Causes and pathogenesis of obesity

According to modern ideas, one of the main pathogenetic mechanisms leading to the development of the disease is the energy imbalance, which is the inconsistency between the amount of calories coming from food and the energy expenditure of the organism. Most often this is due to eating disorders: excessive energy intake from food in comparison with energy expenditure, qualitative deviations in the ratio of nutrients from accepted norms of rational nutrition (excessive consumption of fatty foods) or disruption of diet - moving the main share of daily calories in the evening hours. Fatty tissue is the main depot of energy reserves. Excess energy, supplied with food in the form of triglycerides, is deposited in fat cells - adipocytes, causing an increase in their size and weight gain.

Not only excessive or incorrect nutrition can lead to the development of obesity, often too large body weight - a consequence of energy consumption disorders in the body, caused by various enzymatic, metabolic defects, disturbances of oxidative processes, the state of sympathetic innervation. So, for example, in healthy individuals with normal body weight, with excessive nutrition, an adaptive increase in the metabolic rate develops, in particular, there is a significant increase in basal metabolism, which is apparently a kind of buffer that maintains the energy balance and helps maintain body mass stability with a change in the amount consumed food. In patients with progressive obesity, such adaptation does not occur.

The study of the food behavior of experimental animals also showed that overfeeding does not always lead to the development of obesity, and in animals with genetically determined obesity, the increase in body weight is not merely the result of hyperphagia and overeating. The peculiarities of adrenergic innervation of adipocytes, in particular, the state of beta ₃ and alpha-adrenergic receptors of cell membranes, can influence the rate of lipolysis and lipogenesis and, in the final analysis, to some extent determine the amount of deposited triglycerides in the adipocyte. Undoubtedly the importance of lipid-lipid lipase activity of adipocytes in the mechanisms of obesity development.

The brown fatty tissue, called brown due to the high color of cytochrome and other oxidative pigments in adipocytes richly endowed with mitochondria, according to mainly experimental studies, can make a difference in the pathogenesis of both genetic and nutritional obesity. It is one of the main places of adaptive and diet-induced thermogenesis. In newborns, brown fat tissue plays an important role in maintaining body temperature and adequate response to cold. According to NV Rothwell et al., With excessive nutrition, brown adipose tissue hypertrophies, turning excess energy from food into heat and thereby preventing its deposition in fat stores.

As shown by the observations of many authors, in obese individuals there is a violation of the specific dynamic effect of food, probably caused by a decrease in the processes of thermogenesis in brown adipose tissue. Small physical activity or lack of adequate physical activity, creating excess energy in the body, also contribute to weight gain. The role of hereditary-constitutional predisposition is undoubted: statistics show that obesity in children of lean parents develops in about 14% of cases compared to 80% when both parents have an overweight. And obesity does not necessarily occur from childhood, the likelihood of its development persists throughout life.

For the emergence of obesity, the value of age, sex, occupational factors, and certain physiological conditions of the organism - pregnancy, lactation, menopause - is established. Obesity often develops after 40 years, mainly in women.

According to modern ideas, with all forms of obesity, there are violations of the central regulatory mechanisms that alter behavioral responses, especially food behavior, and cause neurohormonal changes in the body. In the hypothalamus, mainly in the field of paraventricular nuclei and lateral perifornical, there is integration of a multitude of impulses coming from the cerebral cortex, subcortical formations, the sympathetic and parasympathetic nervous system, hormonal and metabolic. Violation of any link in this regulatory mechanism can lead to changes in food intake, fat deposition and mobilization and ultimately to the development of obesity.

Peptides of the gastrointestinal tract (cholecystokinin, substance P, opioids, somatostatin, glucagon), which are peripheral saturation mediators, as well as neuropeptides and monoamines of the central nervous system are important in the formation of food behavior. The latter affect the amount of food consumed, the duration of food, determine food habits. Some (opioid peptides, neuropeptide Y, growth hormone releasing factor, noradrenaline, y-aminobutyric acid, etc.) increase, others (cholecystokinin, corticotropin releasing factor, dopamine, serotonin) reduce food intake. However, the final result of their effect on food behavior depends on their concentration, interaction and interference in certain areas of the central nervous system.

An important component of the mechanisms of the pathogenesis of obesity and its complications is the fat tissue itself. As shown in recent years, it has endo-, auto- and paracrine functions. Substances that are secreted by fat tissue (leptin, tumor necrosis factor A, angiotensinogen, inhibitor of plasminogen activator 1, etc.) have a variety of biological effects and can influence the activity of metabolic processes in tissues and various body systems, either directly or indirectly through the neuroendocrine system, interacting with pituitary hormones , catecholamines, insulin. The adipostatic hormone leptin, the product of the sheep, plays a special role in the regulation of food behavior, the energy expenditure of the organism and the regulation of the neuroendocrine system. It is assumed that the main effect of leptin is directed to the preservation of fat stores. Obesity is characterized by hyperleptinemia, which is supposed to be a consequence of resistance to its action.

A major role in the development of obesity and its complications is played by the endocrine system.

Pancreas. One of the leading links in the pathogenesis of obesity and its complications is a change in the secretion of insulin. Characterized by hyperinsulinemia, combined with a normal or exceeding the normal level of glucose in the blood. Already with obesity of the 1st degree, carrying out a glucose-tolerant test reveals the hyperreaction of insulin to the introduction of glucose. With the increase in the degree of obesity, its basal level in most patients becomes high and with obesity III-IV degree can significantly exceed that of healthy ones, and the introduction of glucose or other insulinotropic stimulants (arginine, leucine) helps to identify inadequate response of beta cells of the pancreas, expressed as in excessive increase, and in a decrease in comparison with the norm of the secretion of insulin in response to stimulation. In patients with long-existing massive obesity, the incidence of diabetes is increasing . Simultaneously with the high content of insulin in the blood, the glycemic parameters are not only not lowered, but are normal or often increased, which suggests a decrease in the effectiveness of the action of endogenous insulin.

The immediate causes leading to an increase in insulin secretion and resistance to its action in patients with excessive body weight have not been sufficiently elucidated to date. In the genesis of hyperinsulinemia in obesity, insulin resistance, disturbances in hypothalamic regulation, realized through the sympathetic and parasympathetic nervous system, opioid peptides, gastrointestinal hormones, in particular the gastric inhibitory polypeptide, nutrition peculiarities are important.

The basis of insulin resistance is a decrease in insulin sensitivity in all studied metabolic pathways, beginning with its binding by receptors. It is assumed that with obesity, the number of receptors to insulin on the surface of effector cells decreases, leading to a decrease in binding and thereby a decrease in the specific effect of this hormone.

Postreceptor defect of insulin action, according to several authors, develops with the prolonged existence of obesity. Insulin resistance promotes the development of compensatory hyperinsulinemia, which leads to a further decrease in the sensitivity of peripheral tissues to the action of insulin.

Glucagon has no significant effect in the pathogenesis of the above deviations. According to the literature, its secretion is not impaired in patients with obesity of varying degrees and duration.

The somatotropic function of the pituitary gland with obesity plays a big role. Its violation is undoubtedly important in the pathogenesis of the onset, development and maintenance of excess body weight. It was shown that, with obesity of I-II degree, basal secretion of somatotropin was not changed, the reaction to insulin hypoglycemia was reduced. With increase in body weight, a decrease in basal secretion and a lack of increase in somatotropin level at night, a reaction to the administration of L-dopa and releasing factor of growth hormone is much lower than normal. The involvement of increased secretion of somatostatin and violations of dopaminergic regulation in the genesis of detected disorders of formation of somatotropin is suggested.

Hypothalamic-pituitary-genital system. It is known that in obese menstrual and reproductive disorders in women and in the sex are very frequent in men.

They are based on changes in central regulatory mechanisms, as well as changes in the metabolism of sex steroids on the periphery, in particular in adipose tissue. Obesity affects both the timing of the appearance of menarche, and the further development of menstrual function. For its appearance and normal cyclic activity of the ovaries, the mass of adipose tissue in the body is of no small importance. According to the hypothesis Frisch-Rovelle, menarche occurs when the body weight reaches the so-called critical mass, which is 48 kg (fat tissue - 22%). Since full girls grow faster and a "critical" mass is recruited at an earlier period, menstruation begins much earlier, although they are often not installed for a long time and are often irregular in the future. Obesity, possibly, causes a greater frequency of infertility, the likelihood of developing polycystic ovaries and an earlier onset of menopause. The results of studying the secretion of gonadotropic hormones during the cycle in women with obesity do not reveal any peculiarities. There have been reports of a decrease in FSH secretion in the follicular phase of the cycle and a low pre-growth in LH. Basal secretion of prolactin in obesity does not differ from that in healthy women; however, in most patients the reaction of prolactin to various pharmacological stimuli (insulin hypoglycemia, tyroliberin, dopamine receptor blocker-sulpiride) is reduced. Expressed individual differences in the reactions of gonadotropins to stimulation with luliberin were found. The revealed disturbances testify to the dysfunction of the hypothalamic-pituitary system in this pathology. Of great importance in the development of sexual disorders in obesity is the peripheral metabolism of estrogens and androgens and their binding to plasma proteins. In adipose tissue, probably in its stromal elements, there is an acceleration of aromatization of androgens, in particular testosterone and androstenedione into estradiol and estrone, respectively leading to hyperestrogenism, which contributes to the occurrence of uterine bleeding. Some patients may experience hyperandrogenism, caused by both steroidogenesis disorders in the ovaries, and an increase in the production of androgens by the adrenal glands. However, if the increase in production of the latter is compensated by the acceleration of the rate of their metabolism, then the symptoms of hyperandrogenism in women may be absent. There is a change in the coefficient of androgens / estrogens in the direction of its decrease. There are indications of a relationship between the nature of the distribution of fat and this indicator. Presence of regional sensitivity of adipocytes to steroids is supposed, the predominance of androgens is combined with an increase in adipocytes mainly in the upper half of the trunk. Some women with obesity have inadequate progesterone production in the luteal phase of the cycle, which may be the reason for their fertility decline. In addition, the development of the syndrome of polycystic ovaries (secondary sclerocystosis of the ovaries) with clinical signs of hyperandrogenism is possible. A major role in the development of these disorders is played by hypothalamic-pituitary dysfunction and impaired peripheral metabolism of sex steroids in stromal cells of adipose tissue.

In men with overweight, a low testosterone level is detected in the plasma in the absence of clinical signs of hypoandrogenism, apparently due to an increase in the free fraction of the hormone. Enhanced peripheral conversion of testosterone to estradiol and androstenedione to estrone, often contributing to the development of gynecomastia. In some cases, there is a decrease in the secretion of lutropin and, respectively, testosterone with moderately expressed clinical symptoms of hypogonadotropic hypogonadism as a result of inhibition of the feedback mechanism of gonadotropin secretion by an elevated level of estrogens.

Hypothalamic-pituitary-adrenal system. In patients with obesity III-IV degree, violations of the circadian rhythm of corticotropin and cortisol secretion are often detected. In this case, as a rule, in the morning hours - the normal levels of ACTH and cortisol in the plasma, in the evening - low or exceeding the norm. The reaction of corticotropin and cortisol to insulin hypoglycemia can be normal, elevated or decreased. For patients with obesity that occurred in childhood, the feedback mechanisms revealed in the study of sensitivity of the hypothalamic-pituitary system to dexamethasone administered at different times of the day (morning and night) are characteristic. A large number of patients (especially with obesity III-IV degree) increased the production rate of cortisol, accelerated its metabolism, increased excretion of 17-hydroxycorticosteroids with urine. The level of cortisol in the plasma remains normal, as an increase in the rate of metabolic clearance of cortisol leads to a decrease in its content in the plasma and through the feedback mechanism stimulates the secretion of ACTH. In turn, an increase in the rate of secretion of ACTH leads to an increase in the production of cortisol, and thus its plasma level is maintained within normal limits. Increased secretion of corticotropin also causes the acceleration of production of androgens by the adrenal glands.

A study of the metabolism of cortisol in in vitro experiments in adipose tissue showed that the tissue is capable of oxidizing cortisol to cortisone. Due to the fact that the latter less inhibits the secretion of corticotropin, it can also stimulate the secretion of cortisol.

Hypothalamic-pituitary-thyroid system. The study of the functional state of the thyroid gland is devoted to the research of many authors in connection with the fact that thyroid hormones are of great importance in the regulation of fat metabolism and in connection with the question, discussed so far, about the possibility of using thyroid hormones with a curative purpose for obesity. It is shown that in the initial stages of the disease the secretion of thyrotropin, basal and stimulated with thyroidiberin, remains within the normal range. And only with obesity III-IV degree in a number of patients there is a decrease in the reaction of thyrotropin to thyreoliberin. In some cases, the basal level of thyroid-stimulating hormone in the plasma also falls.

As a rule, in most patients with excessive body weight, there is no change in the content of total and free fractions of thyroid hormones. The nature of food largely determines the content of thyroxine (T4) and triiodothyronine (T3) in plasma and their ratios. The total calorie of food, as well as the ratio of carbohydrates, proteins and fats are important parameters that determine the levels of T ₄, T ₃ and RT ₃ in the blood. Detectable changes in the content of thyroid hormones in the blood, depending on the amount of food taken (especially carbohydrates), apparently, are compensatory and are aimed at maintaining body mass stability. For example, overeating leads to faster peripheral conversion of T ₄ to T ₃, T3 increase in blood and there is a decrease in fasting levels of T3 and T4 in the blood increase.

Some authors note a change in the sensitivity of peripheral tissues (the presence of resistance) to thyroid hormones due to a decrease in receptor sites. It is also reported the violation in some cases, the binding of T ₄ thyroxine binding globulin, strengthening the collapse of T ₄, resulting in a reduction of thyroxine and triiodothyronine, respectively, in the tissues, the development of the relative thyroid insufficiency and clinical signs of hypothyroidism in these patients.

[1], [2], [3], [4], [5], [6], [7]