Transplanted brown-fat-like cells hold promise for obesity and diabetes
Obesity is the main cause of type 2 diabetes and related chronic illnesses that together will kill more people around the globe this year than the Covid-19 coronavirus. Scientists at Joslin Diabetes Center have delivered a proof of concept for a novel cell-based therapy against this dangerous condition.
The potential therapy for obesity would transplant HUMBLE (human brown-like) fat cells, human white fat cells that have been genetically modified to become similar to heat-generating brown fat cells, says Yu-Hua Tseng, PhD, a Senior Investigator in Joslin’s Section on Integrative Physiology and Metabolism.
Brown fat cells burn energy instead of storing energy as white fat cells do, says Tseng, senior author on a paper about the work in Science Translational Medicine. In the process, brown fat can lower excessive levels of glucose and lipids in the blood that are linked to metabolic diseases such as diabetes.
However, people who are overweight or obese tend to have less of this beneficial brown fat — a barrier that HUMBLE cells are designed to overcome, Tseng says.
She and her colleagues created the cells from human white fat cells in a progenitor stage (not yet fully developed into their final fat form). The investigators used a variant of the CRISPR-Cas9 genome editing system to boost expression of a gene called UCP1, which triggers white fat cell progenitors to develop into brown fat-like cells.
Transplanted into mice lacking an immune system, the HUMBLE progenitor cells developed into cells that functioned very much like the mice’s own brown fat cells, says Tseng, who is also a professor of medicine at Harvard Medical School.
Her team compared transplants of these cells versus the original white fat cells in mice who were put on a high fat diet. Mice given the HUMBLE transplants displayed much greater sensitivity to insulin and ability to clear glucose from the blood (two key factors that are impaired in type 2 diabetes).
Additionally, the mice receiving 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.
Perhaps surprisingly, the Joslin scientists demonstrated that these benefits were mostly due to signals from the transplanted cells to endogenous (existing) brown fat cells in the mice. “Cells in different tissues communicate with each other,” Tseng says. “In this case, we found that our transplanted HUMBLE cells secrete a molecule called nitric oxide, which is carried by red blood cells to the endogenous brown cells and activates those cells.”