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mTORC2 signaling study published in Cell Reports

Date Posted: Friday, October 16, 2020

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In people who are overweight or obese, storing excess nutrients in fat can protect them from developing insulin resistance and type two diabetes, at least to a point, before something breaks down. Newly published data in the scientific journal Cell Reports describes research in the Guertin Lab, knocking out a gene, specifically in a precursor cell population, that gives rise to new fat cells, to understand how to make a healthy fat cell. The scientists study a signaling pathway called mTOR Complex 2 (mTORC2).  

“We’re excited, because it looks as if mTORC2 is involved in the process of forming a healthy insulin sensitive fat cell at least in part through regulating gene called PPAR gamma,” said David Guertin, PhD.

PPAR gamma is considered to be the master regulator of fat formation because it turns on many genes required to turn a precursor stem cell into a mature fat cell. It has many targets, and mTORC2 seems to specifically regulate a subset of those targets that are important for making and storing fat (called lipids) in the cells. Within cells, altered mTORC2 signaling is associated with type 2 diabetes, and appears to be most important for establishing how a cell handles fats and lipids.

“We’ve found a key regulatory input that helps to establish not only insulin sensitivity, but the ability of fat tissue to use insulin to take up and store energy as lipids,” said Dr. Guertin.

For the first time, this establishes mTORC2 as a key regulator of a developing fat cell. During development, it appears to be required for many pathways that handle how adipocytes (fat cells) take care of lipids. Adipocytes are the major energy storage sites in the body and they provide critical endocrine functions that control how the body manages nutrients.

“The cells still become fat cells, but they’re smaller and have a disrupted lipid handling pathway,” said Dr. Guertin. “They also have some downregulation of proteins that respond to insulin. Now we’re trying to determine the mechanism that connects the mTORC2 activity to PPAR gamma.”

The Guertin Lab will conduct additional experiments to determine how and why adipocyte function is controlled by mTORC2.