When inflammation occurs around certain neurons in the brain, the molecular membrane around the cells becomes thicker, causing these neurons to stop sensing insulin and causing them to eat more.
After eating, the insulin level in the blood increases. It forces the body’s cells to absorb glucose, which is formed during the digestion of food and serves as the main fuel – it is sent to energy reactions first. Insulin is also sensed in the brain, but here it has another role: special neurons determine how to regulate eating behavior and metabolic reactions based on the insulin level. These neurons are located in the so-called arcuate nucleus of the hypothalamus and use the neuropeptide AgRP, which is sometimes called the appetite hormone, as a signaling substance. The hypothalamus as a whole regulates a wide variety of biochemical and physiological processes; neurons of the arcuate nucleus are known for directly sensing hormones and various other substances floating in the blood. Obviously, if there is a lot of insulin, then it is time to stop looking for food, it is time to curb the feeling of hunger and appetite, and energy reactions can be brought to the maximum. If there is little insulin, then you need to eat more, and it is better to save nutrients – and you can save them by creating fat reserves; This is exactly the signal that neurons send using AgRP.
But it may be that there is actually a lot of insulin floating around in the blood, but those same neurons for some reason do not sense it. How can this happen? For example, for some reason the neurons no longer have enough insulin receptors, or the intracellular signaling chains that transmit the signal from the receptors have for some reason stopped transmitting it, and the neuron continues to work as if there was little insulin around. Employees of the University of Melbourne write in Naturethat there is another reason why neurons of the arcuate nucleus stop feeling insulin – it is too dense extracellular substance, which simply does not allow insulin to reach the receptors. Extracellular (intercellular) substance, or matrix, as you can understand from the name, fills the space between cells, but its properties can differ depending on what kind of cells they are and where exactly this substance is located relative to the cells. Close to neurons, the intercellular matrix forms a molecular network, one of the main components of which is chondroitin sulfates, complex polymers of proteins and carbohydrates. Chondroitin sulfates are usually discussed in connection with cartilage tissue and joints, but, as we can see, they are also in the intercellular substance near neurons. It is known that this perineuronal network affects the excitability of neurons and their ability to connect with each other.
Now, in experiments with mice, it has been possible to show that the neurons of the arcuate nucleus associated with food are enveloped in a particularly dense network if the mouse suffers from obesity, if it eats a lot of fatty and carbohydrate foods, if it has metabolic diseases. It turned out that such a network simply prevents insulin from reaching the receptors on the neurons, and the neurons become too active. If the connective tissue perineuronal network was destroyed, insulin reached the neurons and suppressed their activity, and since it was destroyed in living mice, then it was possible to observe how the mice began to eat less, how their energy metabolism increased, and how they lost excess weight. The issue was precisely in the availability of neurons for insulin: when the insulin receptor gene was deliberately switched off in cells, there was no effect from the destruction of the pericellular substance.
The perineuronal network around AgRP neurons can be thinned by metalloproteinase enzymes, but during inflammation their activity drops due to proteins that block their activity. As a result, the network becomes too dense and does not allow insulin to reach its receptors. The lack of insulin signals through the rearrangement of potassium ions causes increased neuronal activity, which affects feeding behavior and metabolism. (Illustration Nature.)
Why does this substance clump around neurons in the first place? They themselves have enzymes called metalloproteinases, which can thin out the molecular network around them. However, the synthesis of metalloproteinases drops if two signaling proteins, TNF-α and TGF-β, begin to act on neurons; they also stimulate the synthesis of other proteins that suppress the work of metalloproteinases. Both TNF-α and TGF-β are known as inflammatory proteins; thus, we see another mechanism that links inflammation with excess weight and the problems that accompany it.
There are experimental drugs that suppress the synthesis of chondroitin sulfates, and the same substances help to lose weight and normalize metabolism. However, it is necessary to thin out the intercellular substance with caution, after all, it supports cells and intercellular connections, and in the nervous tissue this is probably more important than anywhere else. At the same time, it is known about insulin that the brain needs it not only to regulate metabolism in the body. Insulin affects the transmission of impulses, and it is assumed that the disruption of insulin signals increases the likelihood of some psychoneurological disorders. Some of these disorders – for example, depression – are accompanied by an increase in the intercellular matrix in some areas of the brain; at least, this is what experiments on mice that were put into a depression-like state suggest. Perhaps, if in the future some drugs are developed that can regulate the density of the perineuronal molecular network, they will be prescribed for a very wide range of diseases.
Source: www.nkj.ru
