While calorie restriction and exercise are promoted as the keys to longevity, running a negative energy balance risks compromising fertility.

In a study — the first of its kind — published in the September 21–25 issue of the Proceedings of the National Academy of Sciences, Meenakshi Alreja, associate professor of psychiatry and neurobiology at the Yale School of Medicine, and her colleagues looked into the molecular interactions that links hunger and infertility. Her research reveals a molecular pathway that becomes amplified during conditions of low food availability, and thereby shuts down the activity of brain cells that control the onset of puberty, ovulation and fertility.

“Reproduction is expensive,” Alreja said. “We cannot afford to enter puberty and reproduce unless there is enough energy.”

The team focused on a protein in the hypothalamus called melanin-concentrating hormone or MCH. MCH secretion is activated by negative energy balance — the state of burning more calories than one consumes, which is caused by calorie restriction or excess amounts of exercise. Animals put on a starvation diet are observed to have increased levels of MCH.

In this study, Yale researchers have shown for the first time that MCH prevents kisspeptin — a key reproductive hormone that triggers puberty and sustains ovulation — from acting. The action of kisspeptin involves an intricate chain reaction: Kisspeptin triggers the release of a particular hormone, called gonadotropin-releasing hormone (GnRH), from the hypothalamus, a part of the brain roughly the size of an almond. GnRH, in turn, stimulates the pituitary, a gland at the base of the hypothalamus, which targets the sex organs.

“It is an interesting story of different neuromodulators interacting,” said Anthony van den Pol, professor of neurosurgery and co-author on the study. “Kisspeptin tells neurons to release more GnRH, MCH tells it not to.”

To conduct the study, the group measured the effect of MCH on membrane potential — which led to a surprising result.

The MCH caused neural membranes to polarize to such a degree that it becomes difficult for the neurons to fire and thereby release GnRH, Van den Pol said.

“It’s the first time anyone has found such a big effect of MCH on membrane potentials,” he said.

“The link between food intake and nutrition, and reproduction and fertility isn’t well understood, and Dr. Alreja’s research gives a potential explanation,” said Ursula Kaiser, associate professor of medicine at Harvard Medical School.

Kaiser added that the study could open up doors to research that helps infertile women recover their reproductive functions.

MCH has been previously linked to obesity and depression. There is initial evidence to show that MCH antagonists — substances that block MCH from binding to receptors and thereby carrying out its function — show promise in combating both obesity and depression.