CINCINNATI--University of Cincinnati (UC) scientists have identified a possible new target for treating obesity and diabetes.
The new target, a molecule called hVps34, is activated by aminoacids (nutrients) entering the cell. This molecule triggers theactivation of an enzyme, S6 Kinase 1 (S6K1), whose function UCresearchers linked last year to obesity and insulin resistance.
"Insulin and amino acids both play a critical role in growthand development," said lead author George Thomas, PhD, interim directorof UC's Genome Research Institute and Department of Genome Science."Both are responsible for 'driving' cell growth. Now we have found thatthey actually work through independent pathways to trigger a moleculethat turns on S6K1.
"Since we know S6K1 is linked to obesity and insulinresistance," he added, "learning that it can actually be turned on bymore than one pathway is important, because it represents a potentialtarget 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'sfunction. Normally turned on through a series of reactions initiated bythe presence of insulin, it works to drive growth. But it also has asecond regulatory function.
When an organism "overfeeds," S6K1 becomes hyperactive,essentially telling insulin to stop bringing more nutrients into thecell. This hyperactive regulation actually results in insulinresistance.
"It would make sense then," said Dr. Thomas, "that once S6K1tells insulin to stop working, this enzyme would become inactive andits other function of promoting growth would also stop."
But in laboratory studies, Dr. Thomas and his team noticedthat mice on high-fat diets continued to grow, even after insulin quitperforming its normal function--indicating that S6K1 was still activeeven after it had seemingly sealed its own fate by shutting down thevery trigger that turns it on.
In single-cell organisms, said Dr. Thomas, feeding is theorganism's main concern. As multicelluar organisms arose, there becamea need to share nutrients within different cell types in order todevelop 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 acomplex 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 thecell at a different location than previously thought, and that thesenutrients are working independently of insulin," said Dr. Thomas.
"Knowing that S6K1 can be activated by more than one pathwaywill allow us to learn more about the mechanisms driving obesity andinsulin resistance."
This research was funded by the National Institutes of HealthMouse Models for Human Cancer Consortium, the Air Force Office ofScientific Research, the Netherlands Genomics Initiative, and theCollaborative 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 forBiomedical Genetics, University Medical Centre, Utrecht, TheNetherlands; Stephen G. Dann and Pawan Gulati, of the Genome ResearchInstitute, University of Cincinnati; Manel Joaquin, Takahiro Nobukuniand So Young Kim, of the Friedrich Miescher Institute for BiomedicalResearch, Basel, Switzerland, and the Genome Research Institute,University of Cincinnati; and Francois Natt, Novartis Institutes forBiomedical Research, Basel, Switzerland.
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