Obesity is a complex disease associated with having an excess amount of body fat, which can cause complications such as metabolic syndrome, high blood pressure and diabetes. Our bodies contain two types of fat: white fat and brown fat. While white fat stores energy, brown fat burns energy and could help us lose weight. Yu-Hua Tseng-led team at Joslin Diabetes Center has described a potential cell-based therapy for obesity that would transplant human white fat cells that have been genetically modified using CRISPR to become similar to heat-generating brown fat cells.
When maintaining a normal weight, brown fat can reduce extreme glucose and lipids in the blood, and therefore lower the risk of metabolic disorders like diabetes. However, people who are obese or overweight have less of this beneficial brown fat.
In this study, the researchers create a kind of cells from human white fat cells in a progenitor phase which are yet to be fully developed into their final fat form. They employed a variant of the CRISPR-Cas9 system to increase the expression of a gene called UCP1. The UCP1 gene can activate white fat cell progenitors to develop into human brown fat-like (HUMBLE) cells.
The researchers compared transplants of HUMBLE cells against the original white fat cells in mice who were given a high-fat diet. Mice received HUMBLE transplants put on less weight than mice with transplanted white fat cells, remaining in the same range as animals who received brown fat cells. Additionally, mice with transplanted HUMBLE cells showed much greater sensitivity to insulin and had the potential to remove glucose from the blood—two main factors that are damaged in type 2 diabetes.
Perhaps unexpectedly, the researchers found that these advantages were largely caused by increased nitric oxide signaling produced by the transplanted HUMBLE cells, which activated endogenous brown fat cells found in the mice.
Reference:
1. Chih-Hao Wang et al., (2020) CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice. Science Translational Medicine. doi:10.1126/scitranslmed.aaz8664.
2. Transplanted brown-fat-like cells hold promise for obesity and diabetes. Joslin Communications. Retrieved August 26, 2020 from https://www.joslin.org/about/news-media/transplanted-brown-fat-cells-hold-promise-obesity-and-diabetes
