Causes and pathogenesis of obesity

According to modern concepts, one of the main pathogenetic mechanisms leading to the development of the disease is an energy imbalance, consisting in a discrepancy between the amount of calories coming from food and the energy expenditure of the body. Most often, this occurs due to nutritional disorders: excess energy intake with food compared to energy expenditure, qualitative deviations in the ratio of nutrients from the accepted norms of rational nutrition (excessive consumption of fatty foods) or a violation of the diet - the shift of the main share of the daily caloric content of food to the evening hours. Adipose tissue is the main depot of energy reserves. Excess energy coming from food in the form of triglycerides is deposited in fat cells - adipocytes, causing an increase in their size and an increase in body weight.

Not only excessive or improper nutrition can lead to the development of obesity, often too much body weight is a consequence of energy expenditure disorders in the body, caused by various enzymatic, metabolic defects, oxidative process disorders, and the state of sympathetic innervation. For example, in healthy individuals with normal body weight, with excessive nutrition, an adaptive increase in the metabolic rate develops, in particular, a significant increase in the basal metabolism is noted, which is apparently a kind of buffer that maintains energy balance and helps maintain body weight stability when the amount of food consumed changes. In patients with progressive obesity, such adaptation does not occur.

The study of the feeding 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 only the result of hyperphagia and overeating. The features of the adrenergic innervation of adipocytes, in particular the state of beta ₃ - and alpha-adrenergic receptors of cell membranes, can affect the rate of lipolysis and lipogenesis and ultimately to some extent determine the amount of deposited triglycerides in the adipocyte. The importance of the activity of adipocyte lipoprotein lipase in the mechanisms of obesity development is undoubted.

Brown adipose tissue, so named because of its brown coloration due to the high content of cytochrome and other oxidative pigments in adipocytes rich in mitochondria, may be important in the pathogenesis of both genetic and alimentary obesity, according to mainly experimental studies. It is one of the main sites of adaptive and diet-induced thermogenesis. In newborns, brown adipose tissue plays an important role in maintaining body temperature and adequate response to cold. According to NV Rothwell et al., with overnutrition, brown adipose tissue hypertrophies, converting excess energy from food into heat and thereby preventing its deposition in fat depots.

As evidenced by the observations of many authors, obese individuals have a violation of the specific dynamic action of food, probably caused by a decrease in thermogenesis processes in brown adipose tissue. Low physical activity or lack of adequate physical exercise, creating an excess of energy in the body, also contribute to weight gain. The role of hereditary-constitutional predisposition is undeniable: statistical data indicate that obesity in children of thin parents develops in approximately 14% of cases compared to 80% when both parents are overweight. Moreover, obesity does not necessarily arise in childhood; the likelihood of its development remains throughout life.

Age, gender, professional factors, and some physiological states of the body - pregnancy, lactation, and menopause - have been established as factors that contribute to the development of obesity. Obesity most often develops after 40 years of age, primarily in women.

According to modern concepts, all forms of obesity are associated with disturbances in central regulatory mechanisms that change behavioral reactions, especially eating behavior, and cause neurohormonal shifts in the body. In the hypothalamus, mainly in the area of the paraventricular nuclei and lateral perifornical, there is an integration of many impulses coming from the cerebral cortex, subcortical formations, through the sympathetic and parasympathetic nervous system, hormonal and metabolic. Disturbance of any link in this regulatory mechanism can lead to changes in food consumption, fat deposition and mobilization, and ultimately to the development of obesity.

Of great importance in the formation of eating behavior are peptides of the gastrointestinal tract (cholecystokinin, substance P, opioids, somatostatin, glucagon), which are peripheral mediators of satiety, as well as neuropeptides and monoamines of the central nervous system. The latter affect the amount of food consumed, the duration of eating, and determine eating inclinations. Some (opioid peptides, neuropeptide Y, growth hormone releasing factor, norepinephrine, y-aminobutyric acid, etc.) increase, others (cholecystokinin, corticotropin-releasing factor, dopamine, serotonin) decrease food consumption. However, the final result of their impact on eating behavior depends on their concentration, interaction and mutual influence in certain areas of the central nervous system.

An important component of the mechanisms of pathogenesis of obesity and its complications is the adipose tissue itself. As shown in recent years, it has endo-, auto- and paracrine functions. Substances secreted by adipose tissue (leptin, tumor necrosis factor A, angiotensinogen, plasminogen activator inhibitor 1, etc.) have a variety of biological effects and can affect the activity of metabolic processes in tissues and various systems of the body either directly or indirectly through the neuroendocrine system, interacting with pituitary hormones, catecholamines, insulin. Of particular importance in the regulation of eating behavior, energy expenditure of the body and regulation of the neuroendocrine system is the adipose-static hormone leptin, a product of ovogen. It is assumed that the main effect of leptin is aimed at preserving fat reserves. Obesity is characterized by hyperleptinemia, which is believed to be a consequence of resistance to its action.

The endocrine system plays a major role in the development of obesity and its complications.

Pancreas. One of the leading links in the pathogenesis of obesity and its complications is a change in insulin secretion. Hyperinsulinemia is characteristic, combined with normal or above-normal blood glucose levels. Even with stage I obesity, a glucose tolerance test reveals an insulin hyperreaction to glucose administration. As the degree of obesity increases, its basal level in most patients becomes high and, with stage III-IV obesity, can significantly exceed that in healthy people, and the introduction of glucose or other insulinotropic stimulants (arginine, leucine) helps to reveal an inadequate reaction of pancreatic beta cells, expressed both in an excessive increase and in a decrease in insulin secretion in response to stimulation compared to the norm. In patients with long-term massive obesity, the incidence of diabetes mellitus increases. At the same time as the high insulin content in the blood, glycemic indices are not only not reduced, but are normal or often increased, which suggests a decrease in the effectiveness of endogenous insulin.

The immediate causes leading to increased insulin secretion and resistance to its action in patients with excess body weight have not yet been sufficiently clarified. Insulin resistance, hypothalamic regulation disorders realized through the sympathetic and parasympathetic nervous systems, opioid peptides, gastrointestinal hormones, in particular gastric inhibitory polypeptide, and nutritional characteristics are important in the genesis of hyperinsulinemia in obesity.

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

Postreceptor defect of insulin action, according to a number of authors, develops with long-term obesity. Insulin resistance contributes to the development of compensatory hyperinsulinemia, leading to a further decrease in the sensitivity of peripheral tissues to the action of insulin.

Glucagon does not have a significant role in the pathogenesis of the above deviations. According to literature data, its secretion is not impaired in patients with obesity of varying degrees and duration.

The somatotropic function of the pituitary gland plays a major role in obesity. Its disruption is undoubtedly important in the pathogenesis of the emergence, development and maintenance of excess body weight. It has been shown that in obesity of I-II degree, the basal secretion of somatotropin is not changed, the response to insulin hypoglycemia is reduced. With an increase in body weight, a decrease in basal secretion and no increase in the level of somatotropin at night are observed, the response to the introduction of L-dopa and the releasing factor of growth hormone is significantly below the norm. It is assumed that increased secretion of somatostatin and dopaminergic regulation disorders participate in the genesis of the detected disorders of somatotropin formation.

Hypothalamic-pituitary-reproductive system. It is known that with obesity, menstrual and reproductive function disorders in women and sexual function disorders in men are quite common.

They are based on both changes in the central regulatory mechanisms and changes in the metabolism of sex steroids in the periphery, in particular in adipose tissue. Obesity affects both the timing of menarche and the further development of menstrual function. The mass of adipose tissue in the body is of no small importance for its appearance and normal cyclical activity of the ovaries. According to the Frisch-Rovelle hypothesis, menarche occurs when body weight reaches the so-called critical mass, which is 48 kg (adipose tissue - 22%). Since overweight girls grow faster and gain the "critical" mass at an earlier period, their menstruation begins much earlier, although it often does not become established for a long time and is often irregular in the future. Obesity may be responsible for a higher 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 are reports of some decrease in the secretion of FSH in the follicular phase of the cycle and a low preovulatory rise in LH. Basal secretion of prolactin in obesity does not differ from that in healthy women, but in most patients the reaction of prolactin to various pharmacological stimuli (insulin hypoglycemia, thyroliberin, dopamine receptor blocker - sulpiride) is reduced. Marked individual differences in the reactions of gonadotropins to stimulation with luteinizing hormone were found. The detected disorders indicate dysfunction of the hypothalamic-pituitary system in this pathology. Peripheral metabolism of estrogens and androgens and their binding to plasma proteins are of great importance in the development of sexual disorders in obesity. 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, contributing to the occurrence of uterine bleeding. Some patients may have hyperandrogenism caused by both impaired steroidogenesis in the ovaries and increased production of androgens by the adrenal glands. However, if the increased production of the latter is compensated by an acceleration of their metabolic rate, then the symptoms of hyperandrogenism in women may be absent. A change in the androgen/estrogen ratio towards its decrease is noted. There are indications of a relationship between the nature of fat distribution and this indicator. The existence of regional sensitivity of adipocytes to steroids is assumed, the predominance of androgens is combined with an increase in adipocytes mainly in the upper half of the body. Some obese women have inadequate production of progesterone in the luteal phase of the cycle, which may be the cause of a decrease in their fertility. Besides,development of polycystic ovary syndrome (secondary sclerocystic ovary syndrome) with clinical signs of hyperandrogenism is possible. Hypothalamic-pituitary dysfunction and disturbance of peripheral metabolism of sex steroids in stromal cells of adipose tissue play a major role in the development of these disorders.

In overweight men, low plasma testosterone levels are observed in the absence of clinical signs of hypoandrogenism, apparently due to an increase in the free fraction of the hormone. Peripheral conversion of testosterone to estradiol and androstenedione to estrone is enhanced, often contributing to the development of gynecomastia. In some cases, decreased secretion of lutropin and, accordingly, testosterone with moderate clinical symptoms of hypogonadotropic hypogonadism is observed as a result of inhibition of the feedback mechanism of gonadotropin secretion by elevated estrogen levels.

Hypothalamic-pituitary-adrenal system. Patients with grade III-IV obesity often have disturbances in the circadian rhythm of corticotropin and cortisol secretion. As a rule, plasma ACTH and cortisol levels are normal in the morning, and low or above normal in the evening. The response of corticotropin and cortisol to insulin hypoglycemia may be normal, elevated, or decreased. Patients with childhood obesity are characterized by disturbances in feedback mechanisms, which are revealed when studying the sensitivity of the hypothalamic-pituitary system to dexamethasone administered at different times of the day (morning and night). A large number of patients (especially with grade III-IV obesity) have an increased rate of cortisol production, accelerated metabolism, and increased excretion of 17-hydroxycorticosteroids in the urine. The plasma cortisol level remains normal, since an increase in the rate of metabolic clearance of cortisol leads to a decrease in its content in the plasma and, through a 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 level in the plasma is maintained within normal limits. An increase in the secretion of corticotropin also causes an acceleration of the production of androgens by the adrenal glands.

In vitro studies of cortisol metabolism in adipose tissue have shown that the tissue is capable of oxidizing cortisol to cortisone. Since the latter inhibits corticotropin secretion to a lesser extent, it may also stimulate cortisol secretion.

Hypothalamic-pituitary-thyroid system. Many authors have devoted their research to the study of the functional state of the thyroid gland due to the fact that thyroid hormones are of great importance in the regulation of fat metabolism and in connection with the still debated issue of the possibility of using thyroid hormones for therapeutic purposes in obesity. It has been shown that in the initial stages of the disease, the secretion of thyrotropin, basal and stimulated by thyrotropin-releasing hormone, remains within the normal range. And only in obesity of grades III-IV, a decrease in the reaction of thyrotropin to thyrotropin-releasing hormone is noted in a number of patients. In some cases, the basal level of thyroid-stimulating hormone in plasma also falls.

As a rule, most patients with excess body weight do not show changes in the content of total and free fractions of thyroid hormones. The nature of nutrition largely determines the content of thyroxine (T4) and triiodothyronine (T3) in plasma and their ratio. The total caloric content of food, as well as the ratio of carbohydrates, proteins and fats are important parameters determining the levels of T4 _, T3 _and RT3 _in the blood. The detected changes in the content of thyroid hormones in the blood depending on the amount of food consumed (especially carbohydrates) are apparently compensatory and aimed at maintaining the stability of body weight. For example, overeating leads to an acceleration of the peripheral conversion of T4 _to T3 _, an increase in T3 in the blood, and during fasting a decrease in the level of T3 and an increase in T4 in the blood are observed.

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 that in some cases the binding of T4 _{to thyroxine-binding globulin is impaired, and thatT4} is more easily broken down, leading to a decrease in the content of thyroxine and, accordingly, triiodothyronine in tissues, the development of relative thyroid insufficiency, and the appearance of clinical signs of hypothyroidism in such patients.

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