By:Tatiana El Bacha, Ph.D.(Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro),Mauricio R. M. P. Luz, Ph.D.(Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz)&Andrea T. Da Poian, Ph.D.(Instituto de Bioquimica Medica, Universidade Federal do Rio de Janeiro)©2010bsci-ch.org Education
Citation:El Bacha,T.,Luz,M.&Da Poian,A.(2010)Dynamic Adaptation of Nutrient Utilization in Humans.bsci-ch.org Education3(9):8
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Food in, energy out? It’s not as simple as that. How do cells meet our bodies’ ever changing energy needs?

The energy needs of the human body must be fulfilleddespite the fluctuations in nutrient availability that the body experiences ona daily basis. How, then, do our different cells use fuel molecules, and whatfactors are involved in this process? We can think of the human body as a dynamic environment whereeach cell has to continually and sometimes cyclically switch the type ofsubstrate that is oxidized and/or produced. This adaptation is crucial and is achievedonly through the several regulatory mechanisms involved in controlling energytransformation and utilization. Moreover, cellular adaptation becomes more crucialwhen we consider the diverse physiological conditions an organism is exposed toon a daily basis. For example, during the night we usually do not eat, a typeof "fasting" that is later disrupted by breakfast, and at other times we aresimply resting, or exercising. In these situations, the type and amount ofnutrients available for cells change abruptly.

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2, with concomitant reduction of NAD+ and FAD to NADH and FADH2, respectively. The electrons are transported from the reduced coenzymes to O2 in the electron transport system, resulting in ATP synthesis.", "true", "All rights reserved.", "750", "583", "http://www.bsci-ch.org/bsci-ch.org_education");">
2, with concomitant reduction of NAD+ and FAD to NADH and FADH2, respectively. The electrons are transported from the reduced coenzymes to O2 in the electron transport system, resulting in ATP synthesis.", "true", "All rights reserved.", "750", "583", "http://www.bsci-ch.org/bsci-ch.org_education");">Figure 1:Schematic representation of fuel molecule entry points in oxidative metabolism
2, with concomitant reduction of NAD+ and FAD to NADH and FADH2, respectively. The electrons are transported from the reduced coenzymes to O2 in the electron transport system, resulting in ATP synthesis.", "true", "All rights reserved.", "750", "583", "http://www.bsci-ch.org/bsci-ch.org_education");">Degradation of lipids, proteins, and carbohydrates gives rise to fatty acids, amino acids, and pyruvate, respectively. These molecules enter the tricarboxylic acid (TCA) cycle in the mitochondrion to be completely oxidized to CO2, with concomitant reduction of NAD+ and FAD to NADH and FADH2, respectively. The electrons are transported from the reduced coenzymes to O2 in the electron transport system, resulting in ATP synthesis.
2, with concomitant reduction of NAD+ and FAD to NADH and FADH2, respectively. The electrons are transported from the reduced coenzymes to O2 in the electron transport system, resulting in ATP synthesis.", "750","http://www.bsci-ch.org/bsci-ch.org_education", "The biochemical pathways used to synthesize ATP are illustrated within a cell. The cell is depicted as an oval with a smaller oval contained inside it, representing the mitochondrion. Arrows point from the outside of the cell into the cytoplasm, showing how lipids, carbohydrates, and proteins are imported and converted to energy. Inside the cell"s cytoplasm, lipids are broken down into fatty acids, carbohydrates are broken down into glucose, and proteins are broken down into amino acids. Glucose is used to generate ATP and pyruvate during glycolysis, which occurs in the cell"s cytoplasm. Arrows indicate that pyruvate, fatty acids, and amino acids are transported into the mitochondrion where they are oxidized to CO2. During the TCA cycle, NAD+ is reduced to NADH and FAD is reduced to FADH2. These two electron carriers transport electrons to the electron transport chain (ETC), where ATP is produced.")" class="inlineLinks"> Figure Detail
In most animal cells, adenosine triphosphate (ATP), a compound with high potential energy, works as the main carrier of chemical energy. In general, the energy to synthesize ATP molecules must be obtained from rather complex fuel molecules. The human body uses three types of molecules to yield the necessary energy to drive ATP synthesis: fats, proteins, and carbohydrates.

Mitochondria are the main site for ATP synthesis in mammals, although some ATP is also synthesized in the cytoplasm. Lipids are broken down into fatty acids, proteins into amino acids, and carbohydrates into glucose. Via a series of oxidation-reduction reactions, mitochondria degrade fatty acids, amino acids, and pyruvate (the end product of glucose degradation in the cytoplasm) into several intermediate compounds, as well as into the reduced electron carrier coenzymes NADH and FADH2 (Figure 1). The intermediates enter the tricarboxylic acid (TCA) cycle, also giving rise to NADH and FADH2. These reduced electron carriers are themselves oxidized via the electron transport chain, with concomitant consumption of oxygen and ATP synthesis (Figure 1). This process is called oxidative phosphorylation.

Over a hundred ATP molecules are synthesized from the complete oxidation of one molecule of fatty acid, and almost forty ATP molecules result from amino acid and pyruvate oxidation. Two ATP molecules are synthesized in the cytoplasm via the conversion of glucose molecules to pyruvate. Both the apparatus (enzymes) and the physical environment necessary for the oxidation of these molecules are contained in the mitochondria.


", "true", "All rights reserved.", "650", "443", "http://www.bsci-ch.org/bsci-ch.org_education");">Figure 2:Relationship between the utilization and production of substrates by different cells in the human body
", "true", "All rights reserved.", "650", "443", "http://www.bsci-ch.org/bsci-ch.org_education");">Red blood cells rely on glucose for energy and convert glucose to lactate. The brain uses glucose and ketone bodies for energy. Adipose tissue uses fatty acids and glucose for energy. The liver primarily uses fatty acid oxidation for energy. Muscle cells use fatty acids, glucose, and amino acids as energy sources.
Most cells use glucose for ATP synthesis, but there are other fuel molecules equally important for maintaining the body"s equilibrium or homeostasis. Indeed, although the oxidation pathways of fatty acids, amino acids, and glucose begin differently, these mechanisms ultimately converge onto a common pathway, the TCA cycle, occurring within the mitochondria (Figure 1). As mentioned earlier, the ATP yield obtained from lipid oxidation is over twice the amount obtained from carbohydrates and amino acids. So why don"t all cells simply use lipids as fuel?

In fact, many different cells do oxidize fatty acids for ATP production (Figure 2). Between meals, cardiac muscle cells meet 90% of their ATP demands by oxidizing fatty acids. Although these proportions may fall to about 60% depending on the nutritional status and the intensity of contractions, fatty acids may be considered the major fuel consumed by cardiac muscle. Skeletal muscle cells also oxidize lipids. Indeed, fatty acids are the main source of energy in skeletal muscle during rest and mild-intensity exercise. As exercise intensity increases, glucose oxidation surpasses fatty acid oxidation. Other secondary factors that influence the substrate of choice for muscle include exercise duration, gender, and training status.

Another tissue that utilizes fatty acids in high amount is adipose tissue. Since adipose tissue is the storehouse of body fat, one might conclude that, during fasting, the source of fatty acids for adipose tissue cells is their own stock. Skeletal muscle and adipose tissue cells also utilize glucose in significant proportions, but only at the absorptive stage - that is, right after a regular meal. Other organs that use primarily fatty acid oxidation are the kidney and the liver. The cortex cells of the kidneys need a constant supply of energy for continual blood filtration, and so does the liver to accomplish its important biosynthetic functions.

Despite their massive use as fuels, fatty acids are oxidized only in the mitochondria. But not all human cells possess mitochondria! Although that may sound strange, human red blood cells are the most common cells lacking mitochondria. Other examples include tissues of the eyes, such as the lens, which is almost totally devoid of mitochondria; and the outer segment of the retina, which contains the photosensitive pigment. You may have already guessed that these cells and tissues then must produce ATP by metabolizing glucose only. In these situations, glucose is degraded to pyruvate, which is then promptly converted to lactate (Figure 2). This process is called lactic acid fermentation. Although not highly metabolically active, red blood cells are abundant, resulting in the continual uptake of glucose molecules from the bloodstream. Additionally, there are cells that, despite having mitochondria, rely almost exclusively on lactic acid fermentation for ATP production. This is the case for renal medulla cells, whose oxygenated blood supply is not adequate to accomplish oxidative phosphorylation.

Finally, what if the availability of fatty acids to cells changes? The blood-brain barrier provides a good example. In most physiological situations, the blood-brain barrier prevents the access of lipids to the cells of the central nervous system (CNS). Therefore, CNS cells also rely solely on glucose as fuel molecules (Figure 2). In prolonged fasting, however, ketone bodies released in the blood by liver cells as part of the continual metabolization of fatty acids are used as fuels for ATP production by CNS cells. In both situations and unlike red blood cells, however, CNS cells are extremely metabolically active and do have mitochondria. Thus, they are able to fully oxidize glucose, generating greater amounts of ATP. Indeed, the daily consumption of nerve cells is about 120 g of glucose equivalent, which corresponds to an input of about 420 kilocalories (1,760 kilojoules). This figure accounts for 60% of glucose utilization (or 20% of the energy needs of the human body in the resting state). However, most remaining cell types in the human body have mitochondria, adequate oxygen supply, and access to all three fuel molecules. Which fuel, then, is preferentially used by each of these cells?


Virtually all cells are able to take up and utilizeglucose. What regulates the rate of glucose uptake is primarily theconcentration of glucose in the blood. Glucose enters cells via specifictransporters (GLUTs) located in the cell membrane. There are several types ofGLUTs, varying in their location (tissue specificity) and in their affinity forglucose. Adipose and skeletal muscle tissues have GLUT4, a type of GLUT which ispresent in the plasma membrane only when blood glucose concentration is high(e.g., after a carbohydrate-rich meal). The presence of this type oftransporter in the membrane increases the rate of glucose uptake by twenty- tothirtyfold in both tissues, increasing the amount of glucose available foroxidation. Therefore, after meals glucose is the primary source of energy foradipose tissue and skeletal muscle.

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The breakdown of glucose, in addition to contributing toATP synthesis, generates compounds that can be used for biosynthetic purposes. Sothe choice of glucose as the primary oxidized substrate is very important forcells that can grow and divide fast. Examples of these cell types include whiteblood cells, stem cells, and some epithelial cells.

A similar phenomenon occurs in cancer cells, whereincreased glucose utilization is required as a source of energy and to supportthe increased rate of cell proliferation. Interestingly, across a tumor mass, interiorcells may experience fluctuations in oxygen tension that in turn limit nutrientoxidation and become an important aspect for tumor survival. In addition, theincreased glucose utilization generates high amounts of lactate, which createsan acidic environment and facilitates tumor invasion.

Another factor that dramatically affects the metabolism isthe nutritional status of the individual — for instance, during fasting or fedstates. After a carbohydrate-rich meal, blood glucose concentration risessharply and a massive amount of glucose is taken up by hepatocytes by means ofGLUT2. This type of transporter has very low affinity for glucose and iseffective only when glucose concentration is high. Thus, during the fed state theliver responds directly to blood glucose levels by increasing its rate ofglucose uptake. In addition to being the main source of energy, glucose isutilized in other pathways, such as glycogen and lipid synthesis byhepatocytes. The whole picture becomes far more complex whenwe consider how hormones influence our energy metabolism. Fluctuations in bloodlevels of glucose trigger secretion of the hormones insulin and glucagon. How dosuch hormones influence the use of fuel molecules by the various tissues?


Human cells and tissues adapt to internal metabolicdemands in many ways, mostly in response to hormones and/or nervous stimuli.Demands by one cell type can be met by the consumption of its own reserves andby the uptake of fuel molecules released in the bloodstream by other cells. Energyuse is tightly regulated so that the energy demands of all cells are met simultaneously.Elevated levels of glucose stimulate pancreatic β-cells to release insulininto the bloodstream. Virtually all cells respond to insulin; thus, during thefed state cell metabolism is coordinated by insulin signaling.


An extraordinary example is how insulin signaling rapidlystimulates glucose uptake in skeletal muscle and adipose tissue and isaccomplished by the activity of GLUT4. In the absence of insulin, thesetransporters are located inside vesicles and thus do not contribute to glucoseuptake in skeletal muscle and adipose tissue. Insulin, however, induces themovement of these transporters to the plasma membrane, increasing glucoseuptake and consumption. As different tissues continue to use glucose, the bloodglucose concentration tends to reach the pre-meal concentration (Figure 3).This, in turn, decreases the stimulus for insulin synthesis and increases thestimulus for the release of glucagon, another hormone secreted by the α-pancreaticcells. Therefore, during fasting, cell metabolism is coordinated by glucagonsignaling and the lack of insulin signaling. As a consequence, GLUT4 staysinside vesicles, and glucose uptake by both skeletal muscle cells andadipocytes is reduced. Now, with the low availability of glucose and thesignals from glucagon, those cells increase their use of fatty acids as fuelmolecules. Adipose and skeletal muscle tissues correspond to nearly 60% of thetotal body mass of a healthy adult. Therefore, the use of fatty acids duringfasting clearly contributes to the maintenance of adequate blood glucoseconcentration to meet the demands of cells that exclusively or primarily relyon glucose as a fuel. But, mentioned above, glucose is used at an apparentlyhigh rate by the brain and constantly by red blood cells. And, underphysiological conditions, blood glucose is maintained at a constant level, evenduring fasting. How, then, is that delicate balance achieved?


The liver is a very active organ that performs differentvital functions. In Greek mythology, Prometheus steals fire from Zeus and givesit to mortals. As a punishment, Zeus has part of Prometheus"s liver fed to aneagle every day. Since the liver grows back, it is eaten repeatedly. This storyillustrates the high proliferative rate of liver cells and the vital role ofthis organ for human life. One of its most important functions is themaintenance of blood glucose. The liver releases glucose by degrading its glycogenstores. This reserve is not large, and during overnight fasting glycogenreserves fall severely. Glycogen stores in the liver correspond to 6% of itsmass. On the other hand, glycogen stores in the muscle correspond to 1% ofmuscle mass but represent three to four times the amount found in liver, since bymass we have more muscle than liver. However, only the liver supplies the blood with glucose since it has an enzyme that make it possible for glucose molecules to be transported across cell membranes.

Since glycogen stores are limited and are reduced within 12-18hours of fasting, and blood glucose concentration is kept within narrow limitsunder most physiological conditions, another mechanism must exist to supplyblood glucose. Indeed, glucose can be synthesized from amino acid molecules.This process is called de novosynthesis of glucose, or gluconeogenesis. Amino acids, while being degraded,generate several intermediates that are used by the liver to synthesize glucose(Figure 2). Alanine and glutamine are the two amino acids whose main functionis to contribute to glucose synthesis by the liver. The kidneys also possess theenzymes necessary for gluconeogenesis and, during prolonged fasting, contributeto some extent to the supply of blood glucose. Furthermore, since de novoglucose synthesis comes from amino acid degradation and the depletion of proteinstores can be life-threatening, this process must be regulated. Insulin,glucagon, and another hormone, glucocorticoid, play important roles incontrolling the rate of protein degradation and, therefore, the rate of glucoseproduction by the liver.


Alterations in factors that control food intake andregulate energy metabolism are related to well-known pathological conditionssuch as obesity, type 2 diabetes and the metabolic syndrome, and some types ofcancer. In addition, many effects and regulatory actions of well-known hormonessuch as insulin are still poorly understood. The consideration of adiposetissue as a dynamic and active tissue, for instance, raises several importantissues regarding body weight and the control of food intake. These factorspoint to the importance of further studies to expand our understanding of energymetabolism, thereby improving our quality of life and achieving a comprehensiveview of how the human body functions.


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