After 25 years studying the links between Type 2 diabetes and obesity, Jackie Stephens and a team of LSU researchers have identified a new player, the protein oncostatin, that could help us better understand how inflammation in fat tissue affects insulin resistance.
“In Baton Rouge and the surrounding parishes, the incidence of diabetes is 50 percent greater than the national average,” says Stephens, Claude B. Pennington Jr. Endowed Chair in Biomedical Research at Pennington Biomedical Research Center and professor of biological sciences in the LSU College of Science. “Type 2 diabetes tends to be a slow killer rather than a quick one and it is a huge threat to the state of Louisiana.”
Stephens and a team of scientists from LSU, Pennington Biomedical Research Center and the LSU School of Veterinary Medicine are investigating the inflammatory aspect of diabetes by observing the direct effects of oncostatin, or OSM, a protein produced in fat, also known as adipose tissue. Until a recently published study, oncostatin was known to be associated with inflammation in adipose tissue, but the exact function of the protein was largely unknown. For example, researchers did not know whether or how the protein could affect different types of cells that are present in fat.
“One thing we’ve known about diabetes since 2003 is that in addition to being a metabolic disease, it is also an inflammatory disease. This inflammation is prominent in the fat cells of people with type 2 diabetes,” says Stephens
Adipose tissue is key to maintaining an environment that allows the body’s metabolism to work at optimal efficiency. In other words, adipose tissue plays a role in systematic metabolic homeostasis. Cell signaling proteins secreted by adipose tissue are critical to the tissue’s function and have been shown to contribute to the insulin resistance often observed in obesity. Insulin resistance is the single best predictor of type 2 diabetes.
Stephens says there have been a number of studies that have shown a link between the protein oncostatin, inflammation and metabolic disorders. Elevated oncostatin levels are markers for a number of inflammatory diseases like rheumatoid arthritis, liver disease and several types of cancers. To better understand the role of oncostatin in adipose tissue inflammation, Stephens and her research team used mouse models to examine the effects of the protein in obese mice. The researchers compared oncostatin activity in three different types of mice. These included normal or "wild-type" mice with a normal diet and natural oncostatin activity, mice fed a high-fat diet for six months, and genetically modified mice.
“We created this really sophisticated mouse model where we were able to knock out the receptor for oncostatin in fat tissues to show that this inflammatory mediator can also promote insulin resistance,” says Stephens.
In the obese mice fed a high-fat diet over six months, the population of adipose tissue immune cells changed due to an increase in oncostatin produced by non-adipocyte cells, or non-fat cells, rendering the mice insulin resistant. The obese genetically modified mice were also insulin resistant. In the genetically modified mice however, the oncostatin was not able to signal in a paracrine manner on adipocytes and yet adipose tissue inflammation increased in these mice. The researchers concluded that the oncostatin appeared to function as a paracrine or autocrine mediator in adipose tissue cell types other than adipocytes, particularly immune cells, and acted to further promote adipose tissue inflammation.
The genetically modified mice also experienced a significant increase in the length of their thigh bones. This peculiar bone phenotype was discovered by Margaret McNulty, assistant professor in comparative biomedical sciences in LSU’s School of Veterinary Medicine.
“Adipocytes are derived from the same lineage as bone cells (mesenchymal stem cells), thusly, there is the potential for connections between the two tissues. However, the limited data on the bone phenotype in this paper doesn’t provide enough evidence to correlate what we’re seeing in the boney tissue to treatments for adipose tissue inflammation,” says McNulty.
Stephens adds, “It was not entirely surprising that we observed a change in the bone of our transgenic mice. Now, we know that when we specifically modulate OSM action in fat, we are also affecting bone development.”
Stephens and her research group are collaborating with scientists at the Indiana University Medical School and Pennington to show that the results are translatable to humans. The team’s complete research results were published in the August 12 edition of the Journal of Biological Chemistry.
Carrie Elks, co-author of the journal paper and assistant professor of research at Pennington, was recently awarded a four-year grant from the National Institutes of Health to continue this project.
“Our next steps are to more closely examine the immune cells in the fat tissue of these mice to see how they are promoting inflammation in this model. We are also going to remove the oncostatin receptor in fat cells of mice only after they become obese and compare those results to those described in the publication,” says Elks.