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102ГОРМОН ЛЕПТИН, ЕГО ФУНКЦИИ И ЗНАЧЕНИЕ В ОРГАНИЗМЕ
Юлдашева Гульнора Эргашева Зумрад Журабоев Бахтиёржон Абдурахимов Абдухалим Нугманов Озодбек
Андижанский государственный медицинский институт
Андижан, Узбекистан
У пациентов, страдающих ожирением и избыточным весом, гормональные изменения влияют на их общее состояние здоровья. Избыток жира в организме может привести к лишнему весу и гормональным проблемам. Лептин - это один из гормонов в организме, который напрямую связан с ожирением. В этой статье рассматриваются имеющиеся данные о гормоне лептине и о том, какую важную роль он играет в организме человека.
Ключевые слова: ожирение, лептин, гормональная изменчивость.
LEPTIN GORMONI VA UNING ORGANIZMDAGI VAZIFALARI HAMDA AHAMIYATI
Semizlik va ortiqcha vazndan aziyat chekadigan bemorlarda gormonal o'zgaruvchanliklar ularning umumiy sog'lig'iga ta'sir qiladi. Tanadagi ortiqcha yog' og'irlik va gormonal muammolarga olib kelishi mumkin. Leptin tanadagi yog 'va semizlik bilan bevosita bog'liq bo'lgan gormonlardan biridir. Ushbu maqolada leptin gormoni va uning organizmda qanday ahamiyat kasb etishi haqida so'z yuritilmoqda.
Kalit so'zlar: Semizlik, leptin, gormonal o'zgaruvchanlik.
LEPTIN HORMONE AND ITS FUNCTIONS AND IMPORTANCE IN THE BODY
For patients struggling with obesity and weight, hormones often affect their overall health. Excess body fat can cause problems with weight and hormonal issues. Leptin is one of the hormones directly connected to body fat and obesity. This article goes on about the hormone leptin and how it plays an important role in the body.
Keywords: Obesity, leptin, hormonal variability.
DOI: 10.24411/2181-0443/2020-10076
Introduction: Leptin, a hormone released from the fat cells located in adipose tissues, sends signals to the hypothalamus in the brain. This particular hormone helps regulate and alter long-term food intake and energy expenditure, not just from one meal to the next. The primary design of leptin is to help the body maintain its weight. Because it comes from fat cells, leptin amounts are directly connected to an individual's amount of body fat. If the individual adds body fat, leptin levels will increase. If an individual lowers body fat percentages, the leptin will decrease as well. Leptin is sometimes called the satiety hormone. It helps inhibit hunger and regulate energy balance, so the body does not trigger hunger responses when it does not need energy. However, when levels of the hormone fall, which happens when an individual loses weight, the lower levels can trigger huge increases in appetite and food cravings. This, in turn, can make weight loss more difficult. When the body is functioning properly, excess fat cells will produce leptin, which will trigger the hypothalamus to lower the appetite, allowing the body to dip into the fat stores to feed
itself. Unfortunately, when someone is obese, that individual will have too much leptin in the blood. This can cause a lack of sensitivity to the hormone, a condition known as leptin resistance. Because the individual keeps eating, the fat cells produce more leptin to signal the feeling of satiety, leading to increased leptin levels. Low levels of leptin are rare, but can occasionally occur. For a few patients, a condition known as congenital leptin deficiency keeps the body from producing leptin. Without leptin, the body thinks it has no body fat, and this signals intense, uncontrolled hunger and food intake. This often manifests in severe childhood obesity and delayed puberty. The treatment for leptin deficiency is leptin injections.
Leptin transport and sites of action. According to S. Ahima, S. Flier [1] leptin circulates as a 16-kDa protein and is partially bound to plasma proteins. In one study, the proportion of bound leptin was reported to be higher in lean (~45%) compared with obese (~20%) individuals. The bound fraction of leptin can be as high as 80% in humans with a leptin receptor mutation due to binding of leptin to circulating leptin receptors. An additional pool of leptin is bound to tissue-binding sites and is likely to contribute to the maintenance of steady-state plasma leptin levels. Based on anatomic and functional data, it appears that leptin exerts its effects on energy balance mainly by acting in the brain. Intravenous leptin injection activates neurons in the arcuate, ventromedial, and dorsomedial hypothalamic nuclei and in brainstem neuronal circuits implicated in the regulation of feeding behavior and energy balance. The long form leptin receptor (Ob-Rb) is present in these hypothalamic regions and colocalized with STAT3 and neuropeptide mediators of leptin action, such as neuropeptide Y (NPY) and proopiomelanocortin (POMC) [2-6]. In contrast, short leptin receptor isoforms are expressed in choriod plexus, vascular endothelium, and peripheral tissues, such as kidney, liver, lung, and gonads, where they may serve a transport and/or clearance role. It is of interest that intracerebroventricular leptin injection inhibits food intake and decreases adiposity more potently that peripheral leptin administration. Leptin enters the rat brain by a saturable transport mechanism, possibly by receptor-mediated transcytosis across the blood-brain barrier, as is the case for some other large proteins. In support of this view, brain microvessels express high levels of the short form leptin receptor Ob-Ra and are also capable of binding and internalizing leptin. Leptin target neurons in the arcuate, dorsomedial, ventromedial, and ventral premammillary nuclei lie within close proximity to the median eminence. Because capillaries in the median eminence lack tight junctions, as in other circumventricular organs, leptin may reach neurons in the adjacent ventrobasal hypothalamus through diffusion. Leptin may also be transported into the brain via cerebrospinal fluid (CSF). It has also been suggested that Ob-Ra, which is highly expressed in the choroid plexus (the site of CSF production), could mediate blood-to-CSF leptin transport. However, leptin is present (albeit at a much lower fraction of the elevated circulating levels) in CSF of obese Koletsky rats, which totally lack leptin receptors, indicating that leptin receptors are not essential for leptin transport into CSF . More importantly, CSF leptin concentration is ~ 100-fold lower than plasma leptin and less than the Kd of the leptin receptor. Therefore, it is unlikely that CSF leptin is a major source of leptin for targets in the brain [7-20]. Leptin is distributed widely in various tissues and is cleared mainly by the kidney. A role for the kidney in leptin clearance is consistent with elevation of leptin levels in patients with renal impairment and end-stage renal disease. Leptin is filtered by the glomeruli and is thought to be degraded by renal epithelial cells. High levels of short form leptin receptors are present in the kidney, and leptin binds to the corticomedullary junction and renal papilla. These receptors may internalize and degrade leptin, as occurs in Chinese hamster ovary (CHO) cells expressing Ob-Ra. Leptin levels are higher in patients with liver cirrhosis, suggesting that the liver may be involved in leptin synthesis or clearance. The liver is unlikely to be involved in leptin clearance because there is no net uptake of leptin by
normal human liver. A study in rats has demonstrated that transdifferentiated stellate cells obtained from rat liver following injury are capable of synthesizing leptin. This finding in humans raises the possibility that the rise in leptin levels in cirrhosis is derived in part from hepatic synthesis [9, 13-21].
The physiological role of leptin in energy homeostasis. In addition, administration of leptin to rodents decreases food intake and increases energy expenditure. In contrast to starvation, weight loss after peripheral or central leptin administration is restricted to adipose tissue, with no loss of lean mass. Leptin activates lipid oxidation, at least in part, by inducing the expression of enzymes of lipid oxidation. In rats leptin also stimulates apoptosis of adipocytes. The ability of leptin to decrease body weight and body fat content led to the prevailing view that leptin is an anti-obesity hormone. However, this view must be reconciled with the failure of high endogenous leptin levels to prevent obesity in humans and other obese mammals. Hyperleptinemia is thought to be indicative of leptin resistance, which may play a role in the development of obesity. Mechanisms thought to underlie leptin resistance include dysregulation of leptin synthesis and/or secretion, abnormalities of brain leptin transport, and abnormalities of leptin receptors and/or postreceptor signaling [22-26].
According to Flier's and Ahima's research [1], studies in obese rodents have provided some insights into the potential mechanisms of leptin resistance. However, there is as yet no direct explanation of the apparent lack of sensitivity of individuals to elevated leptin levels during the course of diet-induced obesity. CSF leptin transport may be limited in obesity, as evidenced by decreased plasma:CSF leptin ratio in obese individuals. Because plasma:CSF ratios are markedly decreased in fa/fa and Koletsky rats with abnormalities of membrane leptin receptor expression, leptin resistance may arise from defects of receptor-mediated leptin transport into the brain. A polygenic mutation that leads to late onset obesity in New Zealand obese (NZO) mice may also offer some insight into the role of brain leptin transport in obesity. These mice are resistant to peripheral leptin administration, but do respond to intracerebroventricular leptin injection, consistent with defective brain leptin transport. Similarly, diet-induced obesity in rodents is characterized by insensitivity to peripheral leptin injection but respond to intracerebroventricular leptin. In contrast, agouti (Ay/a ) mice have impaired melanocortin (MC4) receptor signaling in the brain and are resistant to both peripheral and central leptin injection. Studies of leptin transport into brain in these models have not been reported.
Studies show that [1,25] a member of the suppressors of cytokine signaling family, SOCS-3, is a potential molecular mediator of leptin resistance. SOCS-3 mRNA levels are conserved by leptin-mediated STAT3 activation, and SOCS-3 protein potently inhibits leptin signaling. In support of its role as an inhibitor of leptin action in the brain, SOCS-3 expression is induced in the arcuate and dorsomedial hypothalamic nuclei of mice after leptin treatment. Leptin resistance may also be mediated by the SH2-containing tyrosine phosphatase, SHP-2, since leptin signaling is reported to be enhanced when the binding site on Ob-Rb for SHP-2 is mutated. Leptin resistance could also reside at steps downstream from the initial step of receptor interaction. The role of leptin in body weight regulation may involve interactions with other metabolic signals, notably insulin and glucocorticoids. These hormones regulate the expression of similar neuropeptides in brain regions involved in feeding behavior and body weight regulation. Glucocorticoids have a permissive effect on obesity, as evidenced by the ability of adrenalectomy to ameliorate obesity. Conversely, hypercortisolism leads to abnormalities of adipose distribution. Further studies are needed to understand the interactions among these metabolic hormones.
Leptin As a Signal for Adaptation to Fasting. The widespread occurrence of leptin-resistant obesity may reflect the fact that inability to store energy efficiently at times of abundance is evolutionarily disadvantageous. According to this view, the dominant role of leptin in energy homeostasis is likely to be as a mediator of the adaptation to fasting. Starvation triggers complex neural, metabolic, hormonal, and behavioral adaptations with the goal of maintaining the supply of energy substrates for use by the brain, protecting lean mass, and promoting survival. A major aspect of this adaptation is the capacity to switch from carbodydrate- to fat-based metabolism during fasting. This change is mediated predominantly by a fall in insulin and rise in counteregulatory hormones, i.e. glucagon, epinephrine, and glucocorticoids. Other adaptations to starvation include a decrease in thyroid and gonadal hormones, increased adrenal glucocorticoids, decreased body temperature, and increased appetite. The net effect of these adaptations is to stimulate gluconeogenesis to provide glucose for vital cellular function and supply fatty acids for use by skeletal muscle. Energy utilization is minimized during fasting, in part through suppression of thyroid thermogenesis and curtailment of procreation and growth. In addition, starvation is characterized by immune suppression, including decreased lymphocyte proliferation and helper T-cell cytokine production. The changes in thyroid hormones, glucocorticoids, and in body temperature are prominent in rodents but limited in humans. Similarly, pertubations of the reproductive axis as a result of starvation develop more rapidly in rodents than humans [27-32].
As a continuation of the research, it can be said that [33] starvation decreases leptin levels. Because leptin-deficient ob/ob mice have similar metabolic, neuroendocrine, and immune abnormalities as those resulting from starvation, we reasoned that leptin deficiency is perceived as a state of continuous starvation in ob/ob mice and that the fall in leptin mediates the adaptation to fasting. To test this hypothesis, leptin was administered twice daily by intraperitoneal injection to mice during a 48-h fast. Prevention of the characteristic fall in leptin during fasting blunted the expected rise in corticosterone and ACTH and prevented the decrease in the levels of thyroid hormone, testosterone, and luteinizing hormone. Leptin administration during fasting also prevented a prolongation of estrus cycles. Studies in rats and non-human primates have also demonstrated that the fall in leptin with fasting is an important mediator of the somatotropic, thyroid, and reproductive alterations. Leptin stimulates inflammatory response, T-lymphocyte proliferation, and Th1 cytokine production during fasting in normal mice and in fed ob/ob mice, indicating that leptin is an important link between nutrition and the immune system. In addition [34] low leptin levels may contribute to the development of obesity. Leptin is inappropriately low (as a function of body fat) in some obese individuals; however, it is not known whether these individuals have defective leptin synthesis and/or release, and this finding has not yet been observed in all populations. Although the functional implications of this observation are yet to be determined, it is plausible that relatively low leptin is perceived as a starvation signal, leading to increased appetite and efficient energy utilization. In contrast, elevation of leptin levels may predispose to cachexia in patients with renal failure and infections by inhibiting appetite and increasing energy expenditure. The plasma:CSF leptin ratio is normal in patients with anorexia nervosa during refeeding (prior to weight restoration) and may create a premature sense of satiety during refeeding.
According to endocrinologists [35] leptin is a peptide hormone released from adipose tissue and encoded by the obese (ob) gene. While leptin's role is classically described in the regulation of appetite, neuroendocrine function, and energy homeostasis, it seems to influence several other physiological processes. These include metabolism, endocrine regulation, and immune function with possible other functions still awaiting characterization. Leptin abnormalities have associations with a variety of
metabolic syndromes, particularly obesity. The study of leptin physiology has contributed to our understanding of energy homeostasis, and it seems likely that it will play a pivotal role in developing an effective treatment and a solution to the growing obesity epidemic. The total body fat mass index (BMI), metabolic hormones, and gender are the factors that have the greatest effect on circulating plasma leptin concentrations. Women have higher levels of circulating leptin compared to men.
As science knows [36,37] Leptin's principal site of action is the brain, specifically in the brainstem and hypothalamus. The major sites of action in the brainstem are the solitary tract and the ventral tegmental area. Leptin acts here to modulate satiety and the control of reward and aversion. In the hypothalamus, the lateral hypothalamic area and the ventromedial, dorsomedial, ventral pre mammillary, and arcuate (ARC) nuclei are leptin's major sites of action. The activation of these areas leads to a variety of changes, including in the thyroid, gonadal, adrenocorticotropic hormone-cortisol growth hormone axes and changes in whole brain cognition, emotions, memory, and structure. Many of these relationships are still being worked out. The most well known of them are leptin's actions on the ARC nucleus. The ARC nucleus is a major player in regulating appetite and energy homeostasis. It contains orexigenic agouti-related protein/neuropeptide Y-containing (AgRP/NPY) neurons and anorexigenic proopiomelanocortin -containing (POMC) neurons. Leptin acts on the ARC nucleus by stimulating POMC-containing neurons and inhibiting AgRP/NPY containing neurons- having the total effect of decreased appetite.
Taken as a whole, leptin's function in the body pertains to regulating the balance between food intake and energy expenditure. The classic primary physiologic role of leptin is to serve as a marker of long-term energy stores for the central nervous system (CNS) [38]. As the amount of adipose tissue decreases, the amount of leptin produced and crossing the blood-brain barrier decreases. The CNS interrupts the decline in leptin as a signal of energy deficit, which triggers a cascade of responses to help the body deal with the stress of starvation. To counteract the energy deficit, the CNS increases hunger while also promoting energy-sparing neuroendocrine and autonomic mechanisms, including decreased sympathetic nervous system tone, thyroid, and reproductive hormone levels, energy expenditure and growth. As this signal, leptin is the catalyst for the bodies transition into a starvation mode, which is a global adaption aimed towards increasing food intake and decreasing energy expenditure. A decrease in serum leptin then is the starvation signal for the CNS. As food intake increases and the level of adipose tissue becomes excessive, there is a concurrent rise in the production and secretion of leptin into the bloodstream. With increased leptin comes an inhibition of the body's starvation mode, thereby promoting reduced food intake and increased energy expenditure to counteract the current energy surplus.
Leptin deficiency or resistance is associated with dysregulation of cytokine production, increased susceptibility to infections, autoimmune disorders, malnutrition, and inflammatory responses. These are the data currently known from leptin-related research which pathophysiology and clinical relevance.
Hypoleptinemia: Complete leptin deficiency results in the clinical phenotypes of severe obesity, impaired satiety, intensive hyperphagia, constant food-seeking behavior, recurrent bacterial infections, hyperinsulinemia, liver steatosis, dyslipidemia, and hypogonadotropic hypogonadism. [39,40] These phenotypes highlight the variety of roles leptin has in the body, many not well understood and still actively under investigation. Congenital forms of hypoleptinemia result from mutations in LEP or the LR gene and are known as congenital leptin deficiencies (CLD). Acquired hypoleptinemias share some of these same phenotypes and are usually due to conditions that cause a low body weight. Examples of acquired conditions are lipodystrophy syndromes and hypothalamic amenorrhea.
Hyperleptinemia: Hyperleptinemia is associated with leptin resistance, which specifically is resistance to the anorectic and body weight reducing effects of leptin. Hyperleptinemia and leptin resistance are components of common obesity. Evidence for this association is a direct correlation between serum leptin concentrations and body fat percentage where obese individuals had higher leptin serum levels and adipocyte LEP mRNA content compared with normal weight individuals. Also, leptin serum levels and adipocyte LEP mRNA content fall with weight reduction. The mechanism of resistance appears related to defects in the transport of leptin across the blood-brain barrier, or intracellular signaling mechanisms downstream of the LR. Other diseases associated with hyperleptinemia include nonalcoholic fatty liver disease, Rabson-Mendenhall syndrome, neurodegenerative disorders, depression, and food addiction [41].
Therapeutics: Recombinant forms of leptin are under investigation in the treatment of both hypoleptinemia and hyperleptinemia related syndrome. Initially studied to reverse obesity, leptin replacement has only reversed obesity in leptin-deficient conditions, with replacement in typically obese individuals with elevated leptin levels showing limited efficacy. It has FDA approval for treatment of congenital or acquired generalized lipodystrophy (non-HIV-related). Particular studies show leptin replacement has efficacy in reversing some abnormalities present in the above-mentioned syndromes, but these conditions are not yet a recognized indication for the use of recombinant leptin as a treatment [42].
Interdependence obesity and leptin resistance. In addition [43,44] obesity and the notion of 'selective' leptin resistance It has been proposed that the maintenance of reproductive function, energy expenditure, sympathetic outflow and other leptin-regulated processes in the setting of DIO indicates impaired leptin action in obesity, restricted to the control of feeding. Note that although the effect of genetic lesions that impair specific leptin-regulated pathways might produce selective leptin resistance, these represent a different case from that of DIO. Several lines of evidence argue against a meaningful selectivity in leptin resistance in DIO. First, a variety of data suggests that leptin acts on both energy expenditure and feeding via overlapping sites and mechanisms and the nature of a process that might interfere with feeding but not energy expenditure is thus unclear. Indeed, although the ARC represents a major site of cellular leptin resistance in DIO, ARC leptin action modulates energy expenditure, glucose homeostasis and other aspects of leptin action in addition to participating in food intake. In addition, endogenous leptin clearly plays a role in limiting appetite in DIO, as food intake rapidly restabilizes after the initial increase of feeding on highly palatable, energy-dense chow. Indeed, increasing the palatability of food promotes increased food intake despite the integrity of cellular leptin action, although food intake returns toward normal as adiposity increases (with the attendant increase of leptin levels and action. The decrease of feeding and body weight upon the reinstatement of a normal chow diet suggests that the initial increase of food intake and subsequent adiposity represents a predictable response to the hedonic characteristics of the novel diet, rather than a response to diminution of leptin action. Thus, the transient increase and subsequent return of energy intake toward baseline during DIO support a model in which elevated leptin levels in obesity contribute to the control of hunger as well as energy expenditure. Furthermore, the response of obese humans to weight loss (which causes responses such as increased hunger, cold intolerance, and decreased thyroid and sympathetic tone) is fundamentally intact, suggesting that the 'extra' leptin in obese individuals exerts biologically relevant effects on parameters additional to those involved in the control of feeding. If it can be postulated that the effect of weight loss from the obese state is to increase hunger and that this reflects ongoing leptin resistance, the same must also be true for the other factors (diminished thyroid tone, cold intolerance and so on) that also accompany weight loss. Thus, a variety of data argues against a
meaningful selectivity (i.e. control of feeding only) in the attenuation of leptin action in DIO and common human obesity.
Conclusion: The discovery of leptin marks an important milestone in our understanding of metabolic physiology and will stimulate further research into effector mechanisms in the brain and other organs involved in energy homeostasis. So far, a lot of research has been done on leptin and scientific articles have been published. Of course, all this serves as a huge basis for the development of science and the development of medicine. Science knows that the role of leptin in the body is very important. And this article has shed some light on leptin and its importance in the body. We hope that further research on this hormone will continue. Indeed, one of the major pathologies associated with leptin has become obesity, the "epidemic of the century".
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