Images of white adipose tissue with white and beige adipocytes (purple staining identifies beige cells) for control (left) and TLE3-deleted (right) samples. [Villanueva Lab]

Our bodies contain different types of fat, not all of which is bad. Scientists at University of Utah Health have now shown that switching off a particular gene in energy-storing white fat cells frees their conversion into energy-burning, or thermogenic, beige fat cells. Tests showed that mice engineered to lack the transducing-like enhancer 3 (TLE3) gene in white fat demonstrated better control of blood glucose levels than control mice, and put on less weight when fed a high-fat diet, due to the activation of beige fat.

The findings could help point to new treatment approaches against diabetes, suggested Claudio Villanueva, PhD, assistant professor in biochemistry at the University of Utah Health. “If we could find therapeutic ways to inhibit TLE3, we may be able to develop interventions for type 2 diabetes. Therapies that help lower blood glucose levels are gravely needed.” Villanueva is senior author on the team’s published report, released today in Genes and Development, titled, “Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism.”

There are three types of fat. White fat, or white adipose tissue (WAT), is the type of energy-storing fat that is associated with obesity and diabetes. Brown adipose tissue (BAT) and beige adipose cells contain greater numbers of mitochondria, and can be triggered to burn fat molecules, rather than store fat. Under cold environmental conditions, for example, brown fat is activated to generate heat. Like brown fat, beige fat is also thermogenic, but while there are many similarities between brown and beige adipocytes, the two cell types originate from different cell lineages, and beige adipocytes are found as clusters within the WAT.

Previous studies have shown that WAT that overexpresses early B-cell factor 2 (EFB2) mobilizes more beige fat cells. The Villanueva team’s studies in engineered mice and in cultured cells have now found that TLE3, which is located relatively close to EFB2, effectively acts like a switch that blocks EFB2-related pathways from converting white fat to beige fat. This blockade holds back energy expenditure and so use of glucose.

Compared with control mice, animals in which the TLE3 gene was deleted specifically in adipocytes mobilized more beige fat cells in their WAT, but only in response to cold exposure, and not at neutral ambient temperatures. The TLE3-knockout mice also lost more weight when kept in cold environmental conditions, showed increased energy expenditure, and better glucose handling.

“We found that loss of TLE3 improved glucose metabolism in the setting of cold exposure, but not at thermoneutrality, and that this effect was correlated with the abundance of beige adipocytes,” the investigators wrote. Further tests suggested that the changes in glucose handling observed in the TLE3 conditional knockouts was likely driven by glucose uptake into beige adipose tissue, and that “increased beige adipose tissue is capable of regulating systemic glucose metabolism.” Additional in vitro analyses suggested that TLE3 was responsible for regulating thermogenesis and glucose clearance in the beige fat cells.

Interestingly, even when housed at ambient temperatures, TLE3-knockout mice gained less weight when fed a high-fat diet than did the control mice, and showed better insulin responses and glucose tolerance. “… these findings suggest TLE3 contributes to the impairment of diet-associated weight gain and glucose intolerance,” the authors wrote.

“The knock-out mice experienced enhanced energy expenditure under normal conditions and weight loss during cold conditions,” commented first author Stephanie Pearson, PhD, a researcher working in Villanueva’s lab. “Even without cold stimulation, the knock-out mice did not gain as much weight.” The results of molecular and genetic tests indicated that the increase in glucose utilization observed as a result of TLE3 deletion was likely due to increased expression of glucose transporters and genes involved in mitochondrial respiration.

Molecular studies highlighted a specific interaction between TLE3 and EBF2, indicating that TLE3 repressed EBF2 target genes, and effectively acted as a negative regulator of beige adipocyte mobilization. The authors say their results suggest “ … a new mechanism by which TLE3 attenuates the beige adipocyte gene expression program by serving as a molecular brake on EBF2.”

The group suggests the ultimate aim is to build on their work and develop TLE3-targeting drugs. “Our findings strongly support the contention that promoting an increase in beige adipocyte activity is sufficient to have beneficial effects on systemic glucose metabolism,” the authors concluded. “… despite the fact that they represent a small fraction of the total adipocyte population, beige adipocytes can exert marked effects on systemic energy balance.”

“Our story highlights that there are different types of fat cells, and TLE3 is one way to address how fat cells are programmed,” Villanueva stated. “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.”

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