Obesity and Protein Metabolism

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A conceptual model of the interdependence between the metabolism of proteins, fats and carbohydrates taking into account the transport of the carbon skeleton and the stages of the relationship between the processes of formation and utilization of ATP
  Journal of Pharmacy and Pharmacology 6 (2018) 956-964 doi: 10.17265/2328-2150/2018.11.002 Obesity and Protein Metabolism Emil Mukhamejanov and Sara Erjanova  JSC National Medical University named after S. Asfendiarov, Almaty 050000, Kazakhstan Abstracts:  A conceptual model of the interdependence between the metabolism of proteins, fats and carbohydrates taking into account the transport of the carbon skeleton and the stages of the relationship between the processes of formation and utilization of ATP  ( Adenosine Triphosphate ) energy, which demonstrates the key role of protein metabolism and the maintenance of glucose homeostasis with different organism availability in energy was proposed. In supporting the processes of vital activity of the body, two periods should be analyzed. The first one is absorptive period, which is for providing rehabilitation processes, the expression of which is the “food pyramid” and the second one is postabsorptive period, which is for the energetic provision of physical and mental work, the expression of which is the “energy pyramid”. These pyramids differ in the ratio of macronutrients, and in their composition, which must  be taken into account when developing the principles of human nutrition. Although obesity is seen as a simple discrepancy between the amount of intake of food calories and their utilization for physical activity, however, do not take into account the large energy expenditure on volatile processes, in particular, the process of protein synthesis. The process of protein synthesis depends on the availability in the substrate (amino acids), the intensity of mRNA expression (transcription) and the speed of reproduction (translation), so the violation at each of these stages will affect the energy balance and promote the development of obesity. Half of the protein mass is muscle, so it largely determines the homeostasis of glucose and the development of energy balance, which is presented in the form of an interdisciplinary model for the development of diabetes, obesity and cardiovascular diseases. In conclusion, technologies were  proposed to support the process of protein synthesis and ways of preventing and treating obesity. Key words: Obesity, protein metabolism, food model, energy homeostasis, non-communicable disease. 1. Introduction   Obesity is seen as a simple discrepancy between the amount of incoming calories and the amount of their use for physical activity. This way of thinking has led the whole problem into a dead end and all of the weight loss technologies are aimed at reducing the consumption of food calories and increasing physical activity. However, on the one hand, the number of obese persons is increasing from year to year, and, on the other hand, many technologies have proven unsafe for human health. It is known that some people can eat a lot and little move and they stay thin, while others try to limit themselves in food and move a lot and they stay fat. It means that the matter is in the metabolism. But, unfortunately, what actually happens in the body doctors do not know. Nutritionists constantly offer variants of different ratios in the diet of macronutrients Corresponding author: Emil Mukhamejanov, Ph.D.,  professor, research field: biochemistry of nutrition. (proteins, fats and carbohydrates), but adequate models of the relationship between the metabolism of proteins, fats and carbohydrates are not suggested. Glucose homeostasis may be maintained on the account of auto-regulation of enzymes involved in its utilization and synthesis [1]. However, such a regulation has limited potential, and one can observe considerable fluctuations of glucose levels at excessive or deficient intake of carbohydrates with food, as well as at various  physiological and pathological conditions that determine the existence of more powerful systems for maintaining glucose homeostasis of the body. Even though carbohydrates usually constitute over half of energy value of daily ration, however, the body is forced to balance on the edge of their deficit and to save glucose molecule from complete oxidation, for instance, by recycling it via lactate (Cori cycle). Later Feling [2] proposed a model of recycling of glucose via amino acid alanine (glucose-alanine cycle). This model considers the involvement of protein metabolism in D DAVID PUBLISHING   Obesity and Protein Metabolism 957 maintaining glucose homeostasis. Based on the ways of transporting the carbon skeleton and the stages of the interconnection between the processes of formation and utilization of ATP energy at various energy supply in the absorptive and  postabsorptive periods a conceptual model was developed for the interconnection between the metabolism of proteins, fats and carbohydrates (Fig. 1). Thus, during the “Surplus energy—Sancho Pancho” the process of glucose dissimilation is associated with the two assimilation processes: with lipogenesis in regard of carbon skeleton, and with protein synthesis in regard of generation and utilization of ATP energy. Even though glycolysis and protein synthesis are interconnected via generation and utilization of ATP energy, however, these metabolic flows are closely interrelated since no protein synthesis occurs without energy supply while reduced utilization of ATP energy  blocks ATP generation or glycolysis. In such case an excess carbon skeleton will be redirected to lipid synthesis resulting in obesity. During the “Energy deficiency—Donkichot” (for utilization endogenous nutrition flow) glucose homeostasis is maintained on the account of its endogenic synthesis from amino acids, those results in  protein catabolism to supply the required substrates while lipolysis and lipid oxidation get activated to supply the energy for gluconeogenesis. This stage is characterized with combination of two dissimilation  processes (protein catabolism and lipid oxidation) and one assimilation process (gluconeogenesis). Glucose synthesis is associated with lipid oxidation through the generation and utilization of ATP energy, while with  protein catabolism—via routes of transportation of carbon skeleton. Though gluconeogenesis and lipid oxidation are associated with each other through the generation and utilization of ATP energy, these metabolic flows are inter-dependent. For example, blockade of lipolysis [3] or lipid oxidation [4] automatically causes the decline of gluconeogenesis resulting in hypoglycemia, and on the contrary, the reduction of concentration of the substrate for gluconeogenesis blocks ATP synthesis from acetyl-CoA and results in condensing of excess acetyl groups in acetoacetate and oxybutyrate, leading to ketosis, for instance, in diabetes or fasting [5]. Thus, glucose homeostasis in the body depends to considerable extent on interrelations between the metabolism of proteins, lipids and carbohydrates. This dependence is determined by the capacity of any component of the food to affect individual steps of conversion of other nutrients with involvement of regulatory function of hormones. This model may serve as a theoretical basis to develop a dynamic model of balanced nutrition.   Fig. 1 The model of the interconnection between metabolism of proteins, fats and carbohydrates, based on the ways of transporting the carbon skeleton and the stages of the interconnection between the processes of formation and utilization of ATP energy in the absorptive (Sancho Pancho) and postabsorptive (Donkichot) periods.  Obesity and Protein Metabolism 958   Metabolism intensity is controlled by neuro-endocrine system. The “Surplus energy” is signaled by acetylcholine and insulin levels while the “Energy deficiency” is mediated through noradrenaline and glucagon levels. Therefore, on the one hand, the neuro-hormonal status reflects energy balance of the  body, and on the other hand, it depends on the intensity and ratio of nutrient flows. Extensive studies on the specifics of metabolism in fasting or intake of individual nutrients are available; therefore these states are a convenient model to assess the intensity of metabolic flows from the position of the  proposed model. Hepatic glycogen stores almost completely disappear after a 24-48 hour fasting [6, 7], therefore the  body is supplied with glucose due to protein catabolism [8] and lipid oxidation. Introduction of the key gluconeogenic amino acid (alanine) causes an increased glucose production in the liver [9] while oleic acid (energy substrate for gluconeogenesis) increases hepatic glucose production almost two fold [10], and on the contrary, the inhibition of lipolysis [3] or fatty acid oxidation [4] result in hypoglycemia. Muscular alanine synthesis in fasting is completely dependent on the levels of branched amino acids  produced in protein catabolism, and their levels are elevated during the first week of starvation [11]. A two-week feeding of rats with low-protein chow did not affect blood glucose level [12], but the starvation caused more expressed hypoglycemia. A low level of alanine in blood plasma of adults [13] and children [14] is mentioned at protein-energy deficiency, and fasting caused more pronounced hypoglycemia. Obesity is the most prevalent metabolic disorder. Among the causes of obesity the most often is over-eating, especially carbohydrates [15]. This correlates well with the considerations on the character of metabolic flows during the “Surplus energy” when the surplus flow of under-oxidized glucose (lactate) is directed to lipid synthesis. There are available data evidencing to the development of lactate-acidosis in obesity [16] and high correlation between blood lactate concentration and size of adipocyte [17]. Obesity causes activation of metabolic flows during the “Surplus energy”, therefore obese patients have an increased blood concentration of insulin [18] while on the contrary glucagon levels are lower [19]. A certain balance between individual nutrient flows should be maintained. During the “Surplus energy” such balance should be met between the flows of glucose and amino acids. Excess glucose flow induces hyperglycemia and lipidemia, while inadequate glucose intake with food leads to a lower inclusion of amino acids in proteins resulting in hyperaminoacidemia. Therefore, adequacy between these nutrient flows is the most important principle of  balanced nutrition. With food, people get about 100 food compounds, so the wide range of people can understand their needs, the United States Department of Agriculture has developed a model of human nutrition in the form of a  pyramid. But it touches upon the needs of a person only during the absorptive period, whereas nutrition should  be presented in the form of two pyramids—food and energy (Fig. 2). If in the food pyramid the main nutrient is carbohydrates, then in the energy pyramid—fats. In addition to the ratio of macronutrients, these pyramids differ in the composition of food compounds necessary to ensure the activity of their metabolic  processes (Fig. 3). Thus, for the food pyramid, saturated fats are required as basic, polyunsaturated plant and fish fats for constructing cell membranes and synthesizing  biologically active compounds; Anabolic amino acids (leucine, valine, isoleucine), essential (lysine, methionine, threonine) and mediator (tyrosine,  phenylalanine) are required as proteins; as carbohydrates—starch polysaccharide, maltose disaccharide and glucose monosaccharide. In the energy pyramid, saturated short-chain (4-10 carbon atoms)   triglycerides,   such as    palm oil,   are   suitable as  Obesity and Protein Metabolism 959   Fig. 2 Two pyramids in human nutrition. Fig. 3 Components of macronutrients for food and energy pyramids. fats; as proteins—gluconeogenic amino acids (alanine, serine and glycine); as carbohydrates—polysaccharide inulin, monosaccharides fructose and galactose. In other words, all food compounds should be divided into two groups: some are required for the food pyramid, but have a negative impact on the functioning of the energy pyramid. For example, glucose promotes the secretion of the hormone insulin and the activation of metabolic pathways that promote  protein synthesis and repair and renew cellular structures (rehabilitation) and store excess energy, but at the same time inhibit energy generation processes. In other words, at the same time the working capacity decreases—“well-fed animal is not a hunter”. When we work, we use the energy deposited in the  body. This is the so-called endogenous nutrition.  Nowadays the life style of a person has changed significantly. This is due to decline in physical labor and a predominance of intellectual and operator activities, which led to a reduction in fat consumption and increased need for glucose. This led to the development of a deficit of the one energy source (glucose), against an excess of the other—fats. An energy imbalance has been developed that contributes to the increase of metabolic pathologies—diabetes, obesity and cardiovascular diseases. It is necessary to adjust the energy imbalance by developing a specialized product for the work phase or the  post-absorptive period. Based on such principles, we have developed a specialized product for feeding obese  Obesity and Protein Metabolism 960  patients, to which English patent GB 2496119 of January 22, 2014 was received. This product does not induce the secretion of insulin, so working capacity does not decrease; it contributes to the maintenance of glucose homeostasis, reducing fat deposit and prevents the development of functional disorders using technologies to reduce body weight. On the other hand, food energy pyramid connections have a negative influence on the  processes of rehabilitation. In the literature, a large amount of information about the negative effect of fructose monosaccharide (20-23) and palm oil (24-25) has accumulated. Many of these aspects have been repeatedly discussed in the scientific literature regarding sugar and its component of fructose as toxic compounds promoting the development of chronic non-communicable diseases (26). Fructose is not used as an energy source in humans, but in the liver it is converted into glucose and in this form is used as an energy source. During high carbohydrate diet, insulin secretion occurs, which is an information signal about the excess intake of glucose from food. Therefore, during insulinemia, gluconeogenesis is blocked in the liver and fructose from the food passes through the liver unchanged, which increases fructose level in  blood (fructosemia) and lead to the development of its toxic effects. However when fructose enters the  postabsorbtive period, it totally turns into glucose and has not its toxic effects. Moreover, in the absorptive  period fructose promotes activation of lipogenesis and obesity, but in the post-adsorption period it promotes fat oxidation and activation of energy use processes (6 ATP molecules are consumed to synthesize glucose from fructose) and lipid oxidation and a decrease in  body mass index are noted. The same dependence is noted for palm oil. Palm oil is not required for rehabilitation processes and entering the absorption  period it contributes to the development of lipidemia,  but when it enters the postabsorptive period it enhances gluconeogenesis, improves glucose homeostasis and activates utilization and promotes weight loss. Therefore, the phasic nature of the intake of food compounds is an important aspect of maintaining health and developing preventive and curative measures against weight gain. In this regard, protein metabolism is at the center of all metabolic processes and largely determines the energy homeostasis, so when the synthesis of myofibrillar proteins decreases, there is a decrease in the need for glucose energy and activation of the discharge of its carbon skeleton into lipids occurs, which is noted in obese individuals [20]. It is believed that insulin is necessary for the expression of genes [21], the transport of glucose into the cell, mainly in the muscle, as they determine the amount of glucose utilization under the influence of insulin by 80% [22]. To penetrate glucose into the cell, it must be phosphorylated with the participation of hexokinase and only in the form of glucose-6-phosphate enters the muscle cell, so the rate of glucose intake into muscles depends on the activity of hexokinase. In connection with this, it was suggested that insulin promotes the activation of hexokinase, but  biochemical confirmation of this situation does not exist. Hexokinase is a kind of energy sensor for the cell’s energy needs, so its activity depends on the level of ATP or the ATP/ADP coefficient [23]. Insulin  promotes the activation of protein synthesis by enhancing gene expression (at the level of transcription) and the aggregation of ribosomes into polysomes (at the translation level), which increases the consumption of ATP energy and activates hexokinase. Therefore, we can make the assumption that the stimulation of glucose utilization by the muscle cell occurs indirectly through the activation of the protein synthesis process. Synthesis of protein is the most energy-consuming  process in the cell. This is due to the fact that 3 ATPs are used to form a peptide bond or to bind two amino acids ( плата   за   точность   и   скорость ). The average  protein consists of 100 peptide bonds, thousands of  proteins are synthesized per day. In the reverse decay of the peptide bond, 1 ATP is released. Therefore, with
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