Leptin

Leptin (from the Greek leptos thin), also known as PN protein, is an adipokine produced mostly by adipocytes (fat cells) although it is also expressed in the hypothalamus, ovary and placenta.

Discovery and mode of action

It was discovered in 1949 in experiments with mice.

“The history of leptin dates back to 1949, when a few mice, part of a normal-weight litter, grew up to be very different from their peers. To the surprise of the scientists, these strange mice were not active or curious, they did not run around the cage like common rodents. In fact, they hardly ever moved, they just ate. They would sit by the feeder and feed throughout the day. Despite the fact that all they had to eat were generic pellets (small food pellets), they acted as if they couldn't stop consuming them; It didn't take long for them to get very, very fat. They loved to eat so much that the only way for them to move was to change the location of the feeder. Then they moved, very slowly, to the new location and began to eat again. Scientists knew that something out of the ordinary was happening with these little animals; so they resumed breeding until the origin of the defect was discovered. Finally, in 1957, after eight years of working with these strange and obese mice, Jeffrey M. Friedman of the Laboratory of Molecular Genetics discovered their problem. A spontaneous mutation had deprived the mice of a mouse-specific recessive gene. Friedman and his colleagues followed the genetic crumbs and discovered that this gene is responsible for the creation of a specific hormone, the job of which is to send a signal to the brain that the mouse needs to stop eating and start activating. Friedman's group named this newly discovered hormone leptin, from the Greek leptos, meaning thin. Were these mice morally defective? Were they lacking in intelligence? Were they lazy? No. They only needed leptin. It turns out that without leptin, the brain thinks it's starving. He will never believe that he is safe enough to stop eating and start moving. And sure enough, after receiving a few injections of leptin, these mice lost interest in food, started running on the wheel of their cage, and lost weight again."

Subsequently, the human Ob gene was located on chromosome 7. Leptin is believed to act as a lipostate: when the amount of fat stored in adipocytes increases, leptin is released into the bloodstream. This is a signal (negative feedback) that informs the hypothalamus that the body has enough reserves and that it should suppress appetite.

When the mass of adipose tissue increases beyond the equilibrium point, the synthesis and secretion of leptin increases, which stimulates several compensatory effects in the hypothalamus:

1. Decrease in appetite for stimulation of annorexigenic peptides (which produce loss of appetite) and suppression of production of orexigénic peptides (from the Greek orexis meaning appetite)
2. Increased energy spending by raising the rate of basal metabolism and body temperature, in addition to the modification of the hormonal balance point to reduce lipogenesis (fat production) and increase lipolysis (the use of accumulated fat to produce energy) in the adipose tissue.

Regulation of leptin secretion is long-term, mainly by varying the level of body mass and stimulatory effects of insulin. However, many obese individuals 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 of body weight.

After its discovery, most research on leptin focused on its role as a regulatory factor in body weight. However, subsequent studies described a wide distribution of receptors for this hormone in various peripheral tissues, thus opening up 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 protein of 167 amino acids, including a signal peptide of 21 amino acids. Its three-dimensional structure presents four alpha helices and a disulfide bridge between the cysteines in 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 white adipose tissue. 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 adipose tissue or brown fat also synthesizes leptin, although to a lesser extent. The role of secreted leptin in brown adipose tissue is not clear, although it may just be an extra supply of leptin to the bloodstream as a reflection of total adipose tissue.

The regulation of leptin expression largely depends on the body's fatty deposits. Thus, larger adipocytes produce more leptin, while visceral fat adipocytes secrete less leptin than subcutaneous fat adipocytes. 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 manner, and modulated by insulin and other hormones. Its frequency is approximately one pulse every 45 minutes. Its concentration increases gradually during the day and reaches a peak at midnight, to decrease until the beginning of a new cycle. This pattern also depends on food.

In this way, circulating leptin concentrations increase in the first hours after ingestion and continue their rise in the event of overfeeding. In fasting situations, there is a decrease in leptin production. On the other hand, it seems that the changes in the secretion pattern associated with feeding are more related to plasma insulin concentration than to body weight. This is because insulin stimulates the expression of leptin in isolated adipocytes and therefore raises its circulating level.

Once secreted into the bloodstream, leptin circulates partially bound to plasma proteins, with the proportion of leptin bound to proteins 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 oscillate in the range of 3-18 ng/ml, with higher levels in women than in men; although in individuals with a body 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 leptin and approximately 90 minutes for exogenous leptin.

Leptin is eliminated mainly via the kidneys. Leptin is mainly metabolized by renal epithelial cells. They capture the molecule through a mechanism involving "short" receptors; for this reason the concentration of leptin increases in patients with renal failure.

Regulatory factors

Leptin and the Hypothalamus

The hypothalamus is a hazelnut-shaped area within the brain that contains a small nucleus that performs a variety of functions. The hypothalamus is the closest thing we have to a thermostat. By secreting hormones that in turn stimulate the pituitary gland, it controls hunger, body temperature, parental attachment, sexual desire, thirst, fatigue, sleep, and circadian rhythms. This is a very important control center and many vital functions are regulated here.

For now, we need to focus on one particular hormone and how it affects the hypothalamus's ability to control our eating. This hormone is known as leptin.

Leptin is the missing link in our satiety feedback mechanism. When we eat a large amount of food, the excess that we cannot burn goes directly to our fat cells. As our fat cells fill up more, we secrete more leptin. Leptin returns to the brain and says, “no more food! Go find something useful to do with all this energy."

So why is all that leptin swimming in our blood without telling our brain to send the signal that we're full? The general answer from most scientists is that people are now leptin resistant, their brains don't register, they don't “see” the leptin circulating in their blood.

Solving the puzzle of leptin resistance would mean cracking the code of the obesity pandemic.

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 leptinemia is a reflection of 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 by 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 the synthesis and secretion of NPY.

There are several studies that have shown that the increase in NPY leads to an increase in the sensation of hunger and with it to 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 to the paraventricular nucleus and the lateral hypothalamic area where the appetite-regulating centers are located, and there they cause the production of peptides that stimulate appetite and wakefulness, such as orexin or NPY itself, which in turn They signal to the centers of the brainstem (among them the vagal complex, which is another important center for the production of orexigenic substances) and to the cholinergic nuclei of the basal forebrain and cortex, producing the sensation of hunger. By eliminating leptin, the initial stimulus of this entire circuit negatively regulates basal levels of appetite based on energy reserves.

In addition, in the absence of stimulation of the neuropeptidergic neurons, the POMC/CART neurons are functioning in the arcuate nucleus, which have an appetite inhibitory function, among others.

Insulin

Nowadays almost everyone knows a little about insulin. We know that it has something to do with diabetes and sugar levels. Here's the thing: our bodies need blood sugar for energy at a cellular level. However, blood sugar cannot directly enter cells. After you eat and your blood sugar levels rise, the hypothalamus signals the pancreas to secrete insulin into the bloodstream. Insulin attaches itself to cells and tells them to open their "gates" and take in sugar, which is why it is often referred to as the "key" hormone. Insulin can tell your body to use sugar for energy now, or store it for later; helps keep blood sugar levels from being too high or too low.

Changes in our global diet mean that insulin levels are too high in virtually all of us.

The scientific community is aware that obesity is related to excess insulin, but it was not until the UCSF (Medical Center) team discovered a link between insulin and leptin; This is how we understood how harmful this excess insulin is, since it blocks leptin, causing an inhibition of the feeling of satiety.

We used to think that leptin was blocked by the hypothalamus, which is true, and that's bad enough, but now we know that leptin is also blocked in another place: the brainstem.

The Brain Stem

The brainstem is sometimes called the “reptilian brain.” It sits at the base of the brain and is structurally contiguous with the spinal cord. But... why does it matter that leptin is blocked by the brainstem? Well, because this is not one of the parts of the brain that helps us reason, debate, or develop possible scenarios. The brain stem is in charge of things we cannot control; basic things like: breathing, swallowing, our blood pressure, heart functions and whether we are awake or asleep. That is, there is no way to ignore the brain stem. You can try, sure, and you might succeed for a second, but at some point, your brain stem would take over, it's the one in charge of keeping us alive in terms of basic functions.

And this is where leptin is blocked! The most primitive part of our brain does not receive the hormonal cue that we are satisfied, that we have received an adequate amount of food. In people with leptin resistance, the brain stem is absolutely convinced that we are starving.

Thyroid hormones

There is an illogical relationship between leptin and thyroid hormones: leptin increases systemic sympathetic activity and in adipose tissue and muscle, producing 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 play a role in the regulation and production of leptin by adipocytes, possibly inhibiting its levels.

Leptin can directly inhibit the production of glucocorticoids in the adrenal glands and, since corticosteroids have a direct effect on the cells of the paraventricular nucleus by reducing TRH levels, the increase in leptin levels can be increased, indirectly., thyroid activity. On the other hand, leptin produces an inhibition of NPY production in the arcuate nucleus, which would also increase TRH production.

It seems that in fasting states, what matters is saving energy and therefore, the increase in cortisol and the decrease in leptin would produce a decrease in TRH levels, both by direct action of cortisol at the central as by increased hypothalamic NPY. On the contrary, in a state of caloric abundance, when leptin levels increase and cortisol levels decrease, there would be an increase in thermogenesis and basal metabolism, both due to the action of leptin and thyroid hormones on the UCPs and due to the decreased hypothalamic NPY.

Mutations in the ob gene

Mutations in the murine Ob gene cause mice carrying the mutation (ob/ob mice) to lack serum leptin and present a phenotype of severe obesity associated with other problems such as lower body temperature, less locomotor activity, less activity the immune system and infertility. The administration of exogenous leptin corrects these alterations. This fact led to the hypothesis that obesity could be due to a mutation in the human Ob gene and, therefore, the administration of exogenous leptin could be the panacea in the treatment of obesity.

However, this idea vanished when it was verified that the frequency of this mutation in the obese population is extraordinarily low and that the vast majority of obese patients have high levels of serum leptin. The few clinical cases of humans with congenital leptin deficiency are characterized by a phenotype similar to that found in ob/ob mice, characterized by severe obesity, hyperphagia, and hyperinsulinemia.

Leptin gene mutations

Leptin deficiency was initially described in two severely obese cousins from a closely related Pakistani family. The cases of this monogenic form studied are very rare and correspond to individuals of Pakistani and Turkish origin. This deficiency is caused by a mutation that results in a truncated and inactive protein. Obesity, before the age of five, and hyperphagia are characteristic phenotypes of this condition.

These children also showed abnormalities in the number and function of T lymphocytes. Leptin deficiency was treated with the application of recombinant leptin with very satisfactory results. The treated cases showed normalization of appetite with an 84% reduction in ad libitum intake, regularization of immune function and body composition. Four other cases have subsequently been described in individuals of Turkish origin. Some of these individuals were adults affected by hypogonadotropic hypogonadism.

Role in obesity and weight loss

Obesity

Although leptin reduces appetite as a sign of circulation, obese individuals generally exhibit higher circulating leptin concentrations than normal-weight individuals and this is because obese individuals have a higher percentage of body fat. These people show leptin resistance very similar to the insulin resistance that patients with type 2 Diabetes mellitus present, although they have high levels of leptin in their body, they fail to control and modulate their weight. A large number of explanations have been proposed.

An important factor for leptin resistance lies in changes in leptin receptor signaling, particularly in the arcuate nucleus, however, deficiencies or major changes in leptin receptors are not thought to be the cause. 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 leptin levels in the cerebrospinal fluid (CSF) provide a muscle-hormonal contingency of leptin reduction by crossing the blood-brain barrier (BBB) and reaching obesity-relevant targets, such as the hypothalamus, in obese people. In humans it has been observed that the ratio of leptin in 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 BBB or because the leptin transporter is saturated. Although the deficit in the transfer of leptin from the plasma to the CSF is seen in obese people, they were still found to have 30 percent more leptin in their CSF i> than that which can be observed in thin individuals.

These higher leptin levels in your CSF fail to prevent your obesity. Since the quantity and quality of leptin receptors in the hypothalamus appear to be normal in most obese humans (judging from studies of leptin on mRNA). Leptin resistance in these individuals is likely due to a downstream leptin receptor deficit, similar to the downstream insulin receptor defect seen in individuals with type 2 diabetes mellitus.

When leptin binds to leptin receptors, a number of pathways are activated. Leptin resistance can be caused by defects in one or more parts of this process, particularly in the JAK/STAT protein. Mice with mutations in leptin receptor genes that prevent STAT3 protein activation are obese and exhibit hyperphagia. The protein PI3K number of pathways may also be involved in leptin resistance, as has been shown in mice that have been artificially blocked from PI3K signals..

The PI3K protein is also activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. The insulin PI3K pathway can cause Proopiomelanocortin (POMC) neurons to become insensitive to leptin through hyperpolarization.

Consumption of a high fructose diet from birth has been associated with reduced leptin levels and reduced leptin receptor mRNA expression in rats. Prolonged consumption of fructose in rats has been shown to increase triglyceride levels and trigger insulin and leptin resistance, yet another study found that leptin resistance only develops in the presence of high fructose and high levels of fructose. levels of fat in the diet. A third study found that high fructose levels reversed leptin resistance in rats fed a high-fat diet. The conflicting results mean that it is uncertain whether leptin resistance is caused by high levels of carbohydrates or fat, 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, leptin-resistant rats, 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 in times of hunger, rather than as a satiety signal to avoid Eat excessively. Leptin levels signal when an animal has enough stored energy to spend on activities other than acquiring food. This would mean that leptin resistance in obese people is a normal part of mammalian physiology and could possibly confer a survival advantage.

Leptin resistance in combination with insulin resistance and weight gain is seen in rats after they are given unrestricted access to energy-dense food. This effect was reversed when the animals were placed back on a low energy diet. This may also have an evolutionary advantage: allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food frequency is low.

Answer to lose weight

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 skeletal muscle energy expenditure, and increases in 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 of the same weight but naturally. These changes are mediated by leptin, as homeostatic responses intended to reduce energy expenditure and promote weight regain as a result of fat cells shrinking below normal size. Many of these changes are reversed by peripheral administration of recombinant leptin to restore pre-dietary levels. A decrease in circulating leptin levels also changes brain activity in areas involved in the regulatory, emotional, and cognitive control of appetite that is reversed by leptin administration.

To restore the body's ability to respond adequately to leptin, a balanced diet is required. Making a transition from simple carbohydrates to complex carbohydrates is essential. On the other hand, it has been experimentally confirmed that leptin levels decrease when physical activity is increased.

Role in joint problems

Obesity and osteoarthritis

Osteoarthritis and obesity are closely related to each other. Obesity is one of the most important preventable risk factors for the development of osteoarthritis. Initially it was considered that the relationship between osteoarthritis and obesity had an exclusively biomechanical basis, according to which being overweight promotes an acceleration of joint wear. However, today it is recognized that there is also a metabolic component, which explains why obesity is a risk factor for osteoarthritis, not only for weight-bearing joints (for example, knees), but also for those that bear weight. do not support it (for example, the hands) consequently, reducing body fat has been shown to reduce osteoarthritis to a greater extent than reducing body weight per se. This metabolic component is related to the release of factors systemic, of a pro-inflammatory nature, by adipose tissue, which are often critically associated with the development of osteoarthritis.

So, the deregulated production of adipokines and inflammatory mediators, hyperlipidemia, and increased systemic oxidative stress are conditions frequently associated with obesity that can favor joint degeneration. In addition, many regulatory factors have been implicated in the development, maintenance, and function of both adipose tissue and cartilage and other joint tissue. Alterations in these factors may be the additional link between obesity and osteoarthritis.

Leptin and osteoarthritis

Adipocytes interact with other cells through the production and secretion of a variety of signaling molecules, including signaling proteins called adipokines. Some adipokines can be considered as hormones, since they regulate remote organ functions, and several of them have been specifically implicated in the pathophysiology of joint disease. There is especially one, leptin, on which research attention has been focused in recent years.

Circulating leptin levels are positively correlated with body mass index (BMI), more specifically with fat mass, and obese individuals have increased levels of leptin in their circulation, compared to non-obese individuals. In obese people, the increase in circulating leptin levels induces unexpected responses, that is, there is no reduction in food intake or body weight, since there is resistance to leptin. In addition to the function By regulating energy homeostasis, leptin plays a role in other physiological functions such as neuroendocrine communication, reproduction, angiogenesis, and bone formation. More recently, leptin has been recognized as a cytokine-like factor with pleiotropic actions also in the immune response and inflammation. For example, leptin can be found in synovial fluid in correlation with body mass index., and leptin receptors are expressed in cartilage, where leptin mediates and modulates many destructive and inflammatory responses of cartilage and other joint tissues. Therefore, leptin emerges as a candidate for linking obesity and osteoarthritis and serves as a putative target for nutritional treatment of osteoarthritis.

As in plasma, leptin levels in synovial fluid are positively correlated with BMI. Synovial fluid leptin is at least partially synthesized in the joint and may originate in part in the joint. circulation. Leptin has been shown to be produced by chondrocytes, as well as other tissues in the joint, including the synovium, osteophytes, meniscus, and bone. Also a block of infrapatellar fat located extrasynovial within the joint of the knee is adjacent to the synovial membrane and cartilage, and has recently been highly appreciated as an important source of leptin, as well as other adipokines and mediators that contribute to the pathogenesis of osteoarthritis.

The risk of osteoarthritis can be decreased with weight loss. This risk reduction is partly related to decreased joint loading, but also to decreased fat mass, central adiposity, and low-grade inflammation associated with obesity and systemic factors.

This growing evidence points to leptin as a cartilage degradation factor in the pathogenesis of osteoarthritis, and as a potential biomarker of disease progression, suggesting that leptin, as well as regulatory and signaling mechanisms, may serve as new and promising targets in the treatment of osteoarthritis, especially in obese patients.

Summarizing; Obese people are predisposed to developing osteoarthritis, not only due to mechanical overload, but also due to overexpression of soluble factors, i.e. leptin and pro-inflammatory cytokines, which contribute to joint inflammation and cartilage destruction.. Therefore, obese people are in an altered situation, due to metabolic insufficiency, which requires a specific nutritional treatment capable of normalizing leptin production and reducing low-grade systemic inflammation, in order to reduce the detrimental impact of these systemic mediators in joint health.

There are nutritional supplements and pharmacological agents capable of addressing these factors and improving both conditions.

Therapeutic use

Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized congenital lipodystrophy.

A synthetic analogue of leptin is metreleptin. It was first approved in Japan in 2013 and in the United States in February 2014. In the United States, it is indicated for the treatment of complications of leptin deficiency and for diabetes and hypertriglyceridemia associated with congenital or acquired generalized lipodystrophy..