Why do we tend to gain weight as we get older?
When the diet doesn't go well, we tend to blame our genes. New research of Weizmann Institute of Science scientists gives this mindset some justification. As we age, we tend to accumulate fat, lose muscle mass and generally gain weight - regardless of the amount of calories we consume. This phenomenon is known as sarcopenic obesity and its causes are still not fully understood. Scientists from the research group of Prof. Eitan Reuvani In the Department of Biomolecular Sciences, they recently showed that a gene that regulates calcium levels in the cell may contribute to this obesity.
Many know that calcium plays an important role in building the skeletal system and bones, but the importance of the mineral for normal physical activity is far from being summed up in this: calcium is stored in all the cells of the body and serves as a messenger to transmit messages within the cell. In response to an external stimulus or an internal change, calcium is released into the intracellular fluid, binds to proteins, accelerates certain processes and inhibits others. In order for the cell to survive and continue to transmit messages in response to changes, it must replenish its calcium stores every time they are depleted as a result of intercellular communication.
Filling the calcium reservoirs is done by a system consisting of two units - a sensor that checks the state of calcium in the reservoirs and a channel that exits the cell membrane and allows the mineral to enter. The channel is normally closed, but when the sensor detects that the reservoirs have been depleted, it opens and allows calcium ions, whose concentration outside the cell is high, to enter the cell where their concentration is low. But how do you make sure that the cell is not flooded with too much calcium when the channel opens? BPrevious research, from 2012, scientists from Prof. Reuben's laboratory discovered a protein called SARAF, whose function is to inhibit the activity of the calcium entry system into the cell. The protein binds to the sensor of the calcium entry system and causes it to stop communicating with the channel, thus preventing excess entry of calcium, a sort of dam that prevents flooding.
In the new study, which was led by Dr. Diana Gatolin, the scientists tested the effect of the activity of the gene encoding the SARAF protein on metabolism and behavior patterns in mice. To examine the issue, they compared healthy mice to mice in which the gene had been deleted through genetic engineering. The scientists noticed that in the transgenic mice Metabolism slowed down, they began to accumulate fat - and at the age of three months their weight was on average 10% more than healthy mice.
"Our research does show how genetics plays a role in obesity, but it is important to note that it does not determine fate. When we put the overweight mice into an exercise program, they successfully lost weight"
"We followed the mice for more than a year and saw how the effect of the gene on metabolism became more and more severe," explains Dr. Gatolin. Mice without the gene had a higher percentage of fat and a lower percentage of muscle. Mice are active at night, but the obese mice moved less from place to place after dark. The changes occurred without the mice eating more, and despite the fact that their blood glucose levels remained similar to those of the healthy. This finding indicates that inactivity of the SARAF gene may be one of the factors involved in sarcopenic obesity, which does not depend on diet."
In a CT scan, the scientists saw that the fat was stored mainly in the abdominal area of the mice and that the drops where the fat is stored in the cells were significantly larger compared to healthy mice. Fat tissues in the body are divided into two types - white fat, which is linked to obesity, and brown fat, which contributes to normal metabolism and heat production. In mice without the gene, white fat levels increased at the expense of brown fat levels. These damages appeared already at the age of three months and worsened as the mice got older. From the age of one, white fat also accumulated in the liver and resulted in fatty liver disease, which increases the risk of liver cirrhosis and even cancer. In addition, the mice without the gene suffered from hypothyroidism, which in itself slows down the metabolism and leads to obesity.
At this stage, the scientists tested the mechanism by which the gene affects the body's metabolism. They first focused on the hormone vasopressin, known to play an important role in normal metabolism. After its release from the pituitary gland in response to a signal from the hypothalamus, the hormone reaches the liver cells and accelerates energy production processes there by releasing calcium from the cellular stores. However, when vasopressin was added in the laboratory to liver cell samples taken from mice without SARAF, the cells responded more slowly to the hormone and were slower to release calcium. In other words, the calcium levels that should have risen when the body needed available energy reached extremely high peak levels too late. Since unused energy in the body is stored as fat, these findings suggest a possible mechanism for obesity in mice without the gene.
When they moved on to examine the brains of the mice, the scientists discovered that SARAF was particularly active in three areas: the hippocampus, a certain area of the hypothalamus known to be involved in obesity, and the amygdala. When they deleted the gene only in the particular area of the hypothalamus and left it active in all the other areas, the scientists discovered to their surprise the opposite effect of the gene: at the age of one year, these mice had a better metabolism than healthy mice; They enjoyed lower weight and body fat percentage and higher muscle mass; They moved more during active hours and also produced more heat.
"Obesity is a global epidemic that endangers the health of hundreds of millions," says Prof. Reuvani. "Understanding the causes of obesity in adults and the discovery of a gene that may play a central role in this process paves the way for the development of a better pharmacological response to obesity in the coming decades. Our research does show how genetics plays a role in obesity, but it is important to note that it does not determine fate. When we introduced the mice who were overweight for an exercise program, they successfully lost weight. Indeed, sports are an effective and available tool for weight loss - even when there is a genetic tendency to obesity."
Also participating in the study were Dr. Yael Kuperman, Dr. Michael Tzuri and Dr. Inbal A. Biton, from the Department of Veterinary Resources at the Institute; Tomer Nathaniel and Dr. Raz Pelati, from the Faculty of Medicine at the Technion; Dr. Yizhar Karabat and Dr. Anna Mashcharyakov, from the Department of Biomolecular Sciences at the institute.
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