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The surprising role of the "big gluttons" in preventing obesity

Scientists from the Weizmann Institute discovered that macrophages are necessary for maintaining the internal balance by ensuring proper heat production

Macrophages (in green) and axons (in red) in brown fat tissue. Photographed using two-photon microscopy. Source: Weizmann Institute magazine.
Macrophages (in green) and axons (in red) in brown fat tissue. Photographed using two-photon microscopy. Source: Weizmann Institute magazine.

In 1880, the Russian zoologist Ilya Machnikov invented the term macrophage - ('big glutton') as a name for a certain type of white blood cells, due to the way they ingest and digest cellular waste and foreign particles as part of the body's immune defense system. Now add Prof. Stephen Jung and his colleagues in the Department of Immunology at the Weizmann Institute have a new perspective on these cells: recent studies show that macrophages also have an effect on obesity.

The original research goal was Rett syndrome - a rare neurological disorder in the brain. Rett syndrome is caused by mutations in a gene called MECP2, whose protein product is found in all body cells and plays an essential role in the normal functioning of nerve cells. After studying macrophages for more than a decade, Jung wondered if gene mutations in these cells might contribute to this syndrome. However, when the researchers in Jung's laboratory, including Dr. Yohai Wolf and staff scientist Dr. Siglit Bora-Halfon, introduced a mutation in this gene in the macrophages of mice, the result was not Rett syndrome. Instead, the mice unexpectedly gained weight and spontaneously developed obesity.

"Obesity may occur due to various reasons, such as excessive eating or burning less energy," says Jung. "At first we didn't understand why these mice got so fat." To discover the reason, the researchers developed two experimental models that allowed them to change the MECP2 gene in the macrophages of newborn mice and in adult mice; Then, they compared the models to the control groups, in which the gene was not changed. Although all the mice received the same food, only the groups whose genes were mutated developed excess weight. The fact that both mouse models suffered from obesity indicates that it is not a developmental problem. With the help of Dr. Yael Kuperman from the Department of Veterinary Resources and her unique experimental setup, excessive food consumption was ruled out as a possible cause. On the other hand, the researchers discovered that the bodies of the mice carrying the mutation produced less heat.

These results are exciting, because macrophages are best known for the role they play in the immune system: cleaning up damaged and dying cells and warding off infections. But now we have identified a new role in maintaining a healthy and balanced state through the control of brown adipose tissue innervation."

Defective thermostat

This observation led the scientists to investigate the brown adipose tissue which helps the body to balance its internal temperature, being responsible for the production of heat that does not result from muscle tremors. Indeed, in mice carrying the mutant gene, a decrease in the level of activity of the protein UCP1, which oversees the production of heat in brown fat tissue, was recorded. Along with the deficiency in heat production, which led to a reduced expenditure of energy, a large accumulation of fat occurred.

From the right: Dr. Siglit Bora-Chalfon, Prof. Stefan Jung and Dr. Yohai Wolf. "At first we didn't understand why the mice got so fat." Source: Weizmann Institute magazine.
From the right: Dr. Siglit Bora-Chalfon, Prof. Stephan Jung and Dr. Yohai Wolf. "At first we didn't understand why the mice got so fat." Source: Weizmann Institute magazine.

Next, the scientists wanted to find out what caused the decrease in UCP1 levels in these mice. Under normal conditions, the production of UCP1 is activated by the release of the hormone norepinephrine, which is transported in axons - long and thin extensions of nerve cells; They found that the mutant mice have fewer such axons.

A more detailed analysis of gene expression by the scientists showed that in the macrophages of the mutant mice there was an increase in the production of an axon-directing protein called Plexin A4. The research team enlisted the help of Prof. Avraham Yaron From the Department of Biomolecular Sciences, who conducted extensive research on this protein, and together with him, presented a possible explanation for the molecular mechanisms that lead to obesity. The research findings Were published in the journal Nature Immunology.

According to the explanation they proposed, MECP2-deficient macrophages overexpress the Plexin A4 protein. Because of its role in nerve growth suppression, the effect of overexpression of this protein on nerve axons is to suppress their growth in brown adipose tissue. The resulting reduction in innervation leads to a decrease in the level of noradrenaline signals, which are needed to activate UCP1 in the brown fat cells. As a result, less heat is produced and energy expenditure is reduced, which ultimately leads to obesity.

"These results are exciting, because macrophages are best known for the role they play in the immune system: cleaning up damaged and dying cells and fighting off infections. But now we have identified a new role of the macrophages in maintaining the internal equilibrium and maintaining a healthy and balanced state by controlling the innervation of brown adipose tissue and ensuring normal heat production.

"Although our mutant model produces a very subtle change - that is, only in the reduced innervation of the brown fat, without the appearance of inflammation or the ingestion of unwanted cells that usually accompany macrophage activity - the change creates a profound and unexpected effect: obesity."

This new role of macrophages adds to recent findings, which show that macrophages in tissues and other organs are essential for the homeostatic function of several biological systems.

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