Turning white fat into brown fat using CRISPR – new perspectives in obesity treatment

Who wouldn't like the idea of losing weight without effort? Imagine going to the doctor and having a significant amount of your "bad" fat turned into "good" fat. Or even a miraculous treatment to make you spend more energy while resting? It would save you a lot of time and money on a gym subscription.

Although it seems impossible nowadays, genome editing technologies could make this happen, perhaps, faster than we might think.

In an article published in August of 2020 in Science Translational Medicine Journal, the authors used CRISPR technology to edit the rat fat cells' genome and create thinner and healthier animals(1). To achieve this, they used the CRISPR-SAM system in human preadipocytes to activate UCP1 gene expression.

Why using CRISPR to treat obesity?

According to WHO, obesity is one of the most neglected public health problems. Obesity has turned into a pandemic that coexists with malnutrition and increased mortality due to several comorbidities such as cardiovascular diseases, diabetes, and cancer(2). 

There are two types of fat tissue in mammals: the white adipose tissue (WAT) and the brown adipose tissue (BAT). WAT is found in superficial fat pads, and BAT is localized in more deep layers, small regions of the cervical, supraclavicular, and paravertebral areas. 

WAT's primary function is storing excess fuel. We know WAT as the "bad fat" because it can build up and cause obesity. While BAT is important for energy dissipation, we know it as the "good fat" because it burns calories to produce heat. Activation of BAT increases energy expenditure. BAT generates heat through the expression of UCP1.

UCP1 (uncoupling protein 1) is a protein expressed in BAT cells that has many roles. It participates in energy balance, cold and diet-induced thermogenesis, and decreasing the production of reactive oxygen species (ROS) by mitochondria. All of these mechanisms are associated with the development of obesity and diabetes type 2 (3). Prolonged exposure to cold activates beige-brown like fat in WAT that expresses UCP1 to produce heat. This process is called browning. Activating UCP1 is an efficient way to waste excess energy and fuel. In fact, rats that express UCP1 in the muscle and fat tissue are less obese (3).

Scientists at Harvard University used the CRISPR/Cas9-SAM system in human preadipocytes to activate UCP1 and create brown-like cells. Then, they injected these cells into rats that were fed a high-fat diet. As a result, the rats improved glucose tolerance, insulin sensibility, and energy expenditure. Besides, the rats gained less weight when compared to control rats. The effects lasted for 12 weeks of study. The results were the same on obese animals. Obese rats that received the modified fat cells gained less weight and had decreased liver fat than controls. 

CRISPR/Cas9-SAM system

CRISPR technology has many applications, especially in the healthcare area. It can correct genetic errors or help to treat and prevent diseases. CRISPR is a natural defense mechanism of bacteria against invaders. When a foreign organism invades these bacteria, they use CRISPR-derived RNA and Cas9 protein to prevent the attack. The system will then destroy the DNA of the invader by chopping it up.

In the study, the authors used an advanced technique to edit human fat cells, the CRISPR SAM system. SAM (Synergistic Activation Mediator) is a potent transcriptional activator protein complex that uses nuclease-dead SpCas9 (dCas9) and guide RNA to bring SAM effector domains to target gene promoters, enabling site-specific transcriptional activation of the gene of interest(4). 

Future directions

The study has shown that HUMBLE cells are a potential anti-obesity therapeutic target. The authors believe that it can bring opportunities to combat obesity and other metabolic diseases. CRISPR Cas9 technology is being used in other studies involving obesity and metabolic syndrome and has shown promising results. Perhaps the future of dieting will be very different from what we know. 

Would you try cell therapy to lose a few pounds? I guess I would, why not? 

1. Wang C, Lundh M, Fu A, Kriszt R, Huang TL, Lynes MD, et al. CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice. 2020;8664(August). 
2. WHO. Controlling the global obesity epidemic [Internet]. 2003. Available from: https://www.who.int/nutrition/topics/obesity/en/
3. Coutinho G, Duarte K, Gross JL, Crispim D. The role of the uncoupling protein 1 (UCP1) on the development of obesity and type 2. 2012;1(1):215–25. 
4. Sigma Aldrich product information. 2020; Available from https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/promo_NOT_INDEXED/General_Information/1/hsamzeobul.pdf

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