Brown Fat Stem Cells for Treating Diabetes and Obesity


Mammals have two main types of fat: brown fat and white fat.  Brown fat is especially abundant in newborns and in mammals undergoing hibernation.  The primary function of brown fat is to produce body heat so that the animal does not shiver.  In contrast to white fat cells, which contain a single lipid droplet, brown fat cells contain numerous smaller droplets and a higher number of mitochondria, and it is these mitochondria and their high iron content that makes this fat tissue brown.  Brown fat also contains more small blood vessels than white fat, since it has a greater need for oxygen than most tissues.

Recently, researchers at the University of Utah School of Medicine have identified stem cells from brown fat.  The principal researcher of this project, Amit Patel, associate professor of medicine, refuted an old dogma – that adult humans do not possess brown fat.  Children have large amounts of brown fat that is highly metabolically active.  Children can eat a great deal and not gain any weight, relative to adults.  Adults, on the other hand, have an abundance of white fat, and accumulation of white fat leads to weight gain and cardiovascular disease (something not seen in brown fat).  As people age, the amount of white fat increases and the amount of brown fat decreases, which contributes to the onset of diabetes and high cholesterol.

As Patel put it, “If you have more brown fat, you weigh less, you’re metabolically efficient, and you have fewer instances of diabetes and high cholesterol.  The unique identification of human brown fat stem cells in the chest of patients aged 28-34 years is profound.  We were able to isolate the human stem cells, culture and grow them, and implant them into a pre-human model which has demonstrated positive effects on glucose levels.”

In vitro differentiation of brown adipose derived stem cells (BADSCs). (A) Gene expression profile comparing undifferentiated BADSCs to undifferentiated white adipose derived stem cells derived from subcutaneous adipose tissue. Genes in red are associated with brown fat phenotype. (B) Gene expression profile comparing undifferentiated brown adipose derived stem cells to differentiated brown adipocytes. Biological replicates performed in triplicate from a single clone were used for gene expression profile. (C) Transmission electron microscopy of 21 day brown adipocyte differentiation induced with fibronectin type III domain containing 5 (FNDC5) demonstrate multiocular intracytoplasmic lipid vacuoles and mitochondria (arrows). (D) Alizarian red staining of brown adipose derived stem cells induced to undergo osteogenesis. (E) Alcian blue staining of brown adipose derived stem cells directionally differentiated into chondrocytes. (F) Fatty acid binding protein 4 (FABP4) immunocytochemistry of brown adipose derived stem cells induced to undergo white adipogenesis. (G) Undifferentiated BADSCs. (H) Western blot 21 days post FNDC5 induction. Lane 1 brown adipose derived stem cells directionally differentiated into brown adipocytes. Lane 2 non- FNDC5 cells.
In vitro differentiation of brown adipose derived stem cells (BADSCs). (A) Gene expression
profile comparing undifferentiated BADSCs to undifferentiated white adipose derived stem cells
derived from subcutaneous adipose tissue. Genes in red are associated with brown fat phenotype. (B)
Gene expression profile comparing undifferentiated brown adipose derived stem cells to differentiated
brown adipocytes. Biological replicates performed in triplicate from a single clone were used for gene
expression profile. (C) Transmission electron microscopy of 21 day brown adipocyte differentiation
induced with fibronectin type III domain containing 5 (FNDC5) demonstrate multiocular
intracytoplasmic lipid vacuoles and mitochondria (arrows). (D) Alizarian red staining of brown
adipose derived stem cells induced to undergo osteogenesis. (E) Alcian blue staining of brown adipose
derived stem cells directionally differentiated into chondrocytes. (F) Fatty acid binding protein 4
(FABP4) immunocytochemistry of brown adipose derived stem cells induced to undergo white
adipogenesis. (G) Undifferentiated BADSCs. (H) Western blot 21 days post FNDC5 induction. Lane 1
brown adipose derived stem cells directionally differentiated into brown adipocytes. Lane 2 non-
FNDC5 cells.

This new discovery of finding brown fat stem cells may help in identifying potential drugs that may increase the body’s own ability to make brown fat or find novel ways to directly implant brown fat stem cells into patients.

Betatrophin, a New Liver Protein that Increases the Number of Insulin-Making Cells


Douglas Melton’s laboratory at the Harvard University Stem Cell Institute in Cambridge, Massachusetts has discovered a liver hormone that stimulates the growth of insulin-secreting beta cells in the pancreas. This discovery could very well lead to new treatments for diabetes.

This hormone, betatrophin, was induced in mice by treating them with a peptide that binds to insulin receptors. The insulin-occupied insulin receptors were unable to bind insulin, and that caused the animals to be resistant to insulin. Under these conditions, the livers of these mice produced betatrophin, which caused the animals’ insulin-secreting pancreatic β cells to proliferate. Melton and others searched for genes that showed increased activity under these insulin-resistant conditions, which allowed Melton and colleagues to isolate and identify betatrophin.

According to Melton and his co-workers, “Transient expression of betatrophin in mouse liver significantly and specifically promotes pancreatic β cell proliferation, expands β cell mass, and improves glucose tolerance” (from the abstract of the paper).

Further experiments showed that when eight-week-old mice injected with betatrophin there was an average 17-fold rise in the proliferation of their insulin-secreting pancreatic β cells. Melton and others published these results in the journal Cell. Fortunately, betatrophin is also found in the human liver, according to Melton and others.

“It’s rare that one discovers a new hormone, and this one is interesting because it’s so specific,” says Melton. “It works only on β cells and it’s so robust and so potent.”

Pancreatic β cells replicate rapidly during embryonic and neonatal stages in both mice and humans, but beta cell growth decreases dramatically in adults. A decrease in the function of beta cells late in life is the main cause of type 2 diabetes. Type 2 diabetes is a metabolic disorder that affects more than 300 million people worldwide. In the United States alone, the two forms of diabetes — type 2 and type 1— account for US$176 billion in direct medical costs each year.

Melton hypothesized that injections of betatrophin once a month, or even once a year, could potentially induce enough activity in pancreatic β cells to provide the same level of blood-sugar control for people with type 2 diabetes as do daily insulin injections. According to Melton, betatrophin would cause fewer complications, since the body would make its own insulin. He also hopes that betatrophin will be able to help people with type 1 diabetes.

Matthias Hebrok, director of the University of California, San Francisco, Diabetes Center, says that the work “is a great advance”. “The findings are very interesting,” he says, although he would like to see the experiments repeated in older mice. “Do mice that are on their way to becoming diabetic at an advanced age truly have an increase in proliferative capacity upon treatment with betatrophin?” he asks. This is a fair question.

Henrik Semb, managing director of the Danish Stem Cell Center in Copenhagen, says that “the identification of a factor, betatrophin, that stimulates mouse β-cell replication with remarkable efficiency is a very important discovery, because it provides the starting point for further studies to elucidate the underlying mechanism of β-cell replication.”

β-cell replication has proved difficult to control in humans, but producing enough betatrophin for testing in human clinical trials will take about two years, according to Melton, who is also working to identify the hormone’s receptor and its mechanism of action.

References: Yi, P., Park, J.-S. & Melton, D. A. Cell http://dx.doi.org/10.1016/j.cell.2013.04.008 (2013).