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TLE3 genetic switch

Genetic switch controls conversion of bad to good fat

Villanueva believes these results could be used to create interventions for metabolic disorders

Researchers at University of Utah Health have identified TLE3, a genetic switch that stops the conversion of white fat into thermogenic varieties. Fat cells come in three varieties: white fat, the most common variety, is stored fat associated with metabolic disorders, like diabetes and obesity – whereas Brown and beige fat contain more mitochondria, the energy centres of the cell, allowing these varieties to burn fuel more efficiently. Brown fat is activated in cold conditions and burned to create heat. Beige fat is found in bundles nestled within white fat, but little is known about it.

The study published in Genes and Development, focused on transducing-like enhancer 3 (TLE3), a protein situated in the same region as early B-cell factor 2 (EFB2). Previous research found that white fat tissue that overexpresses EFB2 recruits more beige fat cells, but this protein-coding gene is triggered by many factors. This latest research reported that TLE3 acts like a switch, stopping EFB2 from converting white to beige fat and preventing energy expenditure and glucose use.

"Our story highlights that there are different types of fat cells, and TLE3 is one way to address how fat cells are programmed," said Dr Claudio Villanueva, assistant professor in biochemistry at U of U Health and senior author on the paper. "If we could find therapeutic ways to inhibit TLE3, we may be able to develop interventions for type II diabetes. Therapies that help lower blood glucose levels are gravely needed."

Images of white adipose tissue with white and beige adipocytes (purple staining identifies beige cells) for control and TLE3 deleted samples (Credit: Villanueva Lab)

The team deleted TLE3 in mice and placed the animals in cold conditions for several days. According to Villanueva, they tried to recreate a situation where an animal would be trying to develop beige fat cells to understand impact of the loss of TLE3. In the absence of this gene, the knock-out mice recruited more beige fat cells. The team examined the impact of the abundance of beige fat on animal metabolism.

"The knock-out mice experienced enhanced energy expenditure under normal conditions and weight loss during cold conditions," said Dr Stephanie Pearson, a researcher working in Villanueva's lab and first author on the paper. "Even without cold stimulation, the knock-out mice did not gain as much weight."

Villanueva believes these results could be used to create interventions for metabolic disorders.

"Long-term we want to identify or develop drugs that will target TLE3 that can be used as an intervention for patients with type 2 diabetes and obesity," he said.

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