red Leptin, a hormone produced by adipose tissue, regulates appetite and is considered key in the development of obesity, a pressing medical, social and economic problem. Leptin is a regulator of body weight and energy homeostasis. Increasing levels of the hormone in the bloodstream minimizes appetite and reduces weight. But when you gain extra pounds, despite the increase in leptin levels, its anorexigenic effect decreases.
This condition is called leptin resistance, which develops due to a defect in the transmission of signals from leptin receptors or a decrease in its ability to cross the blood-brain barrier. There are no clear criteria for diagnosis of the pathological condition. However, data on leptin’s tropic capacity: association with immunity, hematopoiesis, formation of new capillaries, heart and vascular pathology, autoimmune disorders, tumors are of great interest. From the article you will learn about modern diagnostics of leptin resistance in order to facilitate the solution of the listed problems.
Contents:
- How leptin signaling works.
- Mechanisms of leptin resistance.
- Diagnosis of leptin resistance.
- Conclusion.
How leptin signaling works
Leptin is a peptide hormone, its receptors belong to the class I cytokine receptor family and are encoded by the db gene. However, given the plurality of coding isoforms of leptin receptors, only the long isoform is able to activate the signal delivery pathway, so the main opportunities of the hormone are realized exactly through it. The Ob receptor isoform travels through the bloodstream as a soluble receptor. Radioimmunoassay found a positive correlation between the amount of leptin in the blood and the amount of fat in the body, which varied with fasting and satiety.
The evidence that obese patients are not deficient in leptin formed the basis for the theory of leptin resistance as a key link in the accumulation of extra pounds and the metabolic abnormalities that accompany this process. This theory was indirectly confirmed by a placebo study after administration of recombinant leptin to overweight patients. No matter what dose of the hormone was administered, the weight of the subjects did not change. In addition, it was proved that the correlation of leptin food intake and energy expenditure was different in thin and obese patients. This means that they have different sensitivity to the hormone.
Mechanisms of leptin resistance
Today, there are several hypotheses that explain leptin resistance:
- Disruption of the ob gene structure.
- Blocked transport of the hormone across the blood-brain barrier.
- Changes in the function of leptin receptors and intracellular mechanisms of its signal transmission, i.e., hormone levels.
Gene mutations
The hereditary nature of leptin resistance is quite rare. Gene homozygous mutations cause wolf’s appetite, obesity, and hypothalamic hypogonadism. Heterozygotes are diagnosed with a drop in leptin levels and a one-third increase in fat volume. Receptors that have been mutated circulate in the bloodstream at maximum concentration, allowing them to bind leptin. But gene mutations of the hormone or its receptor cannot be considered major factors in the development of leptin resistance.
Hematoencephalic barrier
Leptin resistance results from impaired transport of leptin from the bloodstream to the hypothalamus across the blood-brain barrier. The cerebral vasculature activates a short form of Ob-Ra leptin receptor that can bind leptin and transport it into the interstitial tissue and cerebrospinal fluid. When leptin concentration in serum reaches 30 ng/ml, its level stabilizes. It turns out that against the background of a large amount of leptin for it decreases the permeability of the blood-brain barrier. In obese patients, the hormone level in the cerebrospinal fluid is minimized on the background of its growth in blood serum. This may play a role in the development of leptin resistance and obesity.
Regulation of hormone levels
Leptin concentration is correlated with the ob gene, so those factors that affect leptin levels also affect adipose tissue and the development of leptin resistance. Minimizing the activity of the ob gene in lipocytes leads to an increase in fat volume until the necessary level of leptin is reached. At the same time, against the background of obesity, the hormone concentration in serum remains normal. This mechanism explains, for example, the predisposition to obesity in patients with low blood levels of the hormone.
Ob gene expression is affiliated with the lipid content of the fat cell and with its size. No mechanism has been identified that could explain how cellular fat affects leptin synthesis. For some reason, cultured lipocytes accumulate significantly less fat than under in vivo conditions, which blocks the possibility of analyzing the intracellular signal system. External signals can also activate leptin.
Leptin itself plays a significant role in the development of resistance to itself, this is called “leptin-induced leptin resistance. A permanent increase in leptin concentration worsens leptin receptors and leads to a decrease in their total number. The resulting leptin resistance further predisposes patients to alimentary obesity. This provokes a further increase in hormone levels and aggravates leptin resistance. A vicious circle is formed in which hypothalamic inflammation, autophagy, and endoplasmic stress are involved.
Diagnosis of leptin resistance
Unfortunately, even today there is no complete clarity on how to effectively assess leptin sensitivity in the clinic. It is assumed that sensitivity to the hormone is directly related to obesity and body fat volume. High leptin concentrations and overexpression of the ob gene in adipose tissue have been found in obesity, so many consider hyperleptinemia a key marker of leptin resistance. Many consider the association between abdominal obesity and high leptin concentrations, and it is this fact that forms the basis of leptin resistance. However, there are no clear criteria for the pathological state of insensitivity to the hormone.
Each individual has an individual response to overeating or obesity. This is indirectly confirmed by sexual dimorphism in circulating leptin concentrations and the minimization of age-related ob gene RNA levels. In addition, one cannot focus only on the level of the hormone, because it depends not only on the intensity of its synthesis, but also on its binding to receptors and clearance.
Several studies suggest that key markers in the diagnosis of leptin resistance can be the cumulation of leptin receptors and their P Metabolism of leptin is focused not only on its level, but also on the number of receptors to it. It has been proved that obesity is affiliated with the minimum activity of genes of short and long OB receptor isoforms in hypothalamus, hepatocytes, lipocytes and muscles. The free leptin index (FLI): the ratio between leptin and OB-R concentration multiplied by 100, is becoming increasingly valuable for diagnosis. But even today there is no reliable data on the reference values of this index, which seriously limits its use.
There is a mathematical model for diagnosing leptin resistance that is based on the assumption that leptin self-adjusts its receptors. The model takes into account the dynamics of leptin concentration, body weight, and food intake control. When fat is normal, constant infusions of leptin provoke a decrease in leptin sensitivity due to a drop in receptor density, which induces a desire to eat. There is speculation that the model could be improved by including the rate at which the hormone crosses the blood-brain barrier.
Receptors for leptin are located in many tissues, but it is not clear in which tissue a decrease in the number of active receptors leads to the development of leptin resistance. No relationship has been found between baseline leptin levels in obesity and hormone receptor expression in skeletal muscle. In contrast, a negative association was found between bloodstream levels of the hormone and OB RNA levels in the hypothalamus and liver.
The contribution of adipose tissue of different localization to the control of leptin secretion and activation of its receptors is of interest. In epicardial fat cells, leptin synthesis is more intense than in the same cells of subcutaneous adipose tissue. Thus, not only the number but also the location of leptin receptors contributes to the development of leptin resistance.
Conclusion
The clinical significance of leptin resistance as a key to the development of metabolic disorders dictates the need for further in-depth research to form clear diagnostic criteria for this condition.
