Hormone that controls maturation of fat cells discovered

Hormone that controls maturation of fat cells discovered

Scientists have discovered a hormone that controls the first step in the maturation of fat cells. Its actions help explain how high-fat diets, stress and certain steroid medications cause obesity.

The new findings are published in Science Signaling.

Around the body, fat depots contain many mature fat cells and small numbers of stem cells. These stem cells can differentiate into more fat cells, but until now, no one has known how the process was triggered.

The new research shows that mature fat cells make a hormone called Adamts1 that toggles the switch controlling whether nearby stem cells differentiate and prepare to store fat. High-fat diets and glucocorticoid medications change Adamts1 production, telling nearby stem cells to begin maturing, the research found.

To identify the role of Adamts1 and understand how it works, the team conducted a series of experiments using fat cells and their precursors in a dish, followed by studies in mice and humans. They started their search by looking for genes that change activity in response to glucocorticoid medications. These medications, which include prednisone and dexamethasone, have the serious, negative side effects of promoting obesity and diabetes. The scientists wanted to understand how. Among their findings:

  • Experiments using fat tissue from mice showed that mature fat cells normally make and secrete Adamts1. Its levels drop when mice are given glucocorticoids.

  • Mice that are genetically engineered to make more Adamts1 than normal have smaller-than-normal fat depots, and fewer mature fat cells.

  • When purified Adamts1 is added to fat stem cells in a dish, it can block glucocorticoid-induced differentiation, suggesting that it normally acts as an extracellular signal.

  • Once it reaches the fat stem cell, Adamts1 transmits its message through a set of intracellular signals that overlap with the cells' glucocorticoid response pathway. A cell-signaling molecule called pleiotrophin plays an important role in the pathway; blocking the molecule's signal blocks the stem cell's entire response to Adamts1.

  • Finally, after gathering this evidence that Adamts1 is a hormone, and that it plays a big role in controlling whether fat stem cells differentiate, the researchers fed high-fat diets to mice and humans and examined how this affected the Adamts1 signal. As expected, mice became fatter after eating a high-fat diet, with new fat cells maturing mostly in the animals' visceral fat tissue, the fat located around internal organs. The mice had decreased Adamts1 in this type of fat tissue. In subcutaneous fat tissue, the fat under the skin, the opposite response was seen: there was more Adamts1 production and less fat cell maturation.

These findings are consistent with earlier research showing that more visceral, but not more subcutaneous, fat cells mature when someone eats a high-fat diet, and suggest that Adamts1 is a major regulator of this difference between the two types of fat. In humans who gained weight while eating a high-fat diet, the research team saw that the Adamts1 responses were consistent with what was seen in mice.

The results suggest how both high-fat diets and synthetic and natural stress hormones are tied to greater obesity. In essence, stress hormones send a message via Adamts1 to make more fat cells mature.

The study's results do not exclude the possibility that other, undiscovered hormones also influence fat cells' decision to mature; however, Adamts1 is probably one of the most important, senior author said. "There may be a group of regulators, but the potency of Adamts1 suggests it's a dominant signal, a major player," senior author said.

The scientists still have many questions left to answer about Adamts1, including whether it might somehow be used as a target for anti-obesity drugs.