The new target, a molecule called hVps34, is activated by amino acids (nutrients) entering the cell. This molecule triggers the activation of an enzyme, S6 Kinase 1 (S6K1), whose function UC researchers linked last year to obesity and insulin resistance.
"Insulin and amino acids both play a critical role in growth and development," said lead author George Thomas, PhD, interim director of UC's Genome Research Institute and Department of Genome Science. "Both are responsible for 'driving' cell growth. Now we have found that they actually work through independent pathways to trigger a molecule that turns on S6K1.
"Since we know S6K1 is linked to obesity and insulin resistance," he added, "learning that it can actually be turned on by more than one pathway is important, because it represents a potential target to regulate obesity."
The findings appear in the Sept. 19, 2005, online edition of Proceedings of the National Academies of Sciences (PNAS).
In 2004, Dr. Thomas led research that identified S6K1's function. Normally turned on through a series of reactions initiated by the presence of insulin, it works to drive growth. But it also has a second regulatory function.
When an organism "overfeeds," S6K1 becomes hyperactive, essentially telling insulin to stop bringing more nutrients into the cell. This hyperactive regulation actually results in insulin resistance.
"It would make sense then," said Dr. Thomas, "that once S6K1 tells insulin to stop working, this enzyme would become inactive and its other function of promoting growth would also stop."
But in laboratory studies, Dr. Thomas and his team noticed that mice on high-fat diets continued to grow, even after insulin quit performing its normal function--indicating that S6K1 was still active even after it had seemingly sealed its own fate by shutting down the very trigger that turns it on.
In single-cell organisms, said Dr. Thomas, feeding is the organism's main concern. As multicelluar organisms arose, there became a need to share nutrients within different cell types in order to develop and grow. It is believed that growth hormones, such as insulin, developed to carryout this function.
But in this transition from a self-serving single cell to a complex organism, the feeding-only amino acid pathways and the sharing, insulin pathways were merged.
Scientists have thought that amino acids began entering the cell at some point along the insulin pathway.
"We have determined that amino acids are actually entering the cell at a different location than previously thought, and that these nutrients are working independently of insulin," said Dr. Thomas.
"Knowing that S6K1 can be activated by more than one pathway will allow us to learn more about the mechanisms driving obesity and insulin resistance."
This research was funded by the National Institutes of Health Mouse Models for Human Cancer Consortium, the Air Force Office of Scientific Research, the Netherlands Genomics Initiative, and the Collaborative Cancer Research Project of the Swiss Cancer League.
Coauthors include: Johannes Bos, Marta Roccio and Fried Zwartkruis, all of the Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Centre, Utrecht, The Netherlands; Stephen G. Dann and Pawan Gulati, of the Genome Research Institute, University of Cincinnati; Manel Joaquin, Takahiro Nobukuni and So Young Kim, of the Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland, and the Genome Research Institute, University of Cincinnati; and Francois Natt, Novartis Institutes for Biomedical Research, Basel, Switzerland.