Obesity and Protein Metabolism

Journal of Pharmacy and Pharmacology 6 (2018) 956-964

doi: 10.17265/2328-2150/2018.11.002

D

DAVID PUBLISHING

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.

(proteins, fats and carbohydrates), but adequate models

of the relationship between the metabolism of proteins,

Obesity is seen as a simple discrepancy between the

fats and carbohydrates are not suggested. Glucose

amount of incoming calories and the amount of their

homeostasis may be maintained on the account of

use for physical activity. This way of thinking has led

auto-regulation of enzymes involved in its utilization

the whole problem into a dead end and all of the weight

and synthesis [1]. However, such a regulation has

loss technologies are aimed at reducing the

limited potential, and one can observe considerable

consumption of food calories and increasing physical

fluctuations of glucose levels at excessive or deficient

activity. However, on the one hand, the number of

intake of carbohydrates with food, as well as at various

obese persons is increasing from year to year, and, on

physiological and pathological conditions that

the other hand, many technologies have proven unsafe

determine the existence of more powerful systems for

for human health. It is known that some people can eat

maintaining glucose homeostasis of the body.

a lot and little move and they stay thin, while others try

Even though carbohydrates usually constitute over

to limit themselves in food and move a lot and they stay

half of energy value of daily ration, however, the body

fat. It means that the matter is in the metabolism. But,

is forced to balance on the edge of their deficit and to

unfortunately, what actually happens in the body

save glucose molecule from complete oxidation, for

doctors do not know. Nutritionists constantly offer

instance, by recycling it via lactate (Cori cycle). Later

variants of different ratios in the diet of macronutrients

Feling [2] proposed a model of recycling of glucose via

Corresponding author: Emil Mukhamejanov, Ph.D.,

amino acid alanine (glucose-alanine cycle). This model

professor, research field: biochemistry of nutrition.

considers the involvement of protein metabolism in

1. Introduction



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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.

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Obesity and Protein Metabolism

Metabolism intensity is controlled by

obesity [16] and high correlation between blood lactate

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

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

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Obesity and Protein Metabolism

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

Obesity and Protein Metabolism

961

an increase in the number of food calories, the

processes of protein synthesis and proteins decay

accelerate, i.e. the acceleration of protein turnover and

the increase in energy expenditure, and, conversely,

with a reduction in food calories, the process of protein

turnover and energy expenditure also decreases. In this

regard, protein metabolism is the physiological

mechanism of controlling the weight of a person.

Consequently, all factors contributing to the synthesis

of protein, will help improve body weight control.

The rate of protein synthesis is accelerated by the

aggregation of ribosomes into polysomes. This process

is influenced by translation kinases, in particular

mTOR, which are activated under the influence of

amino acids and glucose [24] or signaling molecules to

ensure the process of protein synthesis by building

material and energy. The process of aggregation of

ribosomes is influenced by many factors (Fig. 4).

However, when this adaptive mechanism fails to

support the homeostasis of glucose, for example, when

the building material (amino acids) is insufficiently

supplied or the protein of the synthesizing apparatus

deteriorates (reducing the ribosome aggregation factors

and increasing the factors of polysomes disaggregation),

the excess flow of food calories is predominantly

deposited as fats, for example, in hypokinesia and

inflammation [25]. Reduction of muscle mass

(sarcopenia) is also an important factor in reducing the

amount of energy utilization on the protein synthesis

process and leads to the development of sarcopenia

obesity [26].

Homeostasis of glucose is one of the most important

principles of life support, so all forms of metabolism,

all organs and tissues, all regulatory systems of the

body participate in its maintenance, which must be

integrated to maintain energy homeostasis [27]. We

tried to express this interconnection in the form of a

scheme (Fig. 5)

Reducing the size of muscle mass leads to a decrease

in the amount of glucose utilization and there is an

increase in the amount of glucose in the blood

(glycaemia). In response to hyperglycemia, increased

insulin secretion and increased the concentration of the

hormone in the blood (insulinemia), i.e. the main

manifestations of diabetes mellitus developed. These

include glycaemia, insulinemia, and reduced glucose

consumption by muscles. Under the influence of

insulin the

carbon skeleton

of glucose

is released into

Fig. 4 Factors affecting the aggregation of ribosomes.

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Obesity and Protein Metabolism

Fig. 5 The model of the relationship between muscle loss and the development of non-communicable diseases.

fats, which leads to the development of lipidemia,

increasing lipid deposition in adipocytes and the

development of obesity.

Rapid growth of adipose tissue leads to a worsening

of its blood supply and development of hypoxia,

macrophage infiltration and secretion of inflammatory

cytokines, so diabetes and obesity are related to chronic

low-grade inflammation. Inflammatory cytokines enter

the liver and promote the secretion of the CRP, which

promotes increased blood pressure and marked the

development of cardiovascular diseases.

Consequently, there is a decrease in the utilization of

glucose and the development of non-communicable

diseases (diabetes, obesity, cardiovascular) in

sarcopenia, so it is necessary to carry out measures to

increase muscle mass in order to interrupt this chain.

First of all, it is an adequate substrate support for the

process of protein synthesis. In this regard, it is

necessary to use high-grade proteins with a high

content of anabolic amino acids, in particular whey

protein [28].

Secondly, use technology to activate protein

synthesis:

(a) Anabolic resistance exercise [29];

(b) Proteins and amino acids with a high of muscle

protein synthesis activity [30];

(c) Vitamins having a positive effect on protein

synthesis [31] and microelements (Са и Мг);

(d) Can use anabolic sex hormones testosterone and

estrogens;

(e) Technologies to restore the function of the insulin

receptor [32];

(f) Reduce inflammation [33];

(g) Use nutraceuticals to reduce absorption and

increase glucose utilization [34, 35].

Accordingly, it should completely change the

ideology of the fight against obesity, taking as a basis

the principles of maintaining glucose homeostasis and

technology to combat sarcopenia. Strange as it may

seem, these technologies have long been tested in in

vitro, in vivo and human studies, only in this review we

tried to give them a theoretical basis.

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