158 Gluconeogenesis and the Atkins Diet

Have you ever wanted to know how the Atkins diet worked. This module will try to explain it by talking about the process of gluconeogenesis. This is in fact the body’s response to starvation, fasting and diet. Your heart and your brain require glucose for energy. They can’t use fatty acids for example, from fat breakdown. It turns out that glucose stored in the liver or kidneys, largely as glycogen, lasts 4-6 hours. And yet we can survive for weeks without food. So how is this possible? Well, the answer again is gluconeogenesis. Gluconeogenesis is the synthesis of glucose from non-carbohydrate sources. This provides the glucose that will be necessary for neural tissue and cardiac function when in fact, dietary glucose is in short supply. Well, this is the body’s response to fasting. In essence by the way, this is very similar to a stress response. And some of you may know a little bit about stress responses. The hypothalamus is a neurosecretory gland at the base of the brain. It releases neurosecretory hormones, or neuohormones which stimulate the pituitary gland very nearby. Among the responses of the pituitary gland, is the production and release of adrenocorticotropic hormone, or ACTH, (which you may have heard of) that stimulates the adrenal glands at the ‘cap’ or top of the kidneys to release glucocorticoids such as cortisone and corticosterone. And these steroid hormones have a number of effects. They affect skeletal muscle by increasing the transcription and translation of proteolytic enzymes, enzymes that catalyze the digestion of proteins. These are called collectively ‘proteases’. So you see that proteases are enzymes that catalyze the breakdown, or hydrolysis of proteins to amino acids The glucocorticoids have other effects as well on many tissues. In most tissues, including adipose tissue, glucocorticoids stimulate an increase in the amount of enzymes called lipases. And lipases are enzymes that catalyze the breakdown of triglycerides, the hydrolysis of the fatty acids from glycerol. And finally, glucocorticoids travel to the liver, where they induce the transcription again, and translation of a number of enzymes, referred to collectively as bypass enzymes. We’ll talk about exactly what they do in just a second. But the function of bypass enzymes is to facilitate the conversion of non- carbohydrate sources, such as amino acids, into glucose in the liver, also to some extent in the kidneys. So here is gluconeogenesis. And watch for the significance of these biologically irreversible reactions that we talked about, largely when we discussed glycolysis. So on this illustration is a summary of glycolysis, showing the various steps, not in detail, but in summary form. And the steps, numbered 1, 2 and 3, catalyzed by hexokinase, phosphofructokinase and pyruvate kinase, are the 3 biologically irreversible reactions of glycolysis, And of course, as you can see at the bottom, the product of glycolysis under aerobic conditions of course, is pyruvic acid (or pyruvate). If you are dieting or fasting, even sleeping, or starving, this sets off a series of hormonal events that I just showed you, that among other things, reverse glycolysis in the liver. As we saw just a moment ago, they also stimulate the use of alternative energy sources like fatty acids for energy, by stimulating the breakdown of triglycerides, freeing up fatty acids for beta oxidation in most cells. In the liver and again to some extent in the kidneys, this is what these hormonal events do. They stimulate the synthesis of these bypass enzymes which carry out the reactions which in glycolysis going in the forward direction, are irreversible. And you can see the names of these bypass enzymes. So, pyruvate kinase is biologically irreversible. So to get pyruvate to go back to phosphoenolpyruvate, you actually have to go through two steps, shown here catalyzed by pyruvate carboxylase and phosphoenol pyruvate carboxylase. The phosphofructokinase biologically irreversible forward reaction of glycolysis, is bypassed by the enzyme fructose bisphosphatase. And finally, since hexokinase cannot go in reverse, you must bypass the hexokinase step using glucose 6-phosphate phosphatase. You may recall that we saw this enzyme earlier in the discussion of glycolysis. These four enzymes are normally not present in the liver or the kidneys, but during fasting or dieting or starvation, glucocorticoid hormones released by the hormonal processes I just showed you, stimulate the transcription and translation of mRNAs for these enzymes in these tissues. Now it turns out that glucocorticoids are actually released right around the time you wake up. It’s a kind of a diurnal rhythm, a daily rhythm every morning, whenever you wake up, glucocorticoids are released. They are released automatically but why do you think they would have been released automatically? They’re released because at dawn, your body is supposed to think that it is fasting. It’s in a gluconeogenic mode. In fact, glucose reserves, glycogen in the liver and the kidneys and other cells that store glycogen, those reserves are tapped out. In fact, you are normally gluconeogenic in the morning. and so your body has evolved a way to ensure that you will be doing gluconeogenesis, or at least have the hormones ready to prime gluconeogenesis when you wake up. Let’s take a look at the centrality of this respiratory pathway. Here it is. I just want to highlight those parts of the pathways that you see here that are in fact gluconeogenic, that is, occur or happen during gluconeogenesis. Lipids are broken down into glycerol and fatty acids. The fatty acids undergo beta oxidation , which can happen at any time but are especially prevalent during gluconeogenic times. The glycerol is a gluconeogenic substrate because it enters the glycolytic pathway where it can either go up or down, depending on the cell’s needs for energy. The conversion of gluconeogenic amino acids to pyruvate is shown here as happening at two levels. Some amino acids are converted to acetyl coenzyme A. Others are converted to one or another of the intermediates in the tricarboxylic acid cycle, So once again the respiratory pathway is central to a lot of biochemical metabolism, including the gluconeogenic response. So why does the Atkins diet work? Because it encourages consumption of lipids, fats, which is the usual source of a lot of obesity. And at the same time, allows the body to use amino acids as a source of energy, rather than glucose, which is especially important because, for the sustenance of neural tissue and cardiac tissue, the amino acids are converted back to glucose in liver and kidney, which is then released to the circulation and can circulate largely to heart and nerve tissue.

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