September 21, 2000
Scientists Link Energy Metabolism and Fertility
Scientists have discovered that a protein that translates insulin
signals during carbohydrate metabolism also plays an important role in
female reproduction and in the regulation of appetite and obesity in
mice.
According to the researchers, the link between energy metabolism and
fertility may underlie an evolutionarily conserved pathway that makes
humans and animals fit for reproduction. Further study of the insulin
receptor substrate-2 (IRS-2) protein may offer alternative avenues for
the treatment of diabetes and infertility.
“If these findings in mice extend to people, it looks as if the IRS-2 branch of the insulin-signaling system promotes a lot of processes that improve our fitness for reproduction.”
Morris F. White
In an article published in the September 21, 2000, issue of the
journal Nature, Howard Hughes Medical Institute investigator
Morris F. White and colleagues at Harvard Medical School report that
female mice that lack IRS-2 show severely impaired reproduction. Mice
lacking IRS-2 have defective ovaries that prevent egg release
and they show abnormal production of the egg-releasing hormone from the
pituitary gland.
The IRS family of proteins mediates the transmission of the insulin
signal to proteins in other tissues. The IRS proteins were discovered
in White's laboratory at Harvard's Joslin Diabetes Center. "In earlier
experiments in which we knocked out IRS-2 in mice, we realized
that it had broad effects on the neuroendocrine system," White said.
"Male IRS-2 knockout mice became diabetic within ten weeks, not
just because their tissues were insulin-resistant, but because IRS-2
also played a major role in keeping beta cells in the pancreas alive to
secrete insulin, compensating for the insulin resistance."
IRS-2-knockout mice mimic non-insulin-dependent diabetes, or
type 2 diabetes, which accounts for more than 90 percent of the cases
of human diabetes. "One of the most striking results in these knockouts
was that the female mice don't develop diabetes until about 20 weeks
after birth, whereas the males get diabetes at 10 weeks," said
White.
Thus, when postdoctoral fellow Deborah Burks, lead author of the
Nature paper, decided to examine fertility in the mice, she
began with the female mice since they remained healthy longer. "One of
the first things she found was that these mice overeat and gain weight,
effects not observable in the males because when their diabetes kicks
in, they begin to waste away," said White. "However, it wasn't until
she tried to breed the females that she found they were terrible
breeders. We realized that these female mice were infertile," he said.
"So, what we thought was an uninformative animal turned out to be
highly informative."
Detailed physiological studies of the females showed that their
ovaries had few mature egg-containing structures called follicles and
there was no production of luteinizing hormone that triggers egg
release. Additional studies showed that the animals' brains were
resistant to the appetite-regulating hormone leptin, causing the
animals to overeat and become obese.
"So, if these findings in mice extend to people, it looks as if the
IRS-2 branch of the insulin-signaling system promotes a lot of
processes that improve our fitness for reproduction," White says. "It
controls our food intake, makes us more fertile and allows our beta
cells to survive to secrete insulin that keeps carbohydrates and
insulin gene expression under control. IRS-2 coordinates reproduction,
feeding behavior, and internal carbohydrate homeostasis, which is
critical since pregnancy and reproduction is a very energy-intensive
process," he said.
Earlier studies by other research teams showed that a similar
linkage of reproduction and energy metabolism exists in the roundworm
C. elegans and in the fruit fly Drosophila, suggesting
that this theme is conserved throughout the animal kingdom, said
White.
The discovery of IRS-2's coordinating role suggests that insulin
resistance might be an underlying trigger of obesity in diabetics, said
White. "Insulin resistance may disrupt the leptin set point," he said.
"The person starts to eat more and gain weight, and that elevated
weight causes an additional layer of insulin resistance that causes the
weight to mushroom out of control."
The key role of IRS-2 highlights the importance of developing
anti-diabetes drugs that enhance IRS-2 activity, he said. Also, he
said, the finding hints that IRS-2 malfunctions may be at the root of
polycystic ovarian syndrome (PCOS). Women with PCOS have a range of
problems, including infertility, obesity and insulin-resistance. "While
the role of IRS-2 in these areas is currently speculative, we will try
to understand in detail how IRS-2 regulates the ovaries to promote
fertility. We will also be looking at IRS-2 function in the brain and
other tissues," said White.
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