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Fatness in older women 'may not be their fault'

‘Why women pile on the pounds as they age - and it may not be their fault,’ is the headline in the Daily Mail.

The story is based on a mouse- and laboratory-based study that found that the enzyme Aldh1 plays a key role in fat formation. Specifically, it can increase levels of what is known as visceral fat (a potentially dangerous type of fat that develops around internal organs), which can increase your risk of developing chronic conditions such as heart disease and type 2 diabetes.

In females oestrogen seems to hold back a form of Aldh1 called Aldh1a3, which may help lessen the effect of the enzymes on fat levels to a certain extent.

But as oestrogen levels fall during the menopause, levels of Aldh1a3 may rise, making menopausal women more likely to gain visceral fat. This could explain why many women put on weight as they go through the menopause.

It should be borne in mind, however, that the majority of this research was performed in mice. Although Aldh1 enzymes might be an attractive target for obesity treatments, as the Daily Mail suggests, these are a long way off. However, the results of the complex animal and human studies carried out by the researchers suggest that further investigation is worthwhile.

Sadly, for those of us suffering from middle-age spread, there are currently no short-cuts to weight loss - just the tried-and-tested methods of eating less and exercising more.

Where did the story come from?

The study was carried out by researchers from The Ohio State University, the University of California, Sanford-Burnham Medical Research Institute, USA, and Karl-Franzens University, Austria. It was funded by the College of Education and Human Ecology and the Food Innovation Centre at The Ohio State University, and a pilot industry partnership.

The individual researchers were also supported by grants, including one from the US National Institutes of Health.

The study was published in the peer-reviewed journal Diabetes.

The study was generally accurate in the Daily Mail, although they sometimes confuse members of the Aldh1 family of enzymes. Despite this confusion, the Mail should be congratulated for summarising an extremely complicated piece of research into something both reasonably accurate and understandable.

What kind of research was this?

This was an animal- and laboratory-based study that aimed to investigate why there are differences between males and females in the location of fat deposits.

Studies of this type are interesting primary research, but require much more work before they can be translated into findings that are useful for human health.

What did the research involve?

The researchers performed several different animal- and laboratory-based experiments to investigate why there are differences between males and females in the location of fat deposits. They were particularly interested in an enzyme called Aldh1, which is present in three forms in mice: Aldh1a1, Aldh1a2 and Aldh1a3.

Aldh1a is an enzyme that produces the chemical retinoic acid. This in turn has a role in cell differentiation (the process where less specialised cell types develop into more specialised cells, such as fat cells) and metabolism in adipose (fat) and other tissues.

Retinoic acid is primarily produced by Aldh1a1 in visceral fat, and by Aldh1a1 and Aldh1a3 in subcutaneous fat (fat that develops underneath the skin).

The researchers genetically manipulated mice so that they lacked the enzyme Aldh1a1. They fed the mice a high-fat diet, and monitored fat deposits under the skin (subcutaneous fat) and fat stored around the organs (visceral fat). They then looked at:

  • differences in the proteins made in the visceral fat in normal mice and modified mice lacking Aldh1a1
  • differences in the Aldh1 enzyme distribution between males and females
  • whether oestrogen could play a role in the regulation of these enzymes and the deposition of fat
  • fat from obese male and female humans

What were the basic results?

The researchers found that:

When fed a high-fat diet, normal females accumulate more visceral fat (fat around the internal organs) than normal male mice. The accumulation of fat under the skin (subcutaneous fat) is similar in normal male and female mice.

Female mice lacking Ald1h1a1 accumulated significantly less visceral fat when fed a high-fat diet than normal female mice. Male mice lacking this enzyme had a similar deposition of visceral fat to normal male mice, except after prolonged exposure to the high-fat diet, where the mice lacking Ald1a1 had less visceral fat.

The researchers identified proteins that were expressed differently in the visceral fat from the modified mice and normal mice. They found that enzymes involved in the use of fat to form heat were present in females, possibly explaining why the female mice did not gain visceral fat, as they were instead “burning” it to form heat.

There are other similar enzymes to Ald1h1a1 - these are present at higher levels in male mice compared with female mice. The researchers found that the differences were partially due to oestrogen.

If the ovaries of normal female mice were removed, the researchers found female mice expressed more of a form of Aldh1 called Aldh1a3, and the mice gained weight and visceral fat.

The researchers also found that male and female responses to high fat diets were different. When mice were fed a normal diet, there was greater activation of genes that respond to retinoic acid in the visceral fat of male mice compared with female mice. However, when the mice were fed a high-fat diet, there was an activation of genes that respond to retinoic acid in the visceral fat of female mice (measured by the reporter as an 860% increase), whereas the activation of genes in male mice remained at the normal diet level.

When looking at human fat, the researchers found that forms of the Ald1h1 enzyme were higher in obese patients compared with lean patients.

How did the researchers interpret the results?

The researchers conclude that in this study they have found that a high-fat diet and/or a lack of oestrogen increases the formation of visceral fat. There seems to be a switch in females, through Aldh1, between the breakdown and storage of fat.

After the menopause, the lack of oestrogen may mean that the body breaks down less fat and stores more, which may account for the weight gain many women experience during the menopause.

Conclusion

This mouse- and laboratory-based study has found that the enzyme Aldh1 plays a key role in fat formation. In females, oestrogen seems to repress the expression of one form of Aldh1, called Aldh1a3. A high-fat diet increases Aldh1a1.

A high-fat diet seems to have different effects on females and males, and appears to signal the deposition of visceral fat around the organs and activate genes sensitive to retinoic acid - which is produced by Aldh1 enzymes - in females.

The researchers have used this finding to suggest that fat deposition in women might change while they age, due to the decrease in oestrogen at menopause and the corresponding increases in Aldh1a3 levels.

It should be borne in mind that the majority of this work was performed in mice, and that although the Aldh1 enzymes might form attractive targets for obesity treatments, as the Daily Mail suggests, these are a long way off.

It is highly likely that this research will lead to further studies, as creating a safe and effective anti-obesity medication is one of the holy grails of pharmaceutical research, not least because it has the potential to earn billions for the drug company that makes the breakthrough.

  • Yasmeen R, Reichert B, Deiuliis J, et al. Autocrine Function of Aldehyde Dehydrogenase 1 as a Determinant of Diet- and Sex-Specific Differences in Visceral Adiposity. Diabetes. Published online January 2013

 

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