August 10, 2022

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CRISPR gene editing treats obesity and let fat cells burn to produce heat

CRISPR gene editing treats obesity and let fat cells burn to produce heat



 

Nature Communications: CRISPR gene editing treats obesity and let fat cells burn to produce heat

 

With economic development and improvement of living standards, obesity has become a major public health problem worldwide.

According to statistics from the World Health Organization (WHO) , nearly 2 billion people are overweight or obese in the world.

From 1975 to 2016, the global obesity rate has nearly tripled. Every year, overweight or obesity causes 2.8 million deaths .

 

More and more studies believe that obesity is actually a chronic disease. Obese people not only have inconvenience in life and decreased exercise capacity, but also are more likely to suffer from metabolic diseases and cardiovascular and cerebrovascular diseases .

 

In addition, many studies show that obesity is more than ten years old. The increased risk of this type of cancer is related to the decreased prognosis and survival rate .

Therefore, there is an urgent need for new interventions to prevent and treat obesity.

 

Recently, researchers from the University of Massachusetts Medical School published a research paper titled: CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease in the journal Nature Communications .

 

The study shows that knocking out the NRIP1 gene in fat cells in vitro through CRISPR gene editing can enhance the browning of white adipose tissue and promote its heat production, thereby promoting metabolic homeostasis, which can be used to help weight loss.

 

CRISPR gene editing treats obesity and let fat cells burn to produce heat

 

We know that in addition to the main white adipose tissue , there are brown adipose tissue and beige adipose tissue .

Unlike the white adipose tissue that stores lipids, brown and beige adipose tissue belong to thermogenesis adipose tissue.

They not only have high oxidizing ability. The expression of high mitochondrial uncoupling protein (UCP1) can also secrete factors that enhance energy metabolism and energy expenditure.

 

Many studies have shown that implanting mouse brown adipose tissue into obese and glucose intolerant mice can improve their glucose tolerance and insulin sensitivity, thereby helping them suppress obesity. However, there are obstacles in applying this method to humans: the brown and beige adipose tissue cells in humans are scarce.

 

Nrip1 gene is a very attractive target for the treatment of obesity. The NRIP1 protein expressed by it can strongly inhibit glucose transport, fatty acid oxidation, mitochondrial respiration, UCP1 expression, and secretion of metabolic beneficial factors including NRG4.

 

Knockout in white adipose tissueNRIP1 can up-regulate the expression of metabolism-related genes in brown adipose tissue, improve the utilization of glucose and fatty acids, and promote thermogenesis. Experiments in mice have shown that mice after knocking out NRIP1 cannot gain weight even if they eat a high-calorie diet.

 

However, NRIP1 protein has many other functions, such as regulating estrogen receptors in the reproductive tract. Therefore, it is not a target of conventional pharmacological intervention.

 

The research team thought that NRIP1 could be targeted to be knocked out in the isolated fat cells and then transplanted, so as to avoid the side effects caused by the inhibition of drugs in the body.

 

The research team obtained human adipocyte progenitor cells from human subcutaneous adipose tissue, and then knocked out the gene NRIP1 that inhibits heat production through CRISPR gene editing .

The research team used ribonucleoprotein (RNP) composed of Cas9 protein and sgRNA .

RNP will be completely degraded by the cell after knocking out NRIP1 efficiently, while minimizing potential off-target effects.

 

Compared with non-genetically modified fat cells, mice implanted with CRISPR gene-edited human or mouse fat cells can reduce obesity and liver triglycerides under high-fat feeding conditions, while enhancing Glucose tolerance.

 

CRISPR gene editing treats obesity and let fat cells burn to produce heat

 

These findings indicate that modifying human fat cells through CRISPR gene editing can improve metabolic homeostasis and have the potential to treat obesity.

Moreover, this method can be carried out in vitro without a delivery vector, which avoids the possible immune response caused by the Cas9 protein itself and the gene delivery vector AAV.

 

 

 

Paper link:
https://www.nature.com/articles/s41467-021-27190-y

CRISPR gene editing treats obesity and let fat cells burn to produce heat

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