A missing link from obesity to infertility found

(Press-News.org) Obesity and infertility frequently go hand in hand. Now, researchers reporting on studies of mice in the September issue of Cell Metabolism, a Cell Press publication, might have figured out why that is, and the results come as something of a surprise.

"There was a sense that the reproductive dysfunction was due to insulin resistance," said Andrew Wolfe of Hopkins Children's. "What we propose is a fundamentally new model showing that different tissues respond to obesity differently and that while cells in the liver and muscle become insulin resistant, cells in the pituitary remain sensitive to insulin."

Infertility arises when those insulin-sensitive pituitary cells get flooded with the rising insulin levels that are so common in obesity, the new research shows.

The pituitary is a gland found at the base of the brain. Special cells inside the pituitary known as gonadotrophs produce hormones (specifically gonadotropin-releasing hormone and luteinizing hormone, or LH) that control ovulation and fertility. It appears that insulin overstimulation in those cells sets off a kind of hormonal chain reaction that leads to infertility.

The researchers earlier discovered that gonadotrophs harbor insulin receptors, but no one really knew what the effect of insulin on those receptors was. In the new study, the researchers investigated by creating mice lacking insulin receptors only in the gonadotroph. When healthy and lean, those mice appeared to do just fine. The researchers asked what might happen if they made the mice obese by feeding them an unhealthy, high-fat diet for three months.

Normal obese mice became infertile, as expected, and showed signs of a condition that is known in humans as polycystic ovarian syndrome (PCOS). (PCOS affects as many as one in ten women and is the most common cause of infertility.) Those symptoms included high LH and testosterone levels, irregular reproductive cycles, and fewer ovulations. But obese mice lacking pituitary insulin receptors maintained normal reproductive cycles and near-normal hormone levels.

To confirm the effects on fertility, the researchers allowed the mice to mate. Lean mice with or without pituitary insulin receptors had six times the number of successful pregnancies compared to otherwise normal obese mice. The obese mice with missing pituitary insulin receptors fared almost as well; they had five times more successful pregnancies than typical obese mice.

"This suggests that insulin receptor signaling in the pituitary is fundamental to the dysregulation of LH secretion associated with the obese state," the researchers wrote.

Wolfe said these effects had been missed before because most studies of obesity and insulin resistance have focused on metabolic tissues, including fat, liver, and muscle. In fact, insulin receptors are found all over the body. That means there may be some other surprises in store as scientists begin to unravel the effects of obesity and rising insulin levels on other body tissues.

The current findings might be most relevant in humans to understanding PCOS, Wolfe said. In many cases, PCOS is related to obesity and insulin resistance. One of the most common treatments for PCOS is insulin sensitizers, which can sometimes restore fertility. Most had assumed the treatment worked by making body tissues more sensitive to insulin. The new results suggest that they could instead work by lowering insulin levels as metabolic tissues regain sensitivity to the hormone, Wolfe said.

Wolfe said they would still like to work out exactly what it is that's different about the pituitary insulin receptors that allows them to remain sensitive. They also plan to explore the role of insulin receptors found in ovarian cells.

### The researchers include Kathryn J. Brothers, Johns Hopkins University School of Medicine, Baltimore, MD Sheng Wu, Johns Hopkins University School of Medicine, Baltimore, MD ; Sara A. DiVall, Johns Hopkins University School of Medicine, Baltimore, MD ; Marcus R. Messmer, Johns Hopkins University School of Medicine, Baltimore, MD ; C. Ronald Kahn, Joslin Diabetes Center, Harvard Medical School, Boston, MA; Ryan S. Miller, Johns Hopkins University School of Medicine, Baltimore, MD ; Sally Radovick, Johns Hopkins University School of Medicine, Baltimore, MD ; Fredric E. Wondisford, Johns Hopkins University School of Medicine, Baltimore, MD; and Andrew Wolfe, Johns Hopkins University School of Medicine, Baltimore, MD.