Transplanted brown-fat-like cells hold promise for obesity and diabetes


Date:
August 26, 2020
Source:
Joslin Diabetes Center
Summary:
A potential therapy for obesity would transplant HUMBLE
(human brown- like) fat cells, human white fat cells that have
been genetically modified using CRISPR to become similar to
heat-generating brown fat cells.



FULL STORY ========================================================================== 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." If the HUMBLE technique continues to
prove out in pre-clinical research, it might eventually be possible to
generate this type of cell for individual patients, Tseng suggests. Such
a procedure would remove a tiny amount of a patient's white fat cells,
isolate the progenitor cells, modify those cells to boost expression of
UCP1, and then return the resulting HUMBLE cells to the patient.

However, that individualized approach would be complicated and expensive,
so the Tseng lab is pursuing two alternative routes that may be more
practical for clinical use.

One alternative is to use cells that are not personalized but instead are encapsulated via biomaterials that protect the cells from rejection by a patient's immune system. (Joslin researchers and their collaborators have
long studied such materials for cell transplants for type 1 diabetes.) The other option is gene therapies that directly express the UCP1 gene in
white fat progenitor cells in the body, so that those cells acquire
HUMBLE-like properties.

Tseng emphasizes that this research is moving ahead despite the Covid-19 pandemic, which puts people with diabetes at much higher risk of serious outcomes if they are infected.

"Employing cell-based or gene therapies to treat obesity or type 2
diabetes used to be science fiction," she says. "Now scientific advances,
such as CRISPR gene-editing technologies, will help us to improve the metabolism, the body weight, the quality of life and the overall health
of people with obesity and diabetes."

========================================================================== Story Source: Materials provided by Joslin_Diabetes_Center. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Chih-Hao Wang, et al. CRISPR-engineered human brown-like adipocytes
prevent diet-induced obesity and ameliorate metabolic syndrome
in mice.

Science Translational Medicine, Aug 26th, 2020 DOI: 10.1126/
scitranslmed.aaz8664 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200826141413.htm

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