Metabolism 101 R. Low, 02/10/14 Need to fix text a la part-1

Metabolism 101 R. Low, 02/10/14 Need to fix text a la part-1
The purpose of this module is to assist your understanding of foodstuff / energy metabolism. The exercise reviews basic metabolic pathways focusing ONLY on pathways of energy metabolism. That is followed by the major operative pathways in Brain, Muscle, Adipose Tissue and Liver. Next is considered the organ-by-organ actions of key regulatory hormones: insulin, glucagon, growth hormone, cortisol and epinephrine. Finally, energy substrate fluxes between organs in the fed and fasted state is considered. Feedback with regard to the value of this module, including changes that would be recommended will be gratefully received:

Absorptive phase of digestion: Have just eaten a meal
Definitions Absorptive phase of digestion: Have just eaten a meal Postabsorptive phase of digestion: Several hours after eating a meal Adapted fast: Changes in brain energy use and overall metabolism that extend the ability to fast out to weeks. Begins within a few days. Three key definitions.

Glycogen Glycogen is the key repository for glucose. Though it is found in most organs, the focus here will be on the glycogen stored in liver and muscle. It is important to realize that the total energy stored as glycogen is not even enough to satisfy total energy needs for a single day.

Trigylceride Triglyceride is the major energy store of the body. Normally it principally is located in adipose tissue. In conditions of caloric excess triglycerides can build up in other tissues such as liver, muscle and heart, but to the significant detriment of those organs.

Protein Protein can be an important source of carbon skeletons / amino acids for satisfying body requirements for glucose. However, protein is functional; and must be used only most sparingly.

Body Energy Stores A big picture view of body composition in terms of carbohydrate, fat and protein. Also their energy content. Note the small amount of glucose both in terms of weight and calories – not enough for the energy needs of a single day. There are substantial amounts of protein, BUT those proteins are functional: from enzymes to contractile to structural proteins. Use of body protein must be kept to a minimum. As will be discussed later, the body goes to great pains to protect protein even during times of prolonged fasting.

The “Full Monty” Cell (which does not exist)
Amino Acids Glucose Ketoacids Triglycerides Fatty Acids Glycogen Triglycerides Protein Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA The goal of this first slide is to provide a basic framework. Again, it is focused ONLY on pathways to consider with regard to overall energy / foodstuff metabolism. The purpose here simply (!) is to present the outlines of the metabolic pathways for carbohydrate, fat and protein. As suggested by the slide title, there is no cell that contains all of these pathways. The intent of this slide, therefore, is to show you the repertoire available, in a sense, to the whole body. Future slides will use this same framework to flesh out the hormonal control of these pathways and, thereafter, show how they are manipulated as one encounters issues of daily living in terms of when one has just eaten (e.g. dinner) as compared with when one has not eaten for several hours (just before breakfast). The discussion will extend into what occurs with prolonged, adapted fasting (think days, indeed weeks). There are many things missing in this slide, for example the pentose phosphate pathway. This is because their focus is on energy metabolism. As well, there are no entries in this first slide indicating where CO2 and ATP are generated or NADH/H+, FADH2 and NADPH/H+ are produced. The purpose here is to keep clutter at a minimum this first time around. Some nomenclature. The red “bar” at the top is supposed to indicate a blood vessel. Ordinarily, all of those things are in the circulation, relative amounts depending on what you ate and when you last ate. NO effort has been made to use different fonts for the different metabolic conditions, i.e. the levels in the blood of each constituent under different metabolic conditions. In addition, the arrows simply show what pathways are present. No effort has been made in terms of the arrow font to indicate the relative importance of the pathways in any tissue or metabolic condition. Later on, when discussing the actions of individual hormones, green arrows are used to indicate a pathway that is stimulated; while red bars indicate a pathway is inhibited. Recall this means tilting a balance, not “black and white” - on / off. Our next task is to walk through this slide piece-by-piece. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Oxidative Phosphorylation H2O
Glucose Amino Acids Glucose Ketoacids Triglycerides Fatty Acids Glycogen Triglycerides Protein Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA This slide begins with glucose, the central metabolic pathway. The first issue is getting glucose into and out of the cell. Gaining entry requires the presence of one or another of the glucose transporter family about which you have heard. The mechanism involves facilitated diffusion. Glucose entry in certain tissues is unregulated as occurs for liver and brain. Glucose entry into certain other tissues is highly regulated, specifically for muscle and adipose tissue. Glucose exit into the circulation is only possible from two organs. That is because of the organ distribution of the key enzyme required to make free glucose, glucose-6-phosphatase. Under normal conditions of “daily living” , ≥ 85% of glucose delivered to the blood comes from the liver, the balance from the kidney. As will be discussed later, there are conditions, particularly prolonged adapted fast, where these proportions change. Once inside the cell, glucose is trapped by phosphorylation (glucose-6-Phosphate). A choice immediately can be made as to whether to use that G-6-P to make glycogen or to send it into glycolysis. Following glycolysis (cytoplasm, oxygen not required), the 3-carbon molecules derived from glucose enter the mitochondrion to be metabolized via the Krebs / TCA cycle, the high energy intermediates created (NADH + H+) then undergoing oxygen-requiring oxidative phosphorylation. Krebs Cycle O2 Oxidative Phosphorylation H2O ATP

Glucose - Fat Amino Acids Glucose Ketoacids Triglycerides Fatty Acids Glycogen Triglycerides Protein Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA To the previous slide has been added in black font the connections between glucose and fat metabolism. The 3-carbon glycerol backbone for triglyceride synthesis must come from glucose: the glycerol coming from triglyceride breakdown cannot be recycled. Fatty acids can be derived from acetyl-CoA. The latter (fatty acid synthesis) is not a major pathway under normal conditions. Rather the fatty acids for most triglycerides made by most tissues (e.g. muscle, adipose tissue and normally to a limited extent liver) are derived from the general circulation. Triglycerides, of course, can be broken down into their glycerol and fatty acid components. The glycerol can be moved back into glycolysis from which it originally came, most often then moving “up” glycolysis to make G-6-P, in preparation in the liver (or kidney to a small extent) to being released into the circulation as free glucose. If this occurs in other tissues such as muscle, adipose, or brain, free glucose cannot be made because those organs do not contain glucose-6-phosphatase. With one small exception that is of little meaning quantitatively from an energy point of view, fatty acids CANNOT be made into glucose. A biochemical reason for this is that the two carbons of the acetyl-CoA generated from fatty acid breakdown are removed early on in the Krebs cycle as CO2 (not shown). Krebs Cycle O2 Oxidative Phosphorylation H2O ATP

Glucose - Protein Amino Acids Glucose Ketoacids Triglycerides Fatty Acids Glycogen Triglycerides Protein Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA We now move on to the connections between glucose and protein. There are several locations where carbon skeletons coming from glucose can be converted to certain amino acids. Conversely, certain amino acids can be put back into the central glucose pathway, either at a point (e.g. pyruvate) where they can move back “up” glycolysis; or at a point (e.g. Krebs cycle) where they cannot be converted “upwards” but can be used to make ATP. The ability to make amino acids into glucose represents the ONLY way one can make new glucose molecules in a quantitatively meaningful way, known as gluconeogenesis. Strictly speaking, and though you will hear otherwise, gluconeogenesis (note the internal “neo”) can only come from amino acids. Certainly, glycerol can be made into glucose (see above) but it WAS glucose to begin with. Similarly glycogen was, of course made from glucose. As will be discussed principally in NMGI,. Gluconeogenesis must be undertaken during fasting (remember the absolute requirement the brain has for glucose). However, this must be kept to a minimum because protein does important things (think muscle contraction of breathing, all of the enzymes involved in these metabolic pathways, etc.). Krebs Cycle O2 Oxidative Phosphorylation H2O ATP

Ketoacids Amino Acids Glucose Ketoacids Triglycerides Fatty Acids Glycogen Triglycerides Protein Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA One more pathway needs to be considered at this point. That is the pathway that either involves synthesis of ketoacids from acetyl CoA for delivery to the circulation; or delivery of ketoacids to the cell to be made into ATP. This pathway is not much used in “daily” living” but becomes very important in fasting (and in Type-1 Diabetes mellitus). This pathway also admirably illustrates how available metabolic pathways are highly tissue-specific. Only the liver can make ketoacids. It does so when the amount of incoming fatty acid exceeds the capacity of the TCA cycle / ox-phos to convert them to ATP. Only other organs such as muscle and brain can use them. The liver cannot use them. Krebs Cycle O2 Oxidative Phosphorylation H2O ATP

Brain Glucose Ketoacids Glucose-6-P Glycolysis Pyruvate Ketoacids
Acetyl CoA Now on to consideration of these pathways in individual tissues. Shown here are the key energy-related pathways for brain. Again, recall that we are focused here ONLY on pathways related to overall energy metabolism. The brain exclusively uses glucose on a daily basis, BOTH in the absorptive (just ate) and the post-absorptive states (just before breakfast – haven’t eaten since dinner). As the post-absorptive state becomes prolonged into days, even weeks, the brain can switch some BUT NOT ALL of its energy needs to ketotacids delivered through the circulation from the liver. Glucose transport into brain cells is NOT regulated. In addition, bear in mind that the “trapping” enzyme, hexokinase, has a low Km, immediately converting glucose to glucose-6-phosphate (the trap). That means that glucose uptake takes place even at low blood glucose concentrations. (High Km indicates a low affinity for glucose and hence little activity until glucose concentrations get quite high. Low Km indicates a high affinity.) TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Muscle Amino Acids Lactate Glucose Ketoacids Triglycerides Fatty Acids
Glycogen Triglycerides Protein Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate Ketoacids Lactate Acetyl CoA Next we turn to muscle. As for brain, low Km hexokinase assures that glucose is “trapped” as glucose-6-phosphate, even at low blood glucose concentrations. HOWEVER, glucose entry is highly regulated, permitted in times of plenty (absorptive / fed) and reduced in times of need (postabsorptive / fast). Once glucose enters, it can be used to replete glycogen stores or to make ATP. It is not used to make the glycerol backbone or fatty acids that are the building blocks for triglyceride. Under anaerobic conditions, glycolysis proceeds ending with the production of lactate which is exported to the liver where it is made back into glucose – the Cori cycle. Fatty acids delivered from the blood coming either from the diet or from adipose tissue stores feed into the ATP-generating pathway via glycerol and fatty acids. Ketoacids are not normally present in the blood until the fasting state becomes prolonged, at which time ketoacids generated by the liver can be an alternative energy source. Muscle protein also plays a role. In the postabsorptive / fasting state, protein is broken down to amino acids for export to the liver where the amino acids are made into glucose – true gluconeogenesis. Correspondingly, in the absorptive / fed state, amino acids from the diet are returned to muscle to replenish protein. This is a crucial part of managing daily living. However, the use of protein from muscle MUST be kept to a minimum as will be explained further in HSF and NMGI. To summarize muscle utilization of energy substrates: Muscle can use either glucose, fatty acids or ketoacids for its energy needs. In fact, most muscles prefer fatty acids or ketoacids over glucose when they are available. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Adipose Tissue Glucose Triglycerides Fatty Acids Triglycerides
Glucose-6-P Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA Now for adipose tissue, whose mission in the context of this module is to store calories as triglyceride in times of plenty (absorptive / fed); and release them as fatty acids (and glycerol) in times of need (postabsorptive / fast). (Adipose tissue otherwise also provides padding and insulation.) As for brain and muscle, hexokinase with its low km assures that, again, glucose is “trapped” as glucose-6-phosphate, even at low blood glucose concentrations. Glucose entry into adipose tissue is regulated, just as for muscle. That will allow glucose to enter adipose tissue in times of plenty but be refused entry (“spared”) in times of need. Once in the fat cell, the glucose can be used to make ATP, or it can be diverted to glycerol to provide substrate for triglyceride synthesis. The glycerol used to synthesize triglyceride MUST come from glucose / glycolysis. The glycerol coming out of triglyceride cannot be used to make new triglyceride, but certainly can exit adipose tissue to be remade into glucose elsewhere (liver). In times of plenty, triglycerides will be converted into fatty acids at the adipose tissue membrane and which will then enter the fat cell to be remade into triglyceride, the backbone being provided by glycerol. It is true, and you will read that acetyl-CoA coming from glucose can be used by adipose tissue to make fatty acids. Relatively speaking, however this is not the normal situation in humans. Rather, the main source of fatty acids for triglyceride synthesis is from the circulation. This energetically makes great sense: why go through the energy-intensive process of making acetyl-CoA into fatty acids (at the expense of precious glucose) when they can be made far less expensively from the fatty acids coming in from the circulation. Similarly, fatty acids from adipose triglyceride certainly can feed into energy generation. However, energy needs for adipose tissue are really modest in comparison with other tissues, the majority therefore being dumped into the circulation to sub serve the needs of other tissues. The energy needs of adipose tissue are not large, necessary for triglyceride synthesis and mobilization, together with housekeeping. Incoming glucose, fatty acids or ketoacids are available. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Liver Amino Acids Glucose Ketoacids Triglycerides Fatty Acids Glycogen
Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA Now on to the liver, the metabolic brain for the body. Glucose entry into liver is UNregulated. However, the enzyme that phosphorylates glucose to glucose-6-phosphate preventing the glucose from exiting the liver, glucokinase, has a high Km. That permits the liver to have a “buffering” effect on blood sugar. Little glucose enters the liver at low to moderate blood glucose levels due to the high glucokinase Km. Rather, much of it bypasses, being distributed to the low Km hexokinase tissues where it will be taken up all the time (e.g. brain) or when permitted (muscle, adipose). Once in the liver due to high blood sugar levels, glucose can be converted to glycogen when glycogen stores have been reduced (as when fasting). It also can enter glycolysis. HOWEVER, glucose does NOT usually proceed through glycolysis to the TCA cycle and oxidative phosphorylation. As explained below amino acids are the dominant source of carbon skeletons to make ATP in times of plenty; and fatty acids in times of need. Unless severely overloaded (e.g. due to chronically high blood sugar levels) though glucose can be made into glycerol for fatty acid synthesis, that does not happen much in humans. Similarly, the healthy human normally does not use glucose to make acetyl CoA for fatty acid synthesis. As for protein / amino acids, the liver is not really in the business of exporting amino acids themselves. (It does export blood proteins BUT that is OFF-TOPIC.) However, it does take up amino acids for conversion to ATP, coming from the diet in times of plenty; and from muscle in times of need. The latter repedsents true gluconeogenesis. For fat, liver is NOT normally in the business of making much triglyceride or storing it. However, it will use fatty acids coming in from the circulation to generate ATP in times of need, when ATP generation switches from amino acids as the source of carbon skeletons to fatty acids (the amino acids now being devoted to gluconeogenesis). In terms of energy substrates, the liver normally does NOT use glucose. During times of plenty, as after a meal, amino acids are the energy substrate. Withy fasting, the liver switches to fatty acids. The liver cannot use ketoacids to make ATP. One more fatty acid pathway of importance. The liver normally does not convert acetyl-CoA to ketoacids for export (the liver cannot use them). But it does so in times of need, as the fasting condition prolongs and fatty acid entry to the liver from the blood has increased substantially. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Kidney Amino Acids Glucose Ketoacids Triglycerides Fatty Acids
Glycogen Triglycerides Glucose-6-P Amino Acids Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA The kidney appears to be similar to liver for carbs, protein and fat with one important exception. The kidney cannot make ketoacids (only the liver can) but it can use ketoacids as an energy source (while the liver cannot). Glucose and fatty acids also can serve as energy substrate. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Hormones and Energy Metabolism
The purpose of the next section is to summarize the effects of key hormones SPECIFICALLY on (whole body) foodstuff metabolism. In doing so, one invariable runs into the problem that the best picture requires one consider the hormones as a group: context is everything. But best to start individually. Accordingly, this section immediately will be followed by one where an attempt is made to put everything together.

HOW DOES ONE DO IT? Daily Living Emergency
Finally, two summary slides. This first one reminds you of the key phrases associated with each hormone and that the workhorses for daily living are INSULIN, growth hormone and glucagon. Epinephrine and cortisol are reserved for emergencies (which does NOT include fasting for a few days or even weeks). Emergency

REDUNDANCY -- COMPLEMENTARITY
This second summary slide reminds you of some of the key metabolic pathways the key hormones affect. Missing, of course, but discussed above, is the issue of which organ is doing what in response to each hormone.

EFFECTS OF INSULIN PRINCIPAL TARGETS: Liver, Adipose, Muscle
CARBOHYDRATE: - Increased Glucose Uptake: Muscle and Adipose - Increased Glycogenesis; decreased glycogenolysis - Decreased Gluconeogenesis FAT: - Increased Triglyceride Synthesis for Storage - Decreased Breakdown of Triglyceride Stores PROTEIN: - Increased Synthesis - Decreased Breakdown A big picture view of insulin action.

Major Insulin Actions: Tissue by Tissue
Liver: INcreased glycogen deposition DEcreased glycogenolysis INcreased glucose use DEcreased gluconeogenesis Muscle: INcreased Glucose transport / use INcreased Protein synthesis DEcreased protein degradation Adipose: INcreased Triglyceride synthesis / storage DEcreased triglyceride breakdown / release This slide summarizes the key actions of insulin in different organs. It is companion to the next cartoons that summarize the same.

Insulin - Muscle Amino Acids Lactate Glucose Ketoacids Triglycerides
Fatty Acids Glycogen Triglycerides Protein Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate Ketoacids Lactate Acetyl CoA Insulin increases glucose transport into muscle, as well as fostering its conversion to glycogen and transit through glycolysis, TCA cycle and Oxidative Phosphorylation. Insulin, of course, also is a growth promoter, certainly for muscle. Though it does increase amino acid transport and also to a degree protein synthesis, its dominant effect is to block protein degradation. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Insulin- Adipose Tissue
Glucose Triglycerides Fatty Acids Triglycerides Glucose-6-P Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA As the “storage hormone” insulin does all it can to assure that incoming calories after a meal (“after dinner hormone”) are disposed of properly. Cardinal here is the ability of insulin to increase glucose transport into adipose tissue (same mechanism as for muscle) such that the glucose can be made into glycerol to enable triglycerides synthesis. (Some glucose as well will be oxidized to ATP, bearing in mind that adipose tissue has limited energy needs.) Insulin has major effects on fats. First, it activates the endothelial cell lipase required to breakdown triglycerides in the blood to fatty acid products that can then enter the tissue. Subsequently, triglyceride synthesis is increased while triglyceride degradation is inhibited. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Insulin - Liver Amino Acids Glucose Ketoacids Triglycerides
Fatty Acids Glycogen Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA Recall that glucose has free entry into the liver, a good thing if the liver is the metabolic brain. So regulation of glucose metabolism occurs subsequent to its phosphorylation by high Km glucokinase. Synthesis of glycogen is increased and glycogen breakdown simultaneously decreased. Remember, however, that the liver normally does NOT use glucose to make ATP, using amino acids in times of plenty and fatty acids in times of need. Similarly, the liver normally does not devote incoming glucose to triglyceride synthesis. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Major Glucagon Actions: Tissue by Tissue
Liver: DEcreased glycogen deposition INcreased glycogenolysis DEcreased glucose use INcreased gluconeogenesis INcreased Fatty Acid Oxidation Muscle: Not much Adipose: This slide summarizes the key actions of glucagon in different organs. It is companion to the next cartoons that summarize the same.

Glucagon - Muscle Amino Acids Lactate Glucose Ketoacids Triglycerides
Fatty Acids Glycogen Triglycerides Protein Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate Ketoacids Lactate Acetyl CoA Glucagon does very little in muscle. Hence, this panel has no green arrows or red bars. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Glucagon - Adipose Tissue
Glucose Triglycerides Fatty Acids Triglycerides Glucose-6-P Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA You doubtless will read and hear that glucagon has effects on adipose tissue. Direct examination of the literature suggests that is not the case in humans. Hence, again, no green arrows or red bars. At the same time Glucagon DOES affect fat metabolism but those effects are found in the liver (see below). TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Glucagon - Liver Amino Acids Glucose Ketoacids Triglycerides
Fatty Acids Glycogen Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids R + NH2 Glycolysis NH3 + Urea Pyruvate Ketoacids Acetyl CoA As its name implies, glucagon has everything to do with glucose metabolism. This is due to its effects in the liver to cause glycogenoloysis and to promote gluconeogenesis. As noted in the panel for adipose tissue, though glucagon in humans does not cause increased lipolysis, glucagon does affect fat metabolism in the liver. Specifically, it increases the ability of the liver to metabolize fatty acids to acetyl-CoA for oxidation to make ATP. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

GROWTH HORMONE AND CARBOHYDRATE
Reduced Glucose Uptake by Muscle Reduced intracellular Glucose Processing Gluconeogenesis: do not believe so? - Glycerol from triglyceride breakdown CAME from glucose - Increased utilization of amino acids for protein synthesis means fewer available for true gluconeogensis. Insulin ANTAGONISM: - Carbohydrate and Fat This slide summarizes the key actions of growth hormone on carbohydrate. Growth Promoter Fat Mobilizer Glucose Sparer

Adipose tissue: Triglyceride Mobilization
GROWTH HORMONE AND FAT Adipose tissue: Triglyceride Mobilization Reduced fat (triglyceride) Synthesis Central role of fat products in the blood as a regulator of Glucose uptake and utilization They BLOCK Insulin Action: Insulin ANTAGONISM The summary for fat.

GROWTH HORMONE AND PROTEIN
INCREASED SYNTHESIS* DECREASED DEGRADATION Insulin AGONISM The same for protein. *Mostly due to increased numbers of ribosomes, i. e. capacity

( ) ( ) ( ) ( ) ( ) ( ) ( ) Growth Hormone - Muscle ( ) = Indirect
Amino Acids Lactate Glucose Ketoacids Triglycerides Fatty Acids Glycogen Triglycerides Protein ( ) ( ) Indirect Glucose-6-P Amino Acids ( ) Glycerol Fatty Acids Glycolysis ( ) Indirect Pyruvate ( ) Ketoacids Lactate Acetyl CoA Glucose entry into muscle is inhibited by Growth Hormone. Studies of humans indicate this is due to the increased presence of fatty acids in the blood, due to the effects of the hormone on adipose tissue (next slide). Hence the parentheses around the negative effect on glucose uptake uptake. Even if glucose entry was not impeded, the presence of fatty acids in the tissue blocks its further utilization as an energy substrate. A key concept expressed here is that fat products in the blood block glucose entry into muscle and adipose tissue – they block insulin action. REMEMBER THIS. Fatty acid delivery to muscle and use to make ATP is enhanced in the presence of growth hormone. The green arrows are marked as indirect effect, again, because the effect of growth hormone essentially is on delivery of fatty acids through the blood. That automatically causes their increased use. Growth Hormone also promotes muscle protein synthesis. As will be discussed later, this is important after a meal in restoring muscle protein used to make glucose between meals. ( ) Indirect ( ) = Indirect TCA Cycle ( ) Indirect O2 Oxidative Phosphorylation H2O ATP

( ) Growth Hormone - Adipose Tissue ( ) = Indirect Glucose
Triglycerides Fatty Acids Triglycerides ( ) Glucose-6-P Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA Glucose entry into adipose is inhibited by Growth Hormone, just as for muscle. Again, the parentheses indicate that this effect is due to increased fatty acids in the blood. Growth hormone has a major positive effect on triglyceride breakdown in adipose tissue, delivering fatty acids and glycerol to the blood. ( ) = Indirect TCA Cycle O2 Oxidative Phosphorylation H2O ATP

( ) ( ) ( ) Growth Hormone - Liver Amino Acids Glucose Ketoacids
Triglycerides Fatty Acids Glycogen Triglycerides ( ) Indirect Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids ( ) Indirect Acetyl CoA The primary effects of Growth hormone on the liver from the point of view of energy metabolism are indirect. Of prime importance is the increased delivery of fatty acids from growth hormone induced breakdown of triglycerides in adipose tissue, releasing fatty acids and glycerol into the circulation. They become the energy substrate for ATP production. Their presence blocks glucose use as an energy source. These effects on energy substrate utilization are similar to what is seen in muscle. An important difference from muscle, however, is that unlike muscle, glucose entry into liver is unregulated at the glucose transporter level. ( ) Indirect TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Cortisol and Foodstuff Metabolism
Increased Appetite: Obesity Insulin Resistance (fatty acids) Carbohydrate: Gluconeogenesis: - Muscle protein breakdown - Increased liver gluconeogenic enzymes - Glycogen deposition - Hyperglycemia Fat: - Increased adipose tissue (appetite) - Selective deposition: trunk / visceral fat Protein: - Profound muscle protein breakdown We now move to one of the two “stress hormones”. Neither really is involved in the management of energy metabolism on a daily basis. This slide summarizes the key actions of cortisol on different energy substrates.

Cortisol and Metabolism
Organ by Organ Muscle Increased Protein Breakdown Adipose Increased Triglyceride deposition – trunk Liver Increased gluconeogenesis Increased glycogen deposition Increased glucose export This slide summarizes the key actions of cortisol in different organs. It is companion to the next cartoons that summarize the same.

Cortisol- Muscle Amino Acids Lactate Glucose Ketoacids Triglycerides
Fatty Acids Glycogen Triglycerides Protein Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate Ketoacids Lactate Acetyl CoA We now move to one of the two “stress hormones”. Neither really is involved in the management of energy metabolism on a daily basis. Cortisol profoundly affects muscle protein breakdown, subsequently delivering amino acids to the circulation. These amino acids travel to the liver where they are converted into glucose (see liver panel below). This is an essential part of the response to an emergency need for gluconeogensis. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Cortisol - Adipose Tissue
Glucose Triglycerides Fatty Acids Triglycerides Glucose-6-P Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA You almost certainly will read and hear that cortisol causes breakdown of triglycerides into fatty acids and glycerol for delivery to the circulation. The evidence for this is weak at best. The confusion here undoubtedly is related to the simultaneous presence of epinephrine coming from the adrenal medula under stress. It is the epinephrine that causes lipoysis (see below). Also related to this issue, cortisol DOES increased lipids in the blood, but these are coming from the effect of cortisol on appetite: you eat more. Hence, this panel shows no stimulated or inhibited pathways. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

( ) ( ) Cortisol - Liver Amino Acids Glucose Ketoacids Triglycerides
Fatty Acids ( ) Indirect Glycogen Triglycerides Glucose-6-P Amino Acids Glycerol R + NH2 Glycolysis ( ) Indirect NH3 + Urea Pyruvate Ketoacids Acetyl CoA Cortisol has both direct and indirect effects on the liver. These are aimed at the process of gluconeogenesis. A key aspect of cortisol action here is delivery to the liver of amino acids derived from cortisol-induced muscle protein breakdown, an indirect effect. A second key aspect of cortisol action is to induce the synthesis of increased amounts of hepatic gluconeogenic enzymes, a direct effect. Confusion often surrounds the fate of the newly formed glucose. The situation actually is quite simple. The increased amount of glucose in the liver, most simply put, will travel down almost all available pathways, from release into the blood to (increased amounts of) glycogen, to the pentose phosphate pathway. The newly formed glucose, however, will not be oxidized to form ATP. A major reason for this is that in the setting of increased cortisol, epinephrine levels invariably also will be increased and epinephrine causes adipose tissue lipolyis (see below). The increased delivery of fatty acids to the liver results in their being oxidized and glycolysis being inhibited. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Epinephrine: Effects on Metabolism
KEY PHRASES EMERGENCY / STRESS ENERGY PROVIDER Carbohydrate: - Glycogen Breakdown: Liver and Muscle - Gluconeogenesis: Liver (works with cortisol) Fat: - Increased Lipolysis: Mobilization Protein: - Little or no effect This slide summarizes the key actions of epinephrine on different energy substrates.

Epinephrine and Metabolism
Organ by Organ Muscle Little effect Adipose Increased Triglyceride breakdown / lipolysis Liver Increased glycogenolysis Increased gluconeogenesis Increased glucose export This slide summarizes the key actions of epinephrine in different organs. It is companion to the next cartoons that summarize the same.

( ) ( ) ( ) ( ) Epinephrine - Muscle Amino Acids Lactate Glucose
Ketoacids Triglycerides Fatty Acids Glycogen Triglycerides Protein ( ) Indirect Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis ( ) Indirect Pyruvate Ketoacids Lactate Acetyl CoA Epinephrine has important effects on glucose metabolism. A highlight in muscle is increased glycogenolysis and decreased glycogenesis. The increased formation of glucose-6-phosphate and its metabolism through gycolysis can provide carbon skeletons for glucose formation in the liver via transfer to the liver in the form of pyruvate / lactate. The fact that epinephrine causes adipocyte lipolysis (see below) provides fatty acids to muscle to be used as an energy source, reducing use of glucose as a substrate. Hence, the effects of epinephrine here are indirect. Thus the parentheses. You may read that epinephrine causes muscle protein breakdown. This is NOT the case in humans, muscle protein breakdown rather being the province of the companion stress / emergency hormone cortisol. At the same time, there may be an effect of epinephrine on muscle triglyceride breakdown providing muscle an energy source. ( ) Indirect TCA Cycle ( ) Indirect O2 Oxidative Phosphorylation H2O ATP

Epinephrine - Adipose Tissue
Glucose Triglycerides Fatty Acids Triglycerides Glucose-6-P Glycerol Fatty Acids Glycolysis Pyruvate Acetyl CoA The dominant effect of epinephrine on adipose tissue is lipolysis, leading to the delivery of fatty acids and glycerol to the circulation for use as energy substrate elsewhere (fatty acids) and for glycerol conversion to glucose in the liver. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

( ) ( ) ( ) Epinephrine - Liver Glycogen Triglycerides Indirect
Amino Acids Glycerol Glucose Ketoacids Triglycerides Fatty Acids Glycogen Triglycerides ( ) Indirect ( ) Indirect ( ) Indirect Glucose-6-P Amino Acids ( ) Indirect Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids ( ) Indirect Acetyl CoA The effects of epinephrine on the liver are more extensive. These include glycogenolysis and gluconeogenesis, both contributing to release of glucose from the liver into the circulation. The effect on gluconeogenesis is due to the stimulatory effect of epinephrine on gluconeogenic enzymes. What is happening here is that amino acids become devoted to gluconeogenesis. Incoming glycerol also can be converted to glucose. Strictly speaking, however, the latter is not gluconeogenesis, since the glycerol originally came from glucose. Again, the presence of fatty acids as an energy substrate blocks the use of glucose for that purpose. The release of fatty acids and glycerol from adipose tissue provides the liver with fatty acids to be used as the dominant energy substrate. Often the resultant increase in acetyl-CoA is sufficient for some of that fatty acid metabolite to be diverted to ketoacids. The increases are marked as indirect here because much of this effect simply is due to increased delivery of fatty acids to the liver. ( ) Indirect TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Daily Living Feeding to Fasting
Examining energy substrate trafficking during feeding and fasting offers an excellent way to begin to synthesize everything so far, both in terms of who uses what from where and when to how hormones manage all of this.

Sources of glucose over time following a Meal
Let’s start by looking at the pattern of change in source of glucose over time since the last meal. Incoming glucose is used first, though doesn’t last long. Next is glucagon, also a limited source some of which must be held in reserve for emergencies. Finally, gluconeogenesis kicks in. What also is going on here but is not shown in the slide is that many of the organs of the body are increasingly switching to fatty acids as the energy substrate. Also note that gluconeogenesis declines at the later times (by 2 days and onwards). That is because total energy demand is reduced and the brain has switched to using ketoacids for some (NOT all) of its energy needs.

Whole Body Substrate Utilization During Fasting
As a companion slide, it is helpful to examine the shift in substrate utilization over time after the last meal. The graph should be self-explanatory from the discussion above.

Feeding to Adapted Fast Organ Integration – Version 1
Metabolism-101 Cartoons Now on to integration between organs, to be presented in three versions, The first uses the same cell cartoons as used above. 48

We are talking about adults Not Children*
We are talking about Adaptation Not starvation / cachexia Rats ≠ People It is critical to bear in mind that this discussion is about NORMAL ADULT HUMANS, not about growing children. What happens in children because they are growing is very different because they are growing. It is this issue of concurrent growth that has caused great confusion in the literature. Much of the research described was done on a growing animal, the rat. What happens to the rat, when fasted, is very different than what happens in the adult, non-growing human. In this sense rats and growing children are pretty much the same. *Low: Protein-Energy Malnutrition Coming up next 49

Big Picture - Fed Carbs: Refill stores: Glycogen, liver, muscle
Burn Remainder (most tissues) Protein: Refill stores (muscle) Burn Remainder Fat: Storage Limited use as ongoing energy source Let's begin with several big picture slides. This describes the use of carbs, protein and fat as an energy source, beginning with the fed condition – just ate a well-balanced meal. Dominant Ongoing Energy Needs: glucose, amino acids

Big Picture – 24 hr Fast Carbs: Some glycogen stores used
Gluconeogenesis Protein: Amino acids (muscle) to liver - gluconeogenesis Fat: Mobilization of triglyceride reserves Here, energy substrates after a 24 hr. fast. Dominant Ongoing Energy Needs: fatty acids (Exceptions: Nerves, Blood Cells – Glucose)

Big Picture – Adapted Fast
Carbs: Some glycogen stores used Gluconeogenesis Protein: Amino acids (muscle) to liver - gluconeogenesis Fat: Mobilization of triglyceride reserves The same under conditions of an adapted fast. Keto Acids as dominant Energy Source, Incl. Brain (exception: liver uses fatty acids) Reduced Gluconeogenesis: Kidney takes over Reduced BMR

Big Picture – Hormone Profiles
Fed: Insulin Glucagon Growth Hormone Thyroid Hormone 24 hr Fast: Adapted Fast: Here is the big picture in terms of the hormones that play a key regulatory role: INSULIN, glucagon and growth hormone, with thyroid hormone (think Basal Metabolic Rate) supportive. Different font sizes are used to illustrate the levels of these hormones found in the blood in the different conditions.

FED Brain - FED Glucose Glucose-6-P Glycolysis Pyruvate Acetyl CoA
We shall start with brain. The obligatory source of energy in the fed condition is glucose. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

24 hr FAST Brain – 24 hr FAST Glucose Glucose-6-P Glycolysis Pyruvate
Acetyl CoA The same is true after a 24 hour fast. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

ADAPTED FAST Brain - ADAPTED FAST Glucose Ketoacids Glucose-6-P
Glycolysis Pyruvate Ketoacids Acetyl CoA A new energy source appears in the adapted fast condition. The brain still and always will require some glucose, but glucose use becomes reduced (note smaller green arrow font) but ketoacids delivered from the liver become increasingly important. This is a REALLY KEY adaptation, as it permits a life-saving reduction in gluconeogenesis at the expense of muscle protein. Hormone levels would appear to have little to do with the increasing use of ketoacids, which occurs simply based on their presence in the circulation and probably begins 2 or so after two or three days of continued fasting. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

FED Muscle - FED Amino Acids Lactate Glucose Ketoacids Triglycerides
Fatty Acids Glycogen Triglycerides Protein Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate FED Ketoacids Lactate Acetyl CoA Muscle uses significant amounts of glucose derived from the diet in the fed condition. Note also that incoming dietary amino acids are used to replenish lost muscle protein that occurs when one has not eaten for several hours (think before breakfast). As well, protein breakdown is blocked. The key hormone here is the after dinner hormone, INSULIN (see slides and following). TCA Cycle O2 Oxidative Phosphorylation H2O ATP

24 hr. FAST Muscle – 24 hr FAST Amino Acids Lactate Glucose Ketoacids
Fatty Acids Glycogen Triglycerides Protein Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate 24 hr. FAST Ketoacids Lactate Acetyl CoA Muscle shifts to fatty acids by 24 hours of fast. Much of this simply is due to their presence in the blood as a result of triglyceride mobilization from adipose tissue. Glucose use by muscle as a source of ATP has become restricted for three principal reasons. First insulin levels have become reduced. Second, fatty acids block insulin action. Third, fatty acids entering the pathway to ATP reduce glycolysis. Muscle also is delivering amino acids from protein breakdown to the circulation for delivery to the liver to support gluconeogenesis. The most important change causing these changes is REDUCED INSULIN levels (and reduced action due to fatty acids). Other changes that provide a supporting role here are increased levels of glucagon and growth hormone. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

Adapted Fast Muscle - ADAPTED FAST Amino Acids Lactate Glucose
Ketoacids Glycerol Fatty Acids Glycogen Triglycerides Protein Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis Pyruvate Adapted Fast Ketoacids Lactate Acetyl CoA Prolonged, adapted fast exaggerates the switch to fatty acids as an energy source, as well as the reduction in glucose utilization. In addition, a new metabolite, ketoacids has become available through their manufacture in the liver. One change actually is REVERSED in the adapted vs 24 hr. fast. Muscle protein breakdown is reduced in comparison to 24 hr. fast. This is a life-saving change, brought about by the reduced need in the body for glucose, much due to the aforementioned increased utilization of ketoacids by the brain. (Ketoacids can cross the blood brain barrier – diffusion, carrier-mediated transport – whereas fatty acids cannot.) The hormone profile behind these changes includes further reduction in insulin as primary, as well as increased levels of glucagon and growth hormone There is one further change of note, one of a more general nature. The levels of thyroid hormone in the blood become reduced, leading toi an overall reduction in the energy needs of the body. The increased levels of Growth hormone might at first seem counterintuitive. For sure, growth hormone induced triglyceride mobilization form adipose tissue is most helpful, but the growth effects most certainly are not. Another change has occurred to obviate this problem. The liver reduces its output of IGF-1 despite elevated levels of growth hormone. So growth effects are negated while mobilization of fat stores still occurs. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

FED Adipose Tissue - FED Glucose Triglycerides Fatty Acids
Glucose-6-P Glycerol Fatty Acids FED Glycolysis Pyruvate Acetyl CoA Fat cells in the fed state are a fat storing machine. Fatty acids from the diet selectively are put into adipocyte triglyceride, a process especially sensitive to insulin. What energy needs the fat cell has are subserved by glucose, noting also that the obligatory source of the glycerol backbone for triglycerides comes from glycolysis. That is responsible for the well-known phenomenon whereby elevated levels of blood glucose lead to triglyceride synthesis. The glycerol derived from triglyceride mobilization cannot be reused as the backbone. Increased levels of insulin are the driving force for the fat cell in the fed state. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

24 hr. FAST Adipose Tissue – 24 hr FAST Glucose Glycerol Fatty Acids
Triglycerides Glucose-6-P Glycerol Fatty Acids 24 hr. FAST Glycolysis Pyruvate Acetyl CoA After 24 hr. of fasting, the fat cell switches to delivery of fatty acids into the circulation. Their presence, plus the reduced level of insulin at 24 hr. leads to reduced glucose uptake and utilization. The key hormonal drivers here are REDUCED INSULIN and increased growth hormone, reduced insulin levels being the main driver. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

ADAPTED FAST Adipose Tissue - ADAPTED FAST Glucose Glycerol
Fatty Acids Triglycerides Glucose-6-P Glycerol Fatty Acids ADAPTED FAST Glycolysis Pyruvate Acetyl CoA Adapted fast for the fat cell for the most part is enhancement of the changes seen after a 24 hr. fast. The hormonal drivers are the same: further reduction in insulin levels (the most important) with further increases in growth hormone. TCA Cycle O2 Oxidative Phosphorylation H2O ATP

FED Liver - FED Amino Acids Glucose Ketoacids Triglycerides
Fatty Acids Glycogen Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA It often is a surprise to learn that the main energy source for the liver in the fed state is NOT glucose but rather amino acids. The amount of amino acid coming in after a well-balanced meal is more than adequate to replenish the (muscle) protein broken down after one has not eaten for awhile (slide 58). One CANNOT build more muscle simply by feeding one’s self amino acids – it is muscle use / exercise that does. The changes that occur in major anabolic hormones such as testosterone and growth hormone simply are not at play in terms of daily living. So the excess incoming amino acids over and above what is needed to restore (muscle) protein simply are oxidized. That increases the availability of glucose for oxidation by most other tissues. Glucose has free entry into liver, not regulated by insulin. REMEMBER, however, that the Km for the key enzyme glucokinase is high so that glucose only enters at high blood glucose levels (as opposed to muscle, adipose tissue, brain with low Km hexokinase). Most of the glucose that does enter is used to restore glycogen stores that also have been used during the fasting period before the meal. As for amino acids, the amount of incoming glucose after a well-balanced meal is in excess of that required to restore glycogen used during the previous fasting period. The excess is oxidized, particularly by tissues possessing low Km hexokinase. This is far more beneficial than using incoming fatty acids as an energy source. Those one wants to store as much as possible. It is much less energy costly to make incoming fatty acids into triglycerides for storage than to use the energy-costly pathway that converts glucose to fatty acids. So preferentially burn the glucose and store the fat. It is often indicated that glucose also is used to support fat synthesis. A number of studies in humans indicate that is not the case with normal meals, though glucose can be shown to be converted to fatty acids and triglycerides under extreme conditions, such as a pure glucose meal. The key controlling element here is elevated insulin. Glucagon and growth hormone are relatively bit players but can assist depending on the composition of the diet. TCA Cycle O2 Oxidative Phosphorylation H2O FED ATP

FAST-24 hr. Liver- 24 hr FAST Amino Acids Glucose Ketoacids Glycerol
Fatty Acids Glycogen Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA The switches that occur after a 24 hr. fast in the liver are aimed at preserving blood glucose. Glycogen provides one source but remember glycogen stores are very limited and some must be held in reserve for an emergency which a 24 hr. fast is not as far as the body is concerned. Glycerol coming from the circulation (fat cell triglyceride breakdown) also provides a substrate for glucose, not really gluconeogenesis, since the glycerol originally was derived from glucose. A key change with the 24 hr. fast is that (muscle) amino acids are being delivered to support the key gluconeogenesis that must occur. The ATP generation to support all of this is now coming from fatty acids that enter from the circulation, having been derived from adipocyte triglyceride breakdown. The key hormonal change, once again, is reduced insulin levels, which has caused the delivery of amino acids form muscle, the delivery of fatty acids and glycerol from adipocytes and which promotes glycogenolysis (also reducing glycogen synthesis). Growth hormone supports (adipocyte triglyceride breakdown) as does glucagon (glycogen breakdown, gluconeogenesis, increased use of fatty acids as an energy source once they enter the liver). TCA Cycle O2 Oxidative Phosphorylation H2O FAST-24 hr. ATP

24 hr FAST Liver – ADAPTED FAST Amino Acids Glucose Ketoacids Glycerol
Fatty Acids Glycogen Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA Several changes to note with the adapted fast. There is still further use of incoming glycerol (to be remade into glucose) and fatty acids (energy source). In addition, the amount of fatty acids coming into the TCA cycle as acetyl-CoA is in excess of what the TCA cycle can bear, leading to the acetyl-CoA being siphoned off to make ketoacids. The liver makes but cannot use them, exporting ketoacids to the blood for use but other tissues, most critically the brain. Note also that the green arrow showing the conversion of incoming amino acids to glucose is REDUCED compared to the 24 hr. fast. This life-saving change has been permitted by the brain adapting to the use of ketoacids for some of its energy needs, as well as the aforementioned overall reduction in metabolism due to reduced levels of thyroid hormone. The hormonal driver here again is reduced insulin levels,. With assistance from elevated glucagon and growth hormone levels. CORTISOL AND EPINEPHRINE ARE NOT PLAYERS in the normal adult even after several weeks of fasting. Indeed, were cortisol to be involved, would mean an increase in life-threatening use of amino acids from protein breakdown for gluconeogenesis. [One last issue to contemplate. What causes a REDUCTION in (muscle) protein breakdown? This remains largely unknown. MY GUESS: ketoacids cause a reduction in protein breakdown.] TCA Cycle O2 Oxidative Phosphorylation H2O 24 hr FAST ATP

FED Kidney - FED Amino Acids Glucose Ketoacids Triglycerides
Fatty Acids Glycogen Triglycerides Glucose-6-P Amino Acids Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA One last organ to consider here: the kidney. The reason relates to an important change that occurs in adapted fast. For the fed condition, glucose is the dominant energy source. TCA Cycle O2 Oxidative Phosphorylation H2O FED ATP

24 hr. FAST Kidney – 24 hr FAST Amino Acids Glucose Ketoacids
Fatty Acids Glycogen Triglycerides Glucose-6-P Amino Acids Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA As for other organs, the kidney switches to fatty acids for its energy substrate in fasting. Note also that thee kidney can convert amino acids into glucose – gluconeogenesis. Not much of this occurs in daily living, the kidney contributing something like 10-15% of gluconeogenesis when it is called upon. TCA Cycle O2 Oxidative Phosphorylation H2O 24 hr. FAST ATP

Adapted Fast Kidney - ADAPTED FAST Amino Acids Glucose Ketoacids
Glycerol Fatty Acids Glycogen Triglycerides Glucose-6-P Amino Acids Glycerol Fatty Acids Glycolysis R + NH2 NH3 + Urea Pyruvate Ketoacids Acetyl CoA Fatty acids become even more dominant as the energy substrate in the adapted fast. There is an important additional change. The kidney has a very minor role in gluconeogenesis in normal conditions or after short-term fast. However, kidney gluconeogenesis increases substantially as fasting proceeds. This has a major positive effect on energy utilization. The manufacture of urea as a byproduct of liver gluconeogenesis and for eventual elimination in the urine is very energy costly. However, stripping amino groups off of amino acids in the liver for immediate dumping into the urine is far less energy costly. Though kidney gluconeogenesis is increased in adapted fast, NONETHELESS TOTAL GLUCONEOGENSIS BETWEEN LIVER AND KIDNEY IS REDUCED. Again, it is critical to preserve (muscle) protein. TCA Cycle Adapted Fast O2 Oxidative Phosphorylation H2O ATP

Add Kidney Glycerol replaces Triglycerides-Fast Add Red Bars Add Slide text including hormone profile

Organ Integration – Version 2
Feeding to Fast Organ Integration – Version 2 (Based on Devlin) Now on to integration between organs, to be presented in three versions, The second view of the fed-fast-adapted fast transitions is derived from figures in Devlin. 70

Absorptive – Just Ate Glucose Glucose Pyruvate Lactate
At the outset, a reminder about red blood cells. Recall they depend on glycolysis for energy, since they do not possess mitochondria. As shown in this slide, they can receive glucose from the diet or from liver. (The kidney also can provide glucose, but this normally is a minor contributor.) RBC then metabolize glucose through glycolysis ending with lactate which goes to the liver to be re-converted to glucose. These relationships proceed through all phases of dietary manipulation. Therefore, they will not be shown in future slides focusing on organ integration. Recall once again that the focus here is on energy substrates. Other pathways of carbohydrate, fat and protein used more for “housekeeping” are not shown.

Absorptive Phase (Just Ate)
Glucose Glycogen Amino Acids ATP ATP VLDL FAT TG CHO This slide shows substrate fluxes between organs in the absorptive phase of digestion. Key here is that there is an exogenous supply of carbohydrate, fat and protein – the diet. Recall first of all that all incoming glucose and amino acids travel first and directly to the liver via the portal vein. Long chain fat products are delivered directly to the circulation via the lymphatic circulations - other organs than the liver get first shot at these. (Shorter chain fatty acids, what there are of them, can go directly to the liver, again via the portal vein.) Most of the glucose coming in through the portal vein after a balanced diet does NOT enter the liver (due to the high Km glucokinase) but travels to other organs (which have a much lower Km hexokinase: note the relative sizes of the dotted glucose arrows). Glucose that does enter the liver mostly is converted to glycogen, repleting stores used up during the preceding postabsorptive period. Some may find its way into the glycerol backbone of triglycerides but recall from previous slides that this is NOT normally an important pathway. In terms of balance, the liver is extracting glucose from the blood in the absorptive phase of digestion. Most fats in the diet enter the circulation as chlomicrons for delivery to organs throughout the body for use as an energy source (e.g. muscle) or for storage (e.g. adipose tissue). Amino acids in the diet travel to muscle to replete muscle protein that was used during the previous postabsorptive phase. Amino acids also are the dominant energy substrate for liver: recall that a normal, balanced meal contains more amino acids than necessary to replete muscle. Better to use them as energy substrate for liver than to use precious glucose. Amino Acids FAT Glycogen ATP

Postabsorptive Phase (No Food Several Hours)
Glucose Glycogen ATP aa Glucose-6-P Lactate / pyruvate Fatty Acids Glycerol CHO Amino Acids FAT The gut is not in the picture in the postabsorbtive phase. The task now is to rearrange substrate utilization to be sure blood glucose levels are preserved (for the brain). The liver has now become a glucose exporter. Recall first that only the liver and to a much lesser degree the kidney can make free glucose due to the presence of glucose-6-phosphatase. In the liver, glycogen is broken down for glucose export (NOT for use by the liver for energy). This is limited and some glycogen needs to be held in reserve in case of a glucose emergency. The liver also can receive glucose synthesizing capacity form muscle in the form of pyruvate / lactate. As well, glycerol backbone coming from adipose tissue triglycerides can be made into glucose by the liver. Finally and most importantly, amino acids from muscle are delivered to the liver for the required task of gluconeogenesis. The fatty acids coming from adipose tissue are distributed to all organs of the body that can use them as an energy source particularly muscle and liver. Brain cannot use them principally because they cannot cross the blood brain barrier.

Adapted Fast Glucose Ketoacids Glucose Ketoacids Fatty Acids Glycerol
Glycogen Glucose Ketoacids ATP ATP Glucose Ketoacids Fatty Acids Glycerol CHO The adapted fast is similar in several ways to the post-absorptive phase. A critical change has occurred, however, all relating back to the requirement to avoid as much as possible using muscle amino acids as an energy substrate. The KEY, here, is that the liver begins to make appreciable amounts of ketoacids for delivery to most other organs of the body, MOST PARTICULARLY the brain. This reduces the need for muscle amino acids (note size reduction in amino acid arrow coming from muscle). This, in turn, explains the reduction in gluconeogenesis that occurs later on in the fast as well as the shift in body substrate utilization. One additional important change is noted on this slide. Kidney gluconeogenesis is increased substantially, allowing liver gluconeogenesis to become (further) reduced. The value here is that getting rid of amino groups through the very energy expensive urea cycle in liver has now been replaced by the energy cheap process of directly dumping amino groups into the urine. Amino Acids aa Glycogen FAT Lactate / pyruvate Glucose-6-P

Organ Integration – Version 3
Feeding to Fast Organ Integration – Version 3 (Based on CMB Lectures - Tracy) Slides show the same features as above but using cartoons shown in CMB lectures (Tracy). What you should do is write your own slide text. Or even delete the arrows and then put them back in, explaining as you go. 75

Absorptive – Just Ate Carbs Fat Amino Acids Glucose Glycogen ATP Amino
Fats Absorptive Phase. Carbs Fat Amino Acids

Post-absorptive – Have not eaten for awhile
ATP Glucose Glycogen Amino Acids ATP Pyruvate Lactate Fats Postabsorptive phase. Carbs Fat Amino Acids

Post-absorptive – Adapted Fast
ATP Glucose Glycogen Amino Acids Ketoacids ATP Pyruvate Lactate Fats Adapted Fast. Carbs Fat Amino Acids

Hormones and Daily Living
How are all of these things managed? Now time to examine the roles that our key hormones play in managing all of this.

HOW DOES ONE DO IT? Daily Living Emergency
This slide is from before reminding you of the key phrases attached to each hormone. From that alone, you should be able to predict what happens in the fed-fast cycle. The workhorses for daily living are INSULIN, growth hormone and glucagon. Thyroid hormone plays more a maintenance role in terms of maintaining the metabolic pathways / metabolism that permits energy substrate utilization. Epinephrine and cortisol are reserved for emergencies (which does NOT include fasting for a few days or even weeks). Emergency

Managing Daily Living Order of importance
1st: Insulin 2nd: Insulin 3rd: Insulin 4th: Glucagon 5th: Growth Hormone As will be discussed in class, there can be absolutely no doubt that insulin is in charge. What happens depends more than anything else on whether insulin is present or absent.

- Increased Glucose Uptake: Muscle and Adipose
EFFECTS OF INSULIN PRINCIPAL TARGETS: LIVER, ADIPOSE, MUSCLE Carbohydrate: - Increased Glucose Uptake: Muscle and Adipose - Increased Glycogenesis; decreased glycogenolysis - Decreased Gluconeogenesis Fat: - Increased Triglyceride Synthesis for Storage - Decreased Breakdown of Triglyceride Stores Protein: - Increased Synthesis - Decreased Breakdown Here is a restatement of insulin action as the “storage” or “after dinner” hormone.

Lack of Insulin Muscle Reduced glucose uptake and utilization
Mobilization of glycogen Increased muscle protein breakdown Adipose Tissue Reduced triglyceride uptake and storage Increased triglyceride breakdown and release into the blood Liver Increased Glycogenolysis Increased gluconeogenesis THE LIVER IS A GLUCOSE EXPORTER And here is what happens with a deficiency in effective insulin. To a large degree (though of course not completely) it does NOT matter what happens to other hormones. (In fact, as discussed in class, changes in their levels and functions that actually occur in this situation worsen the problem.)

Hormones and Daily Living
Here is a table showing results from a study of humans illustrating what happens to hormone levels as fasting proceeds. There should be no surprises here. Note that cortisol does not change. Epinephrine does not either*. They will increase only if some sort of stress, physical / mental is superimposed on the body. ALSO, when all the fat stores are used up = terminal phases of starvation. One thing of further note. Clearly elevated Growth Hormone is helpful due to its ability to mobilize fat and spare glucose. But the energy-requiring growth effects of growth hormone would be a problem. Here, a neat trick is at play. In times of fasting, the liver refuses to put out more IGF-1 (the agent of growth) in response to growth hormone. (Indeed, the liver begins to produce less of a number of blood proteins including albumin.) That means the growth effects of growth hormone will not occur but the effects on fats and carbs will. *Here is a major problem with a literature (and many lectures) that is based mainly on studies of rats. Rats grow throughout their lives and, accordingly, cannot tolerate a fast for long. The SAME is true, of course, of growing human children. The above discussion is based on studies of normal ADULTS. Fasting in children quickly can become life-threatening.

Please help fellow students by providing suggestions as to how to improve this exercise. Send comments to: The End 85 85

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Metabolism 101 R. Low, 02/10/14 Need to fix text a la part-1

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