Leptin . Also known as OB protein , it is a hormone produced mostly by adipocytes (fat cells) although it is also expressed in the hypothalamus, ovary, and placenta.
Summary
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- 1 Discovery
- 2 Structure
- 3 Synthesis and secretion
- 4 Regulatory factors
- 1 Neuropeptide Y (NPY)
- 2 Thyroid hormones
- 5 Mutations in the obgene
- 6 Role in obesity and weight loss
- 7 Therapeutic use
- 8 See also
- 9 Sources
Discovery
It was discovered in 1994 in the mouse . Subsequently, the human Ob gene was located on the chromosome . Leptin is believed to act as a lipostat: when the amount of fat stored in adipocytes increases, leptin is released into the blood stream, constituting a signal ( negative feedback ) that informs the hypothalamus that the body has enough reserves and that must inhibit appetite. When the mass of adipose tissue increases beyond the equilibrium point, the synthesis and secretion of leptin increases, therefore several compensating effects are stimulated in the hypothalamus: the decrease in appetite by stimulation of peptidesanorexigenic (causing loss of appetite) and suppression of the production of orexigenic peptides (from the Greek orexis meaning appetite); increased energy expenditure by increasing the rate of basal metabolism and body temperature in addition to modifying the hormonal balance point to reduce lipogenesis (fat production) and increase lipolysis (use of accumulated fat to produce energy) in adipose tissue.
Regulation of leptin secretion is long-term, mainly due to changes in the level of body mass and stimulating effects of insulin . However, many obese people have high serum leptin concentrations or leptin resistance, indicating that other molecules such as ghrelin , serotonin , cholecystokinin, and neuropeptide Y also have an effect on satiety and contribute to regulation. body weight.
Following its discovery, most research around leptin focused on its role as a regulator of body weight. However, subsequent studies described a wide distribution of receptors for this hormone in various peripheral tissues, thus opening a vast field of research on the biological functions of this hormone. Leptin participates in physiological processes as diverse as reproduction , immunity, or angiogenesis .
Structure
Leptin is a 167 amino acid protein, including a 21 amino acid signal peptide. Its three-dimensional structure has four alpha helices and a disulfide bridge between cysteines at position 96 and 146, the latter being necessary for the biological activity of the hormone.
Synthesis and secretion
Leptin synthesis occurs mainly, although not exclusively, at the level of adipose tissueWhite. This fact allowed us to propose that leptin secretion acts as a signal to the brain, informing about the size of adipose tissue and acting as a satiating factor. Brown fat or brown fat tissue also synthesizes leptin, although to a lesser extent. The role of secreted leptin in brown adipose tissue is unclear, although it could only be an extra contribution of leptin to the blood stream as a reflection of the total adipose tissue. The regulation of leptin expression is highly dependent on the body’s fatty deposits. Thus, larger adipocytes produce more leptin, while adipocytes from visceral fat secrete less leptin than adipocytes from subcutaneous fat. The amount of triglycerides stored in the adipocyte is also proportional to the amount of leptin produced by each adipocyte. For this reason, circulating leptin levels are proportional to the amount of body fat.
Leptin secretion varies according to the circadian rhythm , being secreted in a pulsatile way, and modulated by insulinand other hormones. Its frequency is approximately one pulse every 45 minutes. Its concentration increases gradually during the day and reaches a peak during midnight, to decrease until the start of a new cycle. This pattern also depends on diet. In this way, circulating leptin concentrations increase in the first hours after ingestion and continue to rise in case of overfeeding. In fasting situations, there is a decrease in leptin production. On the other hand, it seems that changes in the pattern of secretion associated with diet are more related to plasma insulin concentration than to body weight. This is due to the fact that insulin stimulates the expression of leptin in isolated adipocytes and, therefore, increases its circulating level. Once secreted into the bloodstream, leptin circulates partially bound to plasma proteins, with the proportion of leptin bound to protein being lower in obese individuals. The OB-Re receptor circulates bound to leptin and functions as a regulator of free hormone concentration. Serum leptin levels in people with normal weight range from 3-18 ng / ml, with higher levels in women than men; although in individuals with a there are higher levels in women than men; although in individuals with a there are higher levels in women than men; although in individuals with abody mass index (BMI) greater than 30, values of 30 ng / ml or even higher can be found. It has a similar half-life in obese and non-obese individuals, about 25 minutes for endogenous and approximately 90 minutes for exogenous leptin.
The elimination of leptin is carried out mainly by the renal route. Leptin is metabolized especially by renal epithelial cells. These internalize the molecule by means of a “short” receptor-mediated mechanism, which is why its concentration increases in patients with renal failure.
Regulatory factors
Neuropeptide Y (NPY)
The fundamental function of leptin seems to be the regulation of appetite, for which they act on hypothalamic nuclei. Leptin is secreted by adipocytes in such a way that leptinmia reflects the body’s fat reserves, thus establishing a negative feedback loop where circulating leptin inhibits NPY production in the arcuate nucleus of the hypothalamus. Leptin molecules cross the blood brain membrane through transcytosis. It can also be taken up from the cerebrospinal fluid. NPY is produced in the hypothalamic arcuate nucleus. NPY increases intake and decreases thermogenesis. The main mechanism by which leptin regulates appetite is, therefore, by inhibiting NPY synthesis and secretion. There are several studies that have shown that the increase in NPY leads to an increase in the sensation of hunger and with it the hyperphagia that in the long term would lead to obesity. There is evidence that leptin acts at the level of the arcuate nucleus, preventing the formation of Neuropeptide Y. The neuropeptidergic neurons of the arcuate nucleus signal the paraventricular nucleus and the lateral hypothalamic area where the appetite regulating centers are located and there cause the production of stimulating peptides. appetite and wakefulness such as orexin or NPY itself, which in turn signal on the brain stem centers, (among them the vagal complex that is another important center of production of orexigenic substances) and on the cholinergic nuclei of the basal forebrain and the cortex, producing the sensation of hunger. By eliminating leptin, the initial stimulus of this entire circuit negatively regulates basal appetite levels based on energy reserves. In addition, in the absence of stimulation of neuropeptidergic neurons, POMC / CART neurons that have an appetite-inhibiting function, among others, are functioning in the arcuate nucleus. By eliminating leptin, the initial stimulus of this entire circuit negatively regulates basal appetite levels based on energy reserves. In addition, in the absence of stimulation of neuropeptidergic neurons, POMC / CART neurons that have an appetite-inhibiting function, among others, are functioning in the arcuate nucleus. By eliminating leptin, the initial stimulus of this entire circuit negatively regulates basal appetite levels based on energy reserves. In addition, in the absence of stimulation of neuropeptidergic neurons, POMC / CART neurons that have an appetite-inhibiting function, among others, are functioning in the arcuate nucleus.
Thyroid hormones
There is a logical relationship between leptin and thyroid hormones: leptin increases sympathetic activity in the systemic and in adipose tissue and muscle, causing an increase in thermogenesis. Thyroid hormones are a major factor in the regulation of basal metabolism, thermogenesis, and sympathetic activity. Both thyroid hormones and leptin increase the activity of mitochondrial dissociating proteins (UCPs) and thereby promote thermogenesis. It is likely that thyroid hormones may have a role in the regulation and production of leptin by adipocytes, possibly inhibiting their levels. Leptin can directly inhibit glucocorticoid production in the adrenals and, Since corticosteroids have a direct effect on the cells of the paraventricular nucleus by reducing the levels of TRH, the increase in leptin levels may indirectly increase thyroid activity. On the other hand, leptin produces an inhibition of the production of NPY in the arcuate nucleus, which would also increase the production of TRH. It seems that in fasting states, what matters is energy saving and, therefore, an increase in cortisol and a decrease in leptin would produce a decrease in TRH levels, both by direct action of cortisol at the central level and by the increase in hypothalamic NPY. Conversely, in a state of caloric abundance, increasing leptin levels and lowering cortisol levels would produce an increase in thermogenesis and basal metabolism.
Mutations in the ob gene
Mutations in the murine Ob gene cause the mice carrying the mutation ( ob / ob mice) lack serum leptin and present a phenotype of severe obesity associated with other problems such as lower body temperature, lower locomotor activity, lower activity of the immune system and infertility. The administration of exogenous leptin corrects these alterations. This fact raised the hypothesis that obesity could be due to a mutation in the human Ob gene and, therefore, the administration of exogenous leptin could be a panacea in the treatment of obesity. However, this idea was dashed when it was found that the frequency of this mutation in the obese population is extremely low and that the vast majority of obese patients have high levels of serum leptin. The rare clinical cases of humans with congenital leptin deficiency are characterized by a phenotype similar to that found in mice. ob / ob , characterized by severe obesity, hyperphagia, and hyperinsulinemia.
Role in obesity and weight loss
Although leptin reduces appetite as a sign of circulation, obese individuals generally exhibit leptin circulation in higher concentrations than normal-weight individuals. This is because obese individuals have a higher percentage of body fat. An important actor for leptin resistance is found in changes in leptin receptor signals, particularly in the arcuate nucleus , however deficiencies or major changes in leptin receptors are not believed to be the definitive cause. Other explanations speak of the way in which leptin crosses the blood-brain barrier or alterations in the development of the individual.
Studies of the levels of leptin in the Cerebrospinal Fluid ( CSF ) provide evidence of the reduction of leptin by crossing the blood-brain barrier ( EHB ) and reaching relevant targets for obesity, such as the hypothalamus, in obese people. In humans it has been observed that the ratio of leptin in the CSF compared to blood is lower in obese people than in people of normal weight. The reason for this may be high triglyceride levels that affect leptin transport through the EHB or because the leptin transporter is saturated. Although the deficit in the transfer of leptin from plasma to the CSFseen in obese people, it was still found that they have 30 percent more leptin in their CSF than can be seen in lean individuals. These higher levels of leptin in your CSF fail to prevent obesity.
Consumption of a high fructose diet from birth has been associated with a reduction in leptin levels and reduced expression of messenger RNAof the leptin receptor in rats. Prolonged consumption of fructose in rats has been shown to increase triglyceride levels and trigger insulin and leptin resistance however another study found that leptin resistance only develops with the presence of high levels of fructose and high dietary fat levels. A third study found that high levels of fructose reverses leptin resistance in rats that received a high-fat diet. The conflicting results mean that it is uncertain whether leptin resistance is caused by high levels of carbohydrates or fats, or whether an increase in both is necessary.
Leptin is known to interact with amylin, a hormone involved in gastric emptying and creates the feeling of satiety. When both leptin and amylin were given to obese rats, with leptin resistance, sustained weight loss was observed. Due to its apparent ability to reverse leptin resistance, amylin has been suggested as a possible therapy for obesity. It has been suggested that the main role of leptin is to act as a hunger signal when levels are low, to help maintain fat stores to survive starvation times, rather than a satiety signal to avoid overeating. . Leptin levels signal when an animal has enough stored energy to spend it on activities in addition to purchasing food.
People on weight loss diets, particularly those with excess fat cells, experience a drop in circulating leptin levels. This drop causes reversible decreases in thyroid activity, sympathetic tone, and energy expenditure in skeletal muscle, and increased muscle efficiency and parasympathetic tone. The result is that a person who has lost weight below their natural body fat has a lower basal metabolic rate than an individual at the same weight but naturally; these changes are mediated by leptin, as homeostatic responses aimed at reducing energy expenditure and promoting weight recovery as a result of fat cells shrinking below normal size. Many of these changes are reversed by the peripheral administration of recombinant leptin to restore pre-diet levels. A decrease in circulating leptin levels also changes brain activity in the areas involved in the cognitive, emotional, and regulatory control of appetite that is reversed by leptin administration.
Therapeutic use
Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized lipodystrophy. A leptin analogue is metreleptin, which was first approved in Japan in 2013 and in the United States in February 2014. In the United States, it is indicated as a treatment for complications of leptin deficiency, for diabetes and hypertriglyceridemia associated with congenital or acquired general lipodystrophy .
