Repaint the adipocytes

Genomic editing turned white fat into brown

Anna Muravyeva, N+1

The researchers disrupted the sequence of the NRIP1 (nuclear receptor-interacting protein 1) gene in white fat cells of mice and turned them into brown fat cells. These cells were implanted into mice that were on a fat-rich diet, which contributed to a decrease in body weight and increased glucose tolerance compared to the control. The same results were obtained with the implantation of edited human cells. The preprint of the study is published on the website biorxiv.org (Tsagkaraki et al., CRISPR-enhanced human adipocyte “browning" as cell therapy for metabolic disease).

Some diseases disrupt the overall metabolism: for example, obesity and type 2 diabetes cause a poor tissue response to insulin, problems with the breakdown of glucose and lipids, as well as concomitant diseases. Despite different approaches to treatment, 400 million people around the world still suffer from diabetes.

At the level of the body, metabolism is regulated, among other things, by adipose tissue, which can be of two types: white, in the cells of which fat drops are stored, and brown, which participates in the processing of the energy of organic compounds into heat. The mitochondria of brown fat also use lipids as fuel, which are stored in drops of white cells.

Researchers from the University of Massachusetts School of Medicine led by Michael P. Cech. Czech) tried to turn white fat cells into brown fat cells by suppressing the NRIP1 gene. This gene, in turn, suppresses the process of thermogenesis – the transfer of energy into heat by brown fat cells. Such a transition would allow "burning" fats from white cells through thermogenesis.

To suppress the NRIP1 gene, the researchers used the CRISPR system: the Cas9 protein, which makes an incision in DNA, and the gRNA, which "leads" the system to its complementary place in the genome. After the operation of the system, the incision is sewn up with cell enzymes, which usually introduce mutations into the rupture site. These mutations disrupt the work of the gene.

However, it was not so easy to edit the genomes of cells in mouse organisms: the system had to be delivered specifically to white fat cells, because the NRIP1 gene in other cells can perform vital functions. Then biologists edited the precursor cells of white fat in the laboratory to implant them in mice. The efficiency of editing in cells was 90 percent and was maintained during the differentiation of progenitor cells into mature ones.

Biologists implanted the edited cells into mice and waited six weeks for the cells to give rise to fat deposits. After that, the researchers began to increase the fat mass of mice using a special diet with fatty food. By the third week, mice with modified fat cells gained weight worse than mice of the control group (p<0.05). These mice were also affected by metabolic changes: low glucose levels and increased tolerance to it.

Then the researchers edited human cells and also implanted them into mice. This experiment also showed a decrease in body weight compared to the control (p<0.01) and an increase in glucose tolerance (p<0.05).

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