"Lying flat" can be thin! Instead of exercising and dieting, just remove obesity-specific genes

Recently, a study published in the International Journal of Obesity found that deleting the obesity-related genes in male mice drastically reduced fat mass. The research results could have a major impact on the treatment of obese patients, and if the technology can be applied to humans, it means knocking out obesity-specific genes, not exercising or dieting, and being able to lose weight while lying down.

The study was conducted by an anatomical and cell biology research team led by Silvia Penuela of the Schulick School of Medicine-Dentistry at the University of Western Ontario in Canada, led by PhD candidate Brent Wakefield, in collaboration with other laboratories at the University of Western Ontario, including Professor Frank Beier and the University of Toronto. The study was published in an article in the International Journal of Obesity titled "Pannexin3 deletion reduces fat accumulation and inflammation in a sex-specific manner."

Research Results (Source: International Journal of Obesity)

Penuela's lab examined a gene called Pannexin 3 (PANX3) and its effect on adipose tissue in mice. Pannexin 3 is a channel-forming glycoprotein that achieves nutrient-induced inflammation in vitro, and genetic linked data suggest it can modulate body mass index. Against the background of forced treadmill running (FEX) and a high-fat diet (HFD), the researchers characterized inflammatory and metabolic parameters in PANX3 knockout mice.

The research team found that after the PANX3 gene of male mice was knocked out, the body fat in the mice decreased and muscle mass increased, which was equivalent to the mice exercising for 1 hour a day, 5 days a week, and lasting 6 weeks of exercise. Penuela, head of the schulik Medical-Dental College laboratory, said this is a remarkable discovery that could eventually have a major impact on the treatment of obesity.

In the human body, there are three PANX3 genes encoding proteins that form channels. These channels are thought of as pores on the cell membrane and contribute to cell-to-cell communication. "Think of them as cell phones. You have a certain number of cell phones at the edges of your cells that send messages to other cells telling them when to grow, when not to grow, and when to perform other functions. Penuela explains.

The PANX3 gene is highly expressed in the body's fat cells. When Penuela's team knocked out the PANX3 gene from mouse embryos with a new model developed, the mice's bodies became significantly thinner and their muscle mass increased as they ageed. Wakefield explains: "Without any exercise, PANX3 knockout mice have the same body composition as mice that are in motion. ”

Male mice with the panx3 gene lost an average of 46% less body fat than male mice with this gene. However, this effect was only found in male mice, not female mice. Penuela's team is still working on why this is happening.

In addition, male mice without the PANX3 gene also had much lower levels of inflammation of visceral adipose tissue, a major indicator of obesity associated with other comorbidities such as cardiovascular disease and diabetes. "We've seen significant reductions in inflammatory markers in fat," Wakefield explains, "knocking out that gene is even better than exercise, and we know that exercise also has anti-inflammatory effects." Mice with the PANX3 gene deletion also appeared to have fewer fat cells overall.

Now, Penuela Labs is seeking to develop a PANX3 drug blocker that will be used to inhibit the function of panx3 in humans. "If we can block it, we have the hope of getting the same therapeutic effect as knocking it out," Penuela said. We hope to one day help patients with obesity. ”

While the results of the collaborative study are promising, Penuela said there is an important caveat to the study. While the reduction in fat mass and increase in muscle caused by knocking out the PANX3 gene is equivalent to an hour a day and lasting six weeks of exercise, the premise is that a healthy diet must be maintained.

Penuela explains: "If you have a high-fat diet and always eat burgers and fries, no matter how well you knock out or block the PANX3 gene, the effect is no different. Wakefield also said: "When we fed mice missing the PANX3 gene a high-fat diet, the difference in weight disappeared, and diet has always been a very important factor." ”

Researchers have partnered with WORLDiscoveries (The Technology Transfer Office of the University of Western Ontario) to explore the development of gene-blocking drugs with industry partners. Saqib Sachani, business development manager at WORLDiscoveries, said: "These findings may lead us to develop new strategies and pharmacological targets for PANX3 channel function in the integrated management of obesity and inflammatory diseases, which provide a new target for therapeutic interventions." Next, we will work closely with our partners to identify and develop pharmacological blockers. ”

The researchers acknowledge that obesity is a complex disease that is influenced by factors such as genetics and lifestyle. Penuela believes that while exercise and a healthy diet remain the most important factors in creating healthy body composition, for obese people, PANX3 blockers may be game-changing. "If we can combine treatment, healthy eating and exercise and block that pathway, then it will really speed up the response of obese people to treatment," she said. ”

The study also found that exercise and diet can play a role in regulating PANX3. When the mice ate badly, the levels of PANX3 in the body's adipose tissue increased. Instead, exercise lowered the MICE's PANX3 levels.

In addition to exploring the creation of PANX3 blockers, the next step in the research team's plan includes further study of human genes. Penuela said her lab aims to analyze PANX3 in human genome sequences, looking for genetic mutations that can determine why some people are more likely to accumulate fat. This could provide researchers with new clues to help explain why some people are more likely to gain weight and gain weight by drinking cold water, while others are more likely to maintain their natural health.

Written by | Li Ying

Typography | Qiao Weijun

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Resources:

[1] Deleting specific gene in male mice reduces fat mass:

https://medicalxpress.com/news/2022-01-deleting-specific-gene-male-mice.html

[2] Wakefield, C.B. Lee V.R. Johnston, D. et al. Pannexin 3 deletion reduces fataccumulation and inflammation in a sex-specific manner. Int J Obes(2021).