A high-fat diet triggers chemical reactions in female mice that could explain why women are more likely than men to gain fat in the abdomen after eating excess saturated fat, new research suggests. The study also sheds light on why women gain fat following menopause.
Scientists identified events in female mice that start with the activation of an enzyme and end with the formation of visceral fat - fat that accumulates around internal organs and is linked to a higher risk for Type 2 diabetes, heart disease and cancer.
At least one function for this enzyme is the production of a powerful hormone, which then drives up the formation of visceral fat cells. The source of this hormone is vitamin A.
This enzyme appears to be activated at higher levels in females than in males when both sexes eat a high-fat diet. When researchers genetically altered mice by deleting the enzyme, female mice stayed lean, especially in the abdominal area, even when they continued to eat a lot of fat. Males without the enzyme also developed less fat, but the effect was far less significant than in females.
The results suggest the enzyme could be a target for sex-specific anti-obesity therapy.
"If you asked most people what they believe causes obesity, they would probably say high food consumption and a sedentary lifestyle. But we see that there are genetic factors telling the body what to do with fat," said Ouliana Ziouzenkova, assistant professor of human nutrition at Ohio State University and senior author of the study. "A high-fat diet acts on our genetics to make us more fat or less fat. The diet is not powerful enough to do this on its own."
Further experiments showed that fat cells in female mice lacking the enzyme could produce proteins that use fat for heat, meaning the fat in females was burned away.
Researchers also studied fat tissue from human surgery patients and found the same enzyme was present in human tissue, and its levels were markedly higher in cells extracted from the visceral fat tissue of obese women compared to cells from lean women.
Finally, the study suggested that estrogen suppresses the enzyme's activity, which might help explain why postmenopausal women with decreased estrogen in their bodies tend to accumulate fat in their bellies.
The research is published online in the journal Diabetes.
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.