Joslin Diabetes Center scientists have found how obesity drives insulin resistance, that might lead to type 2 diabetes.
They uncovered that excess weight wreaks its havoc by altering the production of proteins that affect how other proteins are spliced together.
The finding may point toward novel targets for diabetes drugs.
Scientists in the lab of Mary-Elizabeth Patti, M.D., began by examining the levels of proteins in the livers of obese people, and finding decreases in number for certain proteins that regulate RNA splicing.
"When a gene is transcribed by the cell, it generates a piece of RNA," stated Dr. Patti, who is also an Assistant Professor of Medicine at Harvard Medical School.
"That piece of RNA can be split up in different ways, generating proteins that have different functions.
"In the case of these proteins whose production drops in the livers of obese people, this process changes the function of other proteins that can cause excess fat to be made in the liver.
"That excess fat is known to be a major contributor to insulin resistance," she explained.
The investigators went on to examine a representative RNA-splicing protein called SFRS10 whose levels drop in muscle and liver both in obese people and in over-fed mice.
Working in human cells and in mice, they demonstrated that SFRS10 helps to regulate a protein called LPIN1 that plays an important role in synthesizing fat.
Their finding was published in Cell Metabolism.