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From the article:
The hormonal effect seen in these mice relates at least in part to how the female body processes vitamin A, a nutrient that is converted into a variety of compounds. These include a molecule that supports the burning of fat for energy, as well as retinoic acid, the hormone in this study that leads to the formation of visceral fat. The scientists showed that a high-fat diet functions as a switching mechanism that breaks down the fat-burning molecule and leads to activation of the enzyme and production of retinoic acid, ending in the development of visceral fat.
A year ago, Ziouzenkova’s lab identified the one of these enzymes that relates to fat accumulation: Aldehyde Dehydrogenase 1, or Aldh1a1. In the current study, she and colleagues conducted numerous experiments in mice to track the events that followed activation of this enzyme.
The researchers compared normal mice with genetically altered mice lacking the enzyme over almost a year of eating a high-fat diet. Male and female normal mice gained weight on the high-fat diet, as expected, though the females developed more visceral fat that surrounds the organs than did males, a trend also seen in humans as the result of eating excess fat. (In contrast, on a regular diet, men are more likely than women to form abdominal fat.) Both sexes of mice developed peripheral subcutaneous fat, which lies just under the skin and has some benefits.
In mice without the enzyme, however, the males developed some fat but females remained lean, and this occurred even when females ate more food than males. The researchers determined that without Aldh1a1, the females were not producing retinoic acid, and that protected them from producing visceral fat. Meanwhile, males retained the ability to produce retinoic acid.
The scientists then analyzed the proteins contained in fat tissue in male and female mice lacking the enzyme, and saw that only the females' fat cells contained high levels of a protein that releases fat from fat cells to support fat burning. This release led to production of another protein that converts fat to heat, essentially burning the fat, in the form of lipids, away.
“Without production of the hormone retinoic acid, females are burning fat and expending the energy in the form of heat. That’s why they stay very lean,” Ziouzenkova said. “And this process was specifically affecting visceral fat.”
The researchers surgically removed the ovaries of mice to test whether estrogen could be related to visceral fat production in females. As soon as the animals became menopausal and weren’t producing estrogen, they began to produce retinoic acid, which led to visceral fat formation.
“Estrogen was sufficient to protect female mice from both hormonal and, partially, diet-induced obesity. This means estrogen is suppressing activation of the obesity-inducing hormone, and as soon as we lose this estrogen during menopause, the visceral fat starts to grow,” said Ziouzenkova, also an investigator in Ohio State’s Comprehensive Cancer Center.
Using another mouse model that allowed researchers to measure hormone production specifically, the researchers observed that female mice on a regular diet barely produced retinoic acid. However, females on a high-fat diet produced high levels of the hormone and, in turn, showed a nine-fold increase in visceral fat compared to visceral fat developed by males on a high-fat diet. This was the final determinant that the high-fat diet triggers this cascade of events ending in visceral fat formation.
Because the human fat tissue samples the researchers analyzed also showed elevated levels of Aldh1a1 in cells extracted from tissue in obese women, “it could be that what we show about this hormone’s importance to visceral obesity in mice is also true for humans,” Ziouzenkova said.