For many years, researchers have envisioned mapping all the cells in adipose tissue. However, this has been virtually impossible because of their size. Now researchers have finally succeeded in characterising all the cells in both mice and humans, with those in humans differentiated by body-mass index (BMI). The result is a single-cell atlas of human and mouse white adipose tissue and a goldmine of knowledge for researchers to explore.
Fat is not merely fat.
Adipose tissue comprises many types of cells, which in addition to the actual adipocytes (fat cells) includes immune cells, vascular cells, adipose stem and progenitor cells and many more. In fact, only about half of adipose tissue is adipocytes.
Researchers have long envisioned mapping all the cells in adipose tissue to determine how it reacts when people develop obesity or develop diseases such as type 2 diabetes.
So far, however, the large size of the adipocytes has precluded mapping them all at a single-cell level.
Researchers have now solved this problem, and the result is a complete atlas of all the cells in adipose tissue.
“The mapping of the adipocytes in adipose tissue enables us to start examining the interactions between individual cell types in the adipose tissue and how they change as people become overweight and their BMI increases. The atlas of adipose tissue can also be used to identify whether the observations we discovered in mouse experiments are also valid for humans,” explains the first author, Margo Emont, Instructor in Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
The research has been published in Nature.
Adipocytes are too large and fragile to analyse using traditional methods
The problem with mapping the adipocytes so far has been that they are too large for conventional methods of examining gene expression.
When researchers map the function of individual cells in tissue, they break down the tissue into the individual cells and run them through a machine that maps each cell’s genetic expression. The machine measures the presence and concentrations of mRNA, which indicates which genes are active in the cells.
This technology can be used to determine how the genetic expression changes in the individual cells, such as the immune cells, as a mouse or human becomes overweight.
“These changes can be better examined by looking at an individual cell rather than a whole tissue sample. Examining adipocytes is impractical because they are very large compared with other cells and cannot pass through the machines that map the genetic expression at the single-cell level,” says Margo Emont.
Mapping genetic expression through single-nucleus sequencing
To solve the problem of the large adipocytes, the researchers further developed the method to investigate gene expression at the single-cell level. Instead of performing single-cell sequencing on whole cells, the researchers only sequenced the cell nuclei, which contain a representative subset of all the mRNA present in the cell, because the nuclei of small and large cells are about the same size.
Using this method, the researchers characterised all the cells in adipose tissue at the single-cell level and thus, for the first time, also the adipocytes.
The researchers then comprehensively analysed adipose tissue from both mice and people. The tissue samples were taken both from with people whose BMI differed and adipose tissue from different places on and in the body.
“We found many differences between the types of adipose tissue and between adipose tissue from different people across a range of body weight. For example, some subpopulations of adipocytes change their genetic expression as BMI changes, and the genetic expression differed greatly between adipocytes from subcutaneous abdominal adipose tissue and that around the organs,” explains Margo Emont.
Available to everyone
The researchers entered the large quantity of data they collected on adipose tissue from both humans and mice into an online tool that other researchers can access and explore.
This means that, regardless of the perspective researchers have on adipose tissue research, they can get new insights by searching the database.
Most researchers carry out experiments on mice and not on humans, and these researchers can now determine whether the observations they discover in the mice are relevant for humans or whether the cells, signalling pathways and protein expression they examine only apply to mice.
Another application may be in the interactions between cells in the adipose tissue. Which cells affect the genetic expression of which cells? How do they achieve this, and can some of the proteins involved be relevant in a medical context?
“We have worked hard to make the database easy to access for other researchers. We hope that many researchers will make use of this resource in their research. Just by looking in the database, you can formulate different hypotheses about how the various cells in adipose tissue communicate with each other, and you can then go back to the laboratory and determine whether this is really the case. Right now, our atlas is the best opportunity to examine these things,” concludes Margo Emont.