'Dual Switch' That Controls Both Fat Formulation and Obesity Cure

A new study has identified a key regulator of fat cell development that may provide a target for obesity and diabetes drugs.

The scientists at the Scripps Research Institute and collaborating institutions described a protein called TLE3 that acts as a dual switch to turn on signals that stimulate fat cell formation and turn off those that keep fat cells from developing. TLE3 works in partnership with a protein that is already the target of several diabetes drugs, but their use has been plagued by serious side effects.

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"There is definitely a need for alternative drug targets," said Scripps Research Associate Professor Enrique Saez, who led the study with Professor Peter Tontonoz of Howard Hughes Medical Institute and the University of California, Los Angeles (UCLA).

"Our goal is to understand how fat cells form so that we can develop better treatments for obesity and related disorders," added Saez.

In today's culture, fat has a bad reputation but it's not all justified. Adipose (fat) tissue stores excess fatty substances, called lipids, obtained from the diet to prevent them from accumulating in other tissues, such as liver and muscle, where they would cause damage. Fat tissue also produces hormones that help control the balance of insulin in the blood and regulate energy production and consumption.

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But in some conditions, such as in obesity, adipose tissue no longer functions as it should.

"When we have too much fat, it tends to become dysfunctional," said Saez.

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"That is when you run into problems like insulin resistance and diabetes," added Saez.

To find additional players in adipocyte formation, Saez, Tontonoz, and colleagues induced cells growing in a dish to differentiate into adipocytes. The scientists then individually tested the ability of 18,000 genes to augment the conversion of undifferentiated cells into fully functioning adipocytes, looking for genes that might play a role in this process.

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In this way, they identified the gene encoding the TLE3 protein, which had never before been linked to fat development.

Saez, Tontonoz, and colleagues discovered that PPAR? turns on the production of TLE3. TLE3 then forms a complex with PPAR? and helps it turn on other genes and pathways needed for adipocyte formation.

In addition, TLE3 turns off Wnt signaling.

"This is how Wnt gets shut off to allow differentiation to occur," said Saez.

"TLE3 has a dual function: it is a positive regulator for PPAR? and a negative regulator for Wnt," added Saez.

The study is detailed in the latest issue of Cell Metabolism.

Source-ANI