Metabolic

Researchers identify protein that plays a key role in the regulation of appetite and metabolism by the brain

Researchers at the Okinawa Institute of Science and Technology Graduate University (OIST) have identified a protein that plays a key role in regulating appetite and metabolism in the brain. Loss of the XRN1 protein from the forebrain resulted in obese mice with insatiable appetites, according to a new study published in the journal iScience.

Obesity is a growing public health problem with over 650 million adults classified as obese worldwide. The condition has been linked to many conditions, including cardiovascular disease, type 2 diabetes, and cancer.

“Basically, obesity is caused by an imbalance between food intake and energy expenditure,” said Dr. Akiko Yanagiya, researcher in the Cell Signal Unit at OIST under the direction of Professor Tadashi Yamamoto. “But we still know very little about how appetite or metabolism is regulated by communication between the brain and parts of the body such as the pancreas, liver and adipose tissue.”

In the study, the scientists created mice that could not produce the XRN1 protein in a subset of neurons in the forebrain. This brain region includes the hypothalamus, an almond-sized structure that releases hormones into the body and helps regulate body temperature, sleep, thirst, and hunger.

At 6 weeks of age, the scientists found that the mice with no XRN1 in the brain gained weight rapidly and became obese by 12 weeks of age. Fat accumulated in the body of the mice, including adipose tissue and liver.

When monitoring feeding behavior, the team found that the mice without XRN1 ate almost twice as much each day as the control mice.

“This finding was really surprising,” said Dr. Shohei Takaoka, a former PhD student in the OIST Cell Signal Unit. “When we first turned off XRN1 in the brain, we weren’t sure what we were going to find, but this drastic increase in appetite was very unexpected.”

To investigate what might be causing the mice to overeat, the scientists measured blood levels of leptin – a hormone that suppresses hunger. Compared to controls, blood leptin levels were abnormally high, which would normally prevent the mice from feeling hungry. But unlike the control mice, the mice without XRN1 did not respond to the presence of leptin – a condition known as leptin resistance.

The scientists also found that 5-week-old mice were resistant to insulin, a hormone released by beta cells in the pancreas in response to high blood sugar levels after eating. This type of failure in how the body responds to glucose and insulin can ultimately lead to diabetes. With increasing age of the mice, in addition to the increased leptin level, the glucose and insulin levels in the blood also increased significantly.

We believe that glucose and insulin levels have increased due to the lack of response to leptin. The leptin resistance meant that the mice kept eating, keeping blood glucose levels high, and thus increasing blood insulin levels. “

Dr. Akiko Yanagiya, researcher

The scientists then checked whether the obesity was also driven by the mice with less energy. They put each mouse in a special cage, which measured how much oxygen the mice used to indirectly calculate their metabolism.

In the 6-week-old mice, the scientists found no overall difference in energy consumption. However, they found something very surprising. The mice without XRN1 used mainly carbohydrates as an energy source, while the control mice could alternate between burning carbohydrates at night when they were most active and fat during the day when they were less active.

“For some reason, this means that the mice without XRN1 cannot use fat effectively as fuel,” said Dr. Yanagiya. “However, we still don’t know why this happens.”

Once the mice were 12 weeks old, their energy expenditure decreased compared to control mice. However, the scientists believed that this was a consequence of obesity, since the mice were less active than a cause.

“Overall, we believe that overeating, due to leptin resistance, was the main reason these mice became obese,” said Dr. Yanagiya.

To further investigate how the loss of XRN1 leads to leptin resistance and increased appetite, the scientists examined whether the activity of appetite-regulating genes in the hypothalamus changes.

XRN1 plays a crucial role in gene activity as it is involved in the final step in the breakdown of messenger RNA (mRNA). When a gene is active, DNA is made into an mRNA molecule that can then be used to build a specific protein. Cells have many ways to regulate the activity of genes, one of which is to break down mRNA more slowly or more quickly, causing more or less protein to be made.

In the hypothalamus, the scientists found that the mRNA from which the protein agouti-related peptide (AgRP) – one of the most powerful appetite stimulants – is made was increased in overweight mice, which led to higher amounts of AgRP protein.

“It’s still just speculation, but we believe that an increase in this protein and abnormal activation of the neuron that produces it could be the cause of leptin resistance in these mice,” said Dr. Yanagiya. “Leptin normally suppresses the activity of the AgRP neuron, but if the loss of XRN1 causes this neuron to remain highly active, it could override the leptin signal.”

However, the exact mechanism by which the loss of XRN1 leads to increased activation of AgRP neurons remains unclear. XRN1 was only removed from a certain subset of neurons in the forebrain, AgRP neurons were not one of them. This suggests that another neuron that has lost XRN1 may be involved and incorrectly signaling the AgRP neurons and keeping them active.

In the future, the lab hopes to work with neuroscientific research units to determine exactly how XRN1 affects the activity of neurons in the hypothalamus to regulate appetite.

“Identifying which neurons and proteins in the brain are involved in appetite regulation and fully determining how resistance to leptin is caused could ultimately lead to targeted treatment for obesity,” said Dr. Yanagiya.

Source:

Okinawa Institute of Science and Technology (OIST) Graduate University

Journal reference:

Takaoka, S., et al. (2021) Neural XRN1 is required for the maintenance of metabolic homeostasis throughout the body. iScience. doi.org/10.1016/j.isci.2021.103151.

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