8.4Human Metabolism and Health
Metabolic Enzymes and ATP
Fig. 8-4. ATP as an Energy Currency
Extracted energy is stored as high energy bonds in the form of ATP. Hydrolyzing the terminal phosphate group (represented as P in the figure) releases more energy than the hydrolysis of other compounds would.
As described above, energy sources for cells are the following three major nutrients: sugar, fat, and protein. In the case of sugar, the carbon skeleton of glucose is burned completely to CO2 and H2O to extract stored energy. However, burning it as in a test tube does not lead to effective utilization of the released energy. In order to avoid this, cells extract the energy little by little in a series of regulated stepwise reactions. Changes in substances that occur in cells are essentially chemical reactions performed by enzymes, and a majority of the released energy is harnessed to perform biological work effectively. Each metabolic reaction is catalyzed by a specific enzyme. To make each reaction progress, either increasing the activity of the enzyme itself or increasing its number is necessary. This adjustment alters the flow of metabolism to the direction that satisfies the needs of whole body, e.g., whether the energy should be released or stored.
The extracted energy is stored as high-energy bonds in the form of adenosine triphosphate (ATP) (Fig. 8-4). One of the characteristics of ATP is that it is used not only for chemical reactions but also for electrical as well as mechanical tasks. In this sense, ATP can be regarded as the "currency" of bioenergy.
The Basic Metabolic Pathway
Intracellular metabolism comprises numerous enzymatic reactions; nevertheless, major pathways are common to many organisms. With regard to sugar, fat, and protein, the basic flow of intracellular metabolism consists mainly of 3 stages (Fig. 8-5):
Fig. 8-5. Basic Metabolic Pathway
Although metabolic pathways comprise several steps of enzymatic reactions, they are represented in single arrows in the figure for simplicity. For the explanations of "glycolysis," "gluconeogenesis," and "glycogen decomposition", see text. Blood glucose levels are related to monosaccharide glucose levels. Insulin promotes glycolysis and glycogen synthesis, therefore, decreases glucose levels (→). Note that each nutrient is interconverted at the level of basic metabolites. For instance, excessive ingestion of glucose leads to glycolysis to produce acetyl-CoA, which then undergoes the synthetic pathway of fatty acids and becomes neutral fat for storage.
(1) Composite compounds such as proteins, polysaccharides, and complex lipids are constituted from their respective units, namely amino acids, monosaccharides, and fatty acids. Conversely, they can be degraded into these units (each metabolic system is independent in this step).
(2) These units are converted into simpler basic metabolites via intermediary metabolites. This step occurs mainly in the cytoplasm.
(3) The basic metabolites can be converted interchangeably.
Conversion of complex substances to constituent units can progress by hydrolysis. In contrast, synthesis of complex substances requires energy. The metabolism of sugars and fatty acids extracts energy through degradation to basic metabolites. For example, in the case of sugar degradation, (1) occurs in the intestinal tracts and is referred to as digestion; (2) is called glycolysis and produces pyruvate, and (3) is fully oxidized into H2O and CO2 in the citric acid cycle; which occurs in the mitochondria. During these steps, approximately 30 net ATP molecules per 1 glucose molecule are synthesized, which are then exploited for cellular activities. In order for heterotrophs such as humans to live, the inflow of energy-rich substances as food, depicted in the upper part of Figure 8-5, is essential.
As evidenced by Figure 8-5, since nutrients, be it sugars or lipids, are converted interchangeably, ingesting substances other than fats results in accumulation of fat in the body. What is important is that the metabolic processes of fats, sugars, etc. are linked together. The system as a whole maintains delicate equilibrium and incredible stability in spite of the influence of food ingestion. Once the equilibrium is disturbed, the cells respond to rectify the situation and intricate cellular networks act on enzymes, thereby adjusting the intracellular metabolism (i.e., homeostasis).
Biological bodies possess the function to regulate energy turnover, and its balance is considered to be as follows:
Energy Intake = Energy burned + Energy stored
Ingested nutrients are absorbed from the intestinal tracts and enter the blood. For example, serum glucose concentrations are maintained at a certain level throughout the day against fluctuation by food. This is mainly due to the regulation by hormonal action in coordination with several organs. Although several hormones elevate blood sugar, insulin, which is produced in the pancreas, is the only hormone to lower the level. Insulin accelerates the intracellular uptake of glucose, absorbed from the intestinal tract (Fig. 8-6), and promotes the metabolism of "monosaccharides (e.g., glucose)" in the glycolytic system.
Fig. 8-6. Blood Glucose Regulation
The blood glucose level elevates by absorption from meal through the intestine and release from the liver because of glycogen degradation and gluconeogenesis; contrarily, the level falls due to glucose uptake by fat and muscle. Interrelations between multiple organs regulate blood glucose level. This process is primarily influenced by insulin, which promotes glucose uptake to muscle and fat while inhibiting its release from the liver. Red lines: Insulin's effect; →: Promotion; --|: Inhibition
Each nutrient has its storage form into which excess molecules are converted*1. A decrease in glucose concentrations between meals or during fasting prompts insulin levels to drop, thus triggering gluconeogenesis—an inverse reaction to glycolysis—in the liver by hormones that act reversely (e.g., glucagon) [shown in Figure 8-5 is an upward flow to "monosaccharides (e.g.,glucose)"]. As long as stored glycogen and neutral fats are degraded and released, and their turnovers are managed smoothly, blood glucose levels can settle within a certain range without displaying large fluctuations (Fig. 8-7).
Fig. 8-7. Postprandial metabolic changes
The figure shows postprandial changes in blood glucose and blood fatty acids as nutrients; insulin as a regulatory hormone to lower blood sugar levels; glucagon to elevate them; and hepatic glycogen as the storage from of sugars. Insulin regulates blood glucose immediately after a meal such that it does not exceed a certain level; conversely, glucagon works to degrade hepatic glycogen and to release glucose into the blood, thereby preventing it from falling below a certain level. Normally, these effects maintain glucose levels within a comparatively narrow range irrespective of eating and prolonged fasting. Nevertheless, changes in lifestyle such as overeating and irregular eating habits are disturbing this regulation noticeably.
Disturbance in Energy Balance
Energy balance is under physiological regulation. Surplus energy is accumulated as lipids in adipocytes and excessive ingestion brings about obesity. Subcutaneous fat, which is not perceived well, is usually the object of cosmetic treatment. Meanwhile, fat that accumulates in the viscera (visceral fat) is drawing attention these days (see Column below). The question of which organ is responsible for energy balance regulation has been discussed for many years. Recent findings have indicated that a brain region called hypothalamus perceives energy balance and accommodates food ingestion to energy consumption to modulate it. What would be the signal to the hypothalamus? Some postulate that it is regulated by blood sugar, body temperature, or neural signals. None of the hypotheses, however, is adequate, and the fact that the biochemical entity of signals could not be illuminated was compounding the problem. Amid such circumstances, research into the causative genes of obesity in mice has come to offer clues to unravel the mystery (described later).
In antiquity, animals could only rarely get to eat food. Consequently, they have been evolving the means to stockpile food-derived molecules so as to cope with fasting when energy sources are depleted. Genes are imagined to have evolved in a manner that enables animals to take complete advantage of rare opportunities to encounter food. It may also be the reason that humans have survived to this date (see Column below). That said, in a fairly short period of time in proportion to the biological scale (up to several million years), humans have developed civilization, initiated cultivation and livestock breeding, contrived ways to secure a stable supply of food, and virtually overcome starvation in industrialized countries. In further-developed phases, the invention of machinery such as automobiles and elevators has reduced chances to exercise considerably (Fig. 8-8). What has happened as a result then? Changes in lifestyle in recent years have substantially disturbed the energy balance, thus giving rise to irregularity in cellular metabolism. Regardless of changes in the external food environment, the human body continues stockpiling ingested nutrients for effective utilization thanks to thrifty genes (see Column below). It has become the norm that people have fat accumulated in their viscera such as the liver. We consume more nutrients than necessary and have lost opportunities to burn them up through exercise ("the age of gluttony").
Cycle of meals is disturbed, and due to overeating and obesity, intracellular metabolism becomes futile for glucose uptake. This phenomenon is referred to as "insulin resistance" on account of the inability of insulin to maintain blood glucose levels. Insulin becomes unable to alter the flow of metabolism in accordance with the objective, and the size of the glucose pool in the blood expands in proportion to the organs. In extreme cases, diabetes develops.
Fig. 8-8. Lifestyle and the increase of Diabetes
A correlation has been established between the increase in the number of diabetic patients and the increase in the number of cars, the amount of fat ingested, etc. Based on Atsunori Kashiwagi "Lifelong Education Series Magazine, Japan Medical Association, vol. 136, extra edition, S6, 2007"
Why are Fats Accumulated?
A molecule of a triglyceride (TG) is constituted by 3 fatty acids bound to a glycerol (Column Fig. 8-1). Since sugars are converted into lipids via basic metabolites, the ingested glucose is stored as TG as well. TG is more effective as a storage substance than glycogen. About twice as much energy as from 1 g glycogen extracted from 1 g fat after oxidation. Since glycogen is combined with abundant water, an attempt to store as much energy as fat with it requires 6 times the weight. Adults store only about 1 day's worth of glycogen for their activities, yet they can reserve several weeks' worth of fat. Substituting this with glycogen would increase the body weight considerably. For these reasons, fats are crucial storage substances, and degradation of TG results in release of exceptionally high energy.
The Thrifty Gene Hypothesis
The surrounding environment of food can influence the turnover of nutrient stocks. Since antiquity, genes are conceived to have evolved to make efficient use of rare opportunities to encounter food. Such genes work in favor of ensuring energy sources by accumulating food ingested in the body as efficiently as possible. In ancient times when the primary risk was starvation, hormones that increase blood sugar levels were in exclusively high demand, whereas only insulin could suffice as the hormone to decrease them.
However, in the present age when excess-calorie diets are predominant, individuals are predisposed to lifestyle-related diseases as they are apt to accumulate energy as fat, and hence, are susceptible to obesity. Genes that function to secure energy sources are called "thrifty genes," of which several candidates have been identified.
The westernization of lifestyle, especially overeating, high-fat diet, and lack of exercise, has led to changes not only in the transient regulation of the enzyme activity, but also in the expression of genes controlling the enzyme amount, thereby generating a permanent shift in metabolic enzymes in the direction of energy storage. The current buzz word "metabolic syndrome" signifies the complications which, in addition to visceral fat obesity, include 2 or more of the following conditions: hyperglycemia, hypertension, and hyperlipidemia. This syndrome stems from the disturbance in metabolism as described above (see Column at the bottom). It is visceral fat, rather than fat in the whole body, which plays pivotal roles here because unlike the ordinary flow toward the heart via the veins, the blood flow from the visceral fat has a positional characteristic of being conveyed directly to the liver. In other words, people with accumulated visceral fat receive a massive influx of glycerol and fatty acids from stored triglyceride as energy sources in the liver, the linchpin organ for metabolism. Lifestyle-related diseases such as diabetes and hyperlipidemia are risk factors even individually. Coexistence or prolongation of these conditions for years, therefore, would have a great influence on the body. The influence is particularly grave on the blood vessels, giving rise to an aberration called arteriosclerosis. This disease, if it occurs in the heart vessels, can cause myocardial infarction and, if in the brain vessels, can trigger cerebral infarction.
Accumulation of visceral fat is drawing attention as the common background of such aggregated risk conditions. A model has been postulated in which visceral fat aggravates the effect of insulin, which is important in terms of metabolic regulation, thus inducing "insulin resistance." However, all details of this mechanism have not been elucidated yet. Nevertheless, exemplified by the discovery of leptin produced in the adipocytes of mice, which regulates energy balance by acting on the hypothalamus, several factors released from adipocytes are being suspected to underlie this pathogenic condition. At present, enlarged adipocytes are understood not only to stockpile fats but also to secrete diverse factors antagonistic to the effect of insulin. These molecules further foment the vicious cycle of metabolism in the whole body (see Column at the bottom). A lack of the insulin effect induces increased production of insulin to compensate for it. However, there is also a view that the elevated levels of insulin itself may have promotive effects on hypertension and arteriosclerosis. Figure 8-9 shows the encapsulation of the current putative model.
In the case of metabolic syndrome, preventing arteriosclerosis is of importance. Above all, it is essential to encourage people to correct ingested calories and burn up fat pursuant to dietary therapy with respect to prophylaxis/resolution of visceral fat accumulation.
Fig. 8-9. Model of Metabolic Syndrome
The advocated model is as follows: Genetic factors along with environmental factors such as a high-fat diet induce visceral fat accumulation, thereby prompting adipocytes to release molecules called adipocytokines ("adipo" means fat). This attenuates the insulin effect and gives rise to arteriosclerosis on account of metabolic disorders etc.
1) Metabolic Syndrome
Described below are the present diagnostic criteria in Japan for reference. WHO and the United States are adopting different criteria. As the Japanese standards are controversial, note that they may be subject to future revisions.
Abdominal obesity: waist circumference
Men ≥ 85 cm, Women ≥ 90 cm
In addition to this, any 2 of the following conditions: hyperglycemia, hypertension, and hyperlipidemia.
Hyperglycemia: fasting blood glucose > 110 mg/dL
Hypertension: systolic blood pressure > 130 mmHg and/or diastolic blood pressure > 85 mmHg
Hyperlipidemia: serum triglyceride > 150 mg/dL and/or highdensity lipoprotein (HDL)-cholesterol < 40 mg/dL.
2) Index of Obesity "BMI"
This index is frequently used to estimate one's adequate body weight.
Body Weight (kg) ÷ Height (m) ÷ Height (kg)
Calculating this formula brings forth a number called "body mass index (BMI)." It is normally somewhere around 22. A high BMI indicates overweight, and exceeding 25 indicates obesity.
Fat Adipocytes and Lean Adipocytes
Until recently, adipocytes have been recognized as a static organ that stores excess energy. In the 1990s, research into mice exhibiting overeating and obesity identified a molecule called leptin that affects obesity. Leptin has been demonstrated to be produced in adipocytes and to act on the hypothalamus to influence appetite. Prompted by this finding, adipocyte-derived secretory factors have since been identified one after another. In addition to leptin, adipocytes secrete adipocytokines (signal molecules of adipocytes) such as TNF-α, IL-6, and adiponectin. Consequently, adipocytes are drawing attention as an endocrine organ that modulates sugars, lipids, and energy metabolism. Obese individuals exhibit insulin resistance. In particular, "fat adipocytes" secrete antagonistic factors (bad cytokines) against the insulin effect including TNF-α. Their abnormal production is considered to cause metabolic disorders, thus contributing to arteriosclerosis etc.
The Problem of BSE
Bovine spongiform encephalopathy (BSE) was discovered in Britain in 1986, leading to a pandemic. The disease was a sort of transmissible spongiform encephalopathies that had been attracting attention as scrapie among sheep and Creutzfeldt-Jakob disease (CJD) among humans. It can be transmitted experimentally by inoculating the brain tissue of a BSE-positive cow into the brains of animals of other species; transmission can occur even orally among cattle. Prusiner, an American researcher who had been pursuing the identity of scrapie, proposed a concept of prion, an infectious protein particle, in 1982. In 1985, prions were revealed not to be exogenous substances, but rather expressed by genes in mammalian cells. Acclaimed for his prion hypothesis that an abnormal prion protein changes the steric structure and properties of a normal one by contacting it to cause disorder of central neuronal cells, Prusiner won a Nobel Prize in 1997.
The source of BSE infection in Britain was estimated to be meat and bone meal (MBM), dry comminution feed made from scrap meat including the brains and spinal cords of infected cows. In order to prevent infections among cattle, the use of MBM was banned in 1988. Owing to the long latency period of 5 years, the incidence culminated in 1992 and plummeted rapidly thereafter. Besides, a measure was taken to remove and incinerate risky parts (brains, spinal cords, dorsal root ganglions), where pathogens accumulate, so as to prevent contagion among humans. Initially, the possibility of infection to humans was excluded, yet mutant CJD that is different from the one prevalent among the elderly was confirmed among the young in 1996. The incidence in humans peaked in 2000 and decreased thereafter.
Although Japan had been importing MBM from the European Union until 1996, it was complacent that BSE had not entered the country. However, the country saw the first BSE-positive cow in 2001, hurriedly prohibiting the use of MBM. Nonetheless, new cases of infections continue to be found as of 2007 among cattle born previously. In EU, cows aged 30 months (2.5 years) or older are being examined. Since the average age of developing the disease is 5, the existing inspection methods, more often than not, tend to overlook it. The Japanese government, however, made a political judgment for the sake of the "sense of security" of the people and has been performing blanket inspection on every cow. What is required more than anything else as a countermeasure against BSE is the definite removal of the risky parts, and performing inspection is meaningful in terms of grasping the epidemic trend. The notion of ensuring security by implementing blanket inspection has taken root among the public since 2003, when BSE was discovered in the US, thus boosting the confidence of domestic cattle. Although the government changed the inspection target to cattle aged 21 months or older in 2005, it has been continuously subsidizing local municipalities to retain their blanket inspection even thereafter. Whether or not the inspection should be maintained even after the planned abolition of the subsidy in 2008 has become a point of contention in each municipality. Adequate risk communication is being called for.