Leptin

Why this test? 

For the differential diagnosis of obesity (especially to exclude its monogenic variants, for example, mutations in the melanocortin receptor gene Mc4r), as well as to resolve the issue of the need to prescribe exogenous leptin. 

To assess the risk of developing type 2 diabetes. 

To assess the risk of coronary heart disease. 

For the differential diagnosis of secondary amenorrhea (especially to exclude hypothalamic amenorrhea against the background of intense physical exertion, stress, starvation, anorexia), as well as to resolve the issue of the need to prescribe leptin.

In what cases is it prescribed? 

With a body mass index of more than 25 (overweight) or more than 30 (obesity). 

In the presence of risk factors for type 2 diabetes: abdominal obesity, hereditary predisposition to type 2 diabetes, history of gestational diabetes, age over 45 years, sedentary lifestyle. 

Risk factors for CHD include male sex, hereditary predisposition to CHD, smoking, high levels of LDL cholesterol, homocysteine, and C-reactive protein, as well as hypertension and diabetes. In case of cessation and absence of menstruation in the patient for 3 or more months.

Test Information 

Leptin got its name from the Greek word leptos, which means thin, thin. This hormone is produced by adipose tissue cells and regulates energy, neuroendocrine and metabolic processes of the body. The function of leptin is carried out through its interaction with ObRs receptors located in the brain, as well as in some peripheral tissues. 

There are several isoforms of ObRs: ObRa and ObRc, which are necessary for the transport of the leptin molecule across the blood-brain barrier (BBB), and ObRb, which provides the main regulatory effects in the hypothalamus. As a result of interaction with ObRb, leptin stimulates the synthesis of anorexigenic (appetite-suppressing) mediators (in particular, proopiomelanocortin) and inhibits the synthesis of orexigenic (appetite-stimulating) mediators (in particular, neuropeptide Y).

In addition, leptin affects the mesolimbic system, which forms the motivation to accept food and the feeling of satisfaction from food, and the neurons of the centers of the medulla oblongata, which also form the feeling of satiety. In fact, leptin is a unique sensor coordinating many neuroendocrine processes of a person according to his energy reserves.

Normally, an increase in leptin concentration occurs after a heavy meal and is accompanied by a decrease in appetite. Hereditary deficiency of this hormone occurs due to some mutations in its gene, which lead to the shortening of the leptin molecule and disruption of its structure. In the absence of the effect of leptin on appetite, people feel a constant feeling of hunger and gain weight. Patients with this rare congenital defect are characterized by severe obesity that develops already in childhood, hypothyroidism, hypogonadism, and delayed sexual development. 

Despite the fact that congenital leptin deficiency is rare (in 5-6% of obese people), it should be taken into account when diagnosing obesity, since the use of exogenous leptin in such patients significantly reduces weight and normalizes the level of sex hormones. However, the vast majority of obese patients have an excess of leptin against the background of insensitivity to its action. 

At the same time, there is no control of the hypothalamus and other brain structures over the frequency and amount of food consumption. 

The patient feels hungry even if there are adequate energy reserves for his physiological expenditure. It is believed that insensitivity to leptin develops as a result of structural and functional defects at the level of the ObRb receptor, excess production of leptin inhibitors, as well as a violation of the transport of the leptin molecule through the blood-brain barrier. 

About 1 billion people worldwide are obese. From an evolutionary point of view, the ability to store energy in the form of fat in the event of an excess of food was necessary for the survival of humans as a species, so natural selection was aimed at fixing mutations that ensure the accumulation of adipose tissue. In today's food-supplied society, these adaptive mechanisms are no longer an advantage, but they are still strong.

Monogenic variants (mutations of one gene) are observed in a small proportion of obese patients, while in the vast majority of cases obesity is a polygenic (caused by abnormalities in several genes) and polyfactorial (caused by a combination of internal and external factors) disease. 

Sedentary lifestyle, smoking and dietary features are of great importance in the development of obesity. 

Obesity is a leading risk factor for the development of diabetes. Excess adipose tissue provokes increased insulin production and hyperinsulinemia, which, in turn, leads to a decrease in the number of insulin receptors in peripheral tissues and insulin resistance. 

Normally, regardless of the effect of insulin, leptin enhances the utilization of glucose by peripheral tissues and the oxidation of fatty acids in the liver, increases the sensitivity of peripheral tissues to insulin and reduces its secretion by beta cells of the pancreas. In this regard, in the presence of leptin resistance, insulin resistance often develops, glucose utilization is impaired, and the risk of developing type 2 diabetes increases, so measuring leptin concentration can be used to assess the risk of developing this disease. 

Coronary heart disease (CHD) is also associated with obesity. A high concentration of leptin stimulates oxidative stress (oxidative damage to cells) in endotheliocytes, growth of smooth muscle cells and deposition of calcium salts in the vascular wall. These changes lead to a violation of the response of the vessel in response to dilatational stimuli (for example, the influence of alcohol, a decrease in blood pressure) and contribute to the development of atherosclerosis.

An excess of leptin is associated with an increase in the concentration of prothrombogenic factors, such as fibrinogen, factor VII, and von Willebrand factor. The structural features of leptin make it possible to attribute it to the family of pro-inflammatory cytokines - proteins that support inflammation. For example, leptin is involved in the maturation of T-lymphocytes in the thymus, maintenance of the NK-cell pool, chemotaxis and activation of neutrophils.

 At the humoral level, leptin stimulates the production of tumor necrosis factor α (TNF-α ) and IL-6. These immunological disorders, due to the increased level of leptin and some other cytokines, allow us to consider obesity as a chronic inflammatory disease. 

An elevated level of leptin is a predictor of myocardial infarction, unstable angina or sudden cardiac death. Thus, an increase in leptin concentration can be considered as a clinical and laboratory marker of the risk of coronary heart disease.

The concentration of leptin is directly proportional to the mass of adipose tissue and reflects the body's energy reserves. Depletion of energy reserves (as a result of starvation, intense physical exertion) is accompanied by a decrease in the concentration of leptin, which provokes characteristic neuroendocrine changes: a decrease in the level of thyroxine (a decrease in body temperature and metabolism, a feeling of cold, slowing of reactions), an increase in the level of the stress hormones somatotropin, adrenaline and cortisol ( increased lipolysis and gluconeogenesis in the liver, hypertriglyceridemia and hyperglycemia) and a decrease in the level of sex hormones (a characteristic sign of exhaustion is secondary amenorrhea and anovulation, as well as osteoporosis). 

Hypothalamic amenorrhea occurs in 3-8.5% of patients aged 13-44 years. It is accompanied by suppressed rhythmic production of gonadotropin-releasing hormone (Gn-RH) of the hypothalamus, which leads to a deficiency of follicle-stimulating (FSH) and luteinizing (LH) hormones of the pituitary gland, a decrease in the level of sex hormones and anovulation. One of the causes of hypothalamic amenorrhea is leptin deficiency. The use of exogenous leptin in such patients normalizes the synthesis of GnRH, FSH, LH and sex hormones. 

Therefore, the measurement of the leptin level can be used to identify the cause of secondary amenorrhea, as well as to determine the tactics of treatment of female infertility.