Obesity – in the head
A group of researchers from the University of Michigan Medical School described the mechanisms occurring inside the hypothalamus cells synthesizing the precursor of appetite regulators and their effect on obesity.
The precursor of the hormone, or prohormone, which is discussed in the article, is called proopiomelanocortin (POMK). It is synthesized in the neurons of the hypothalamus and is the progenitor of several hormones that regulate appetite.
The authors found out that before leaving the cell, the POMC is checked for errors in the chain of its constituent amino acids. If an error is detected, the defective molecule does not leave the cell and does not enter the blood. This "quality control" occurs in the endoplasmic reticulum of the cell and is called ERAD (endoplasmic reticulum-associated protein degradation – protein degradation in the endoplasmic reticulum).
The ERAD process is closely related to the level of POMC in the blood and indirectly affects appetite. When ERAD is violated, all POMK molecules are recognized as defective and accumulate in the cell. This leads to a decrease in POMK and its derivatives in the blood, impaired appetite and obesity.
In the experiment, mice with a violation of the ERAD process showed increased appetite and rapid weight gain, even if they were fed low-calorie food.
There is a rare form of childhood obesity associated with a mutation of the C28F gene encoding the synthesis of POMK. The researchers decided to study more deeply the relationship of this mutation with the ERAD process.
The presence of a mutation in the C28F gene leads to the patient feeling a constant feeling of hunger and loss of control over the amount of food eaten. Severe obesity develops at an early age.
Scientists have found that the mutation leads to the synthesis of defective POMC, which does not pass quality control of the endoplasmic reticulum. It accumulates in the cell and interferes with its normal operation. This leads to a decrease in the level of POMK in the blood and the development of obesity.
In the case of mice with a disrupted ERAD process, as with the mutation of the gene encoding POMK, there is an accumulation of POMK molecules in the cell, which, sticking together, forms conglomerates. Surprisingly, the cell does not die at the same time, but simply ceases to perform its function.
The results of observations allow us to conclude that the cells of the hypothalamus need free space for normal operation. The development of drugs that accelerate ERAD, or prevent the accumulation and adhesion of POMCS inside cells, can solve the problem of obesity.
The researchers decided to test the work of the endoplasmic reticulum in the cells of the hypothalamus synthesizing precursors of other hormones. Thus, the suppression of ERAD in cells that produce a precursor of vasopressin (a hormone that regulates water metabolism in the body) leads to the development of a condition in mice similar to diabetes insipidus in humans. At the same time, the patient is constantly thirsty and loses a lot of fluid with urine as a result of a lack of the hormone vasopressin in the blood.
Thus, ERAD plays a key role in the normal physiology of the body. Treatment by acting on one of the links of this process can cure obesity and other metabolic disorders.
Article by G. H. Kim et al. Hypothalamic ER–associated degradation regulates POMC maturation, feeding, and age-associated obesity published in the Journal of Clinical Investigation.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of mHealth Lab: Clues to Obesity's Roots Found in Brain's Quality Control Process.