Genetic Aspects Of Obesity And Diabetes In Women

Manipulating the performance of mitochondria

Karen Reue, PhD - Research scientist researching obesity and diabetes in women

Karen Reue, PhD, a professor of human genetics at UCLA, works to identify the genes and genetic mechanisms that underlie both obesity and diabetes. Her work is revealing correlations between genes, the X chromosome and treatment of high cholesterol and diabetes.

Isolating Lipin-1 to regulate weight 

Reue and her team have already isolated one “fat gene.” Now, they are closing in on a gene that increases a woman’s susceptibility to metabolic disorders. They were the first to:

  • Isolate the lipin-1 gene (the founding member of the three-gene lipin family)
  • Link mutations in lipin-1 to severe fat gain (obesity)
  • Further link lipin-1 mutations to lipodystrophy, a condition of severe weight loss in which the body cannot produce fat

She has found that the lipin-1 gene functions in diverse ways to affect body weight. Mice with excess lipin-1 protein gained weight because their bodies stored more fat and their metabolism was repressed, causing them to burn fewer calories than normal mice.

The XX Chromosome’s 'Double Whammy'

Reue is uncovering the genetic mechanisms that underlie sex differences in obesity and risk of diabetes. Her work asks how much can be explained by differences in male/female hormones, versus the XX versus XY genetic differences between males and females.

Reue and her colleagues study mice with four 'sexes':

  • Typical XX (female) and XY (male) mice
  • XX (male) and XY (female) mice

This work allows researchers to distinguish:

  • Differences that result from male vs. female gonadal hormones
  • Differences that result from XX vs. XY chromosome complement

Reue has found that regardless of hormones, having two X chromosomes versus having an X and a Y chromosome predisposes a mouse to obesity. She has learned that XX mice:

  • Gain more weight when they are eating a normal chow diet, which has very low fat content
  • Have a particularly increased accelerated weight gain when they are fed a high-fat diet
  • Develop all of the comorbidities that go along with obesity, such as fatty liver and insulin resistance

All together, these conditions can snowball into Type 2 diabetes. To learn more about all of the projects around this area of research, visit the Reue Lab.

Reue Lab

Silenced X gene not so quiet

Reue believes the gene responsible for this “evolutionary advantage” is on a female’s second X chromosome. Traditionally, researchers have considered this chromosome to be transcriptionally inactivated, meaning the body’s metabolism disregards it.

“It has long been thought that the genes on one of the two X chromosomes that a female inherits are not expressed, so both men and women have only one functional X chromosome. It turns out that this is not quite true,” she says. “A handful of genes are expressed on the inactivated X chromosome in females. Those genes are likely candidates for the effect of the second X chromosome on obesity.”

After testing those genes one by one in mice, Reue has settled on a promising candidate and is now conducting tests to validate that discovery.

The Statin Effect in women

As an offshoot of her work on diabetes, Reue is searching for the genes that dictate how the use of statins to control cholesterol levels induces diabetes in some people. The statin effect is far more prevalent in women than men.

“We’re only now recognizing this novel consequence of statin use,” she says. “By modeling statin adverse effects in the mouse, we hope to identify the corresponding genetic and sex components that dictate who may develop statin-related diabetes.”

Karen Reue, PhD

Females get a double whammy, because female gonadal hormones also influence food intake and body weight. There are evolutionary reasons why a little extra fat might be helpful in women – as a survival buffer during pregnancy, for example. But in the modern world, this advantage becomes a liability.

Karen Reue, PhD