecules depress cellular protein phosphorylation reactions because their receptors interact with G, protein. When Gi is activated, its ( subunit dissociates from the /fydimer and prevents the activation of adenylate cyclase. For example, because its receptors in adipocytes are associated with G PGK, (prostaglandin H,) depresses lipolysis. (Recall that lipolysis is stimulated by glucagon and epinephrine.)... 

Glucagon causes increases in cAMP in the adipose and liver. In the adipose this causes an increase in lipolysis and release of nonesterified fatty acids to the blood. These fatty acids stimulate gluconeogenesis in the liver and decreased use of glucose in the muscle. The increased cAMP in the liver results in increased glycogenolysis and increased gluconeogenesis, both of which help increase blood glucose levels. 

Fig. 43.6. Effects of epinephrine on fuel metabolism and pancreatic endocrine function. Epinephrine (Epi) stimulates glycogen breakdown in muscle and liver, gluconeogenesis in liver, and lipolysis in adipose tissue. Epinephrine further reinforces these effects because it increases the secretion of glucagon, a hormone that shares many of the same effects as epinephrine. Epi also inhibits insulin release but stimulates glucagon release from the pancreas.

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