Leptin (from the Greek leptos, thin) sometimes called “satiety hormone” is a peptide digestive hormone that regulates fat reserves in the body and appetite by controlling the feeling of satiety. It is an anorectic hormone unlike orexigenic hormones (ghrelin, cortisol).
This hormone is secreted by white adipose tissue which, in addition to its function of storage and mobilization of fatty acids, also has a very important endocrine activity1. Leptin is also secreted by other tissues such as the stomach, skeletal muscle, bone marrow …
The hypothesis of a substance capable of normalizing the weight of an obese mouse strain was suspected in 19732. The gene responsible for its manufacture was isolated in 19943, allowing its synthesis a year later.
It is a protein of around 16 kDa (kilodaltons), encoded by the “OB” 5 gene located on human chromosome 7.
Six different receptors have been identified, called Ob Ra-f, the most studied in humans being type b6.
When food enters the stomach, in about fifteen minutes the gastric wall secretes a “flash” of leptin which induces a satiety effect on three levels:
it acts in synergy with the cholecystokinin secreted almost simultaneously by the duodenum, another hormone of satiety whose action is longer;
it promotes intestinal absorption of proteins (by mobilizing a specific transporter for enterocytes) to the detriment of lipids, thus intervening in the control of energy intake; it joins the arcuate nucleus of the hypothalamus, binds to its receptors (alpha-msh and neuropeptide Y) and stimulates the secretion of anorectic peptides which, by the effect of satiety, decrease food intake.
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Leptin is produced and secreted into the bloodstream by fat cells (adipocytes) permanently and in large quantities, depending on the volume of the fatty tissue, allowing a balance to be achieved (the “fair weight”, called set point by the researchers).
Its presence in larger amounts also increases energy expenditure by increasing the body’s production of heat (thermogenesis). The main target of leptin is the arcuate nucleus of the hypothalamus (some recent sources tend to show that leptin receptors are found rather in the brainstem where it acts on serotonin, a neurotransmitter). The latter expresses two orexigenic neuropeptides, neuropeptide Y and AgRP whose secretion is inhibited by leptin and insulin and two anorexigenic neuropeptides, POMC (Pro Opio Mélano Cortine) and CART (en) whose expression is stimulated by leptin and insulin.
Metabolically, an important secretion of this hormone (induced by an amount of higher fat mass), induces lipolysis, inhibits lipogenesis and increases sensitivity to insulin. In addition, it also decreases insulin secretion and reduces interprandial neoglucogenesis. Conversely, the lack of leptin induces an increase (via its affinity with alpha msh and neuropeptide Y) of fat mass storage as well as an increase in affinity for food.
Leptin has also been identified as a potent inhibitor of bone formation when present in large quantities, stimulating resorption and depressing osteoblastic formation. In low doses, it would prevent this bone loss.
It seems that there is a gender difference in the secretion of leptin since, with the same amount of subcutaneous tissue, female adipocytes secrete three times more leptin than male adipocytes.
Leptin and health
A mutation in the leptin receptor gene (called DB) results in extreme obesity. A mutation in the leptin gene most often leads to the formation of an ineffective leptin10 and is responsible for almost 3% of severe juvenile obesity but the level of circulating leptin would in this case remain almost normal, which requires a diagnosis génétique11. In rare cases, the leptin level has collapsed.
Leptin levels may decrease with diet13, smoking. It is modified, in one way or another, by various drugs.
The therapeutic use of leptin to achieve weight loss could give promising results.
Leptin plays on the development and evolution of the brain. It would decrease the concentrations of beta-amyloid16, the main component of the plaques that develop in the brains of people affected by Alzheimer’s disease. Having a low leptin level statistically predisposes four times the risk of Alzheimer’s disease.
Leptin could thus be a biomarker of Alzheimer’s disease, or even a future co-drug, however a low level of leptin does not imply the appearance of dementia either. Its effectiveness against Alzheimer’s disease therefore remains to be demonstrated.
A high leptin level seems to be correlated with a higher risk of myocardial infarction, regardless of the level of obesity5. Similarly, the risk of developing diabetes could increase in the same register, at least in humans.
Leptin is thought to stimulate the proliferation of breast cancer cells in vitro.
A low concentration of leptin could also affect central sleep apnea.
Its role in joint problems and obesity.
Obesity and osteoarthritis
There is a close link between obesity and osteoarthritis. Obesity is one of the main preventable risk factors in the development of osteoarthritis. It was first thought that the relationship between osteoarthritis and obesity was exclusively of a biomechanical nature, overweight promoting the acceleration of joint wear. However, it is now 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, the knees), but also for those who do not support it (for example, the hands); therefore, it has been shown that reducing body fat results in greater improvement in osteoarthritis than reducing body weight per se. This metabolic component is linked to the release by adipose tissue of pro-inflammatory systemic factors which are frequently critically associated with the development of osteoarthritis.
Thus, the deregulated production of adipokines and inflammatory mediators, hyperlipidemia and increased systemic oxidative stress are conditions frequently associated with obesity that can promote joint degeneration. In addition, many regulatory factors have been implicated in the development, maintenance and function of both adipose tissue, cartilage and other joint tissue. Changes in these factors can be an additional link between obesity and osteoarthritis.
Leptin and osteoarthritis
Fat cells interact with other cells through the production and secretion of different signaling molecules, including signaling proteins called adipokines. Some adipokines can be considered hormones because they regulate the functions of organs at a distance, and several of them have been specifically involved in the pathophysiology of joint disease. One of them in particular, leptin, has attracted the attention of the research world in recent years. Circulating leptin levels have a positive correlation with body mass index (BMI), more specifically with fat mass, and obese people have high levels of leptin in their circulation, compared to non-obese people. In obese people, the increase in circulating leptin levels leads to unexpected responses, that is, there is no reduction in food intake or body weight because it resistance to leptin exists. In addition to the regulatory function of 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 factor with pleiotropic actions also in the immune response and inflammation. For example, leptin can be found in synovial fluid in correlation with the body mass index, and leptin receptors are expressed in cartilage, where leptin modulates and is involved in many inflammatory and destructive cartilage responses and other joint tissue. Leptin is therefore a possible candidate for establishing a link between obesity and osteoarthritis, and serves as a putative objective for the nutritional treatment of osteoarthritis.
As in plasma, leptin levels in synovial fluid have a positive correlation with BMI. The leptin in the synovial fluid is synthesized at least partially in the joint, and may have partly originated in the circulation. Leptin has been shown to be produced by chondrocytes, as well as by other tissues in the joint, including synovia, osteophytes, meniscus and bone. A block of infrapatellar fat located outside the synovium within the knee joint is adjacent to the synovial membrane and cartilage, and has recently been highly valued 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 reduced by weight loss. This reduction in risk is partially linked to the decrease in joint load, but also to the decrease in fat mass, central adiposity and low grade inflammation associated with obesity and systemic factors.
This growing body of evidence points to leptin as a cartilage degrading factor in the pathogenesis of osteoarthritis, and as a potential biomarker for disease progression, suggesting that leptin, along with the regulatory and signaling, may be promising new goals in the treatment of osteoarthritis, particularly in obese patients.
Obese people are predisposed to suffer from osteoarthritis, not only because of mechanical overload, but also because of the overexpression of soluble factors, i.e. leptin and pro-inflammatory cytokines, which contribute to inflammation of the joints and destruction of cartilage. Obese people are therefore in a modified situation, due to metabolic insufficiency, which requires specific nutritional treatment capable of normalizing the production of leptin and reducing low-grade systemic inflammation, in order to reduce the harmful effect of these mediators. systemic joint health.
There are nutritional supplements and pharmacological agents capable of controlling these factors and improving both problems.
As a medicine
A synthetic analogue of leptin exists under the name of metreleptine. The latter has been tested in certain forms of obesity with significant leptin deficiency in children or adults.
Impact of sleep on leptin
Professor Cappucio of the University of Warwick and other studies have shown that sleep deprivation can lead to obesity. In fact, a lack of sleep leads to an increased production of the hormone ghrelin, which stimulates appetite, and would also cause a decrease in the production of leptin. Sleep would have an impact on the secretion of these two antagonistic hormones.