Israeli scientists uncover gene’s role in regulating metabolism, mood

Israeli researchers from the Weizmann Institute of Science outside Tel Aviv have discovered that a gene once thought to play a role only in brain development before birth continues to regulate metabolism, stress and mood throughout adulthood in male mice.

The gene, known as Orthopedia (Otp), also exists in humans, raising the possibility that the findings could eventually contribute to new treatments for metabolic disorders, stress and anxiety.

The study, published in Endocrinology, found that Otp regulates several critical biological functions, including blood sugar, metabolism, cholesterol levels and potential feelings of depression.

“Otp does not stand for a one-time password,” the Weizmann Institute senior researcher Dr. Yael Kuperman said in an interview with The Times of Israel.

“The Otp gene is a multitasker that regulates physiological daily life activities that are important for our well-being,” Kuperman’s research collaborator Prof. Gil Levkowitz explained. “The gene is related to survival responses, including eating, drinking, social behaviors, reproduction and coping with stress.”

The research builds on work Levkowitz began about a decade ago studying the Otp gene in zebrafish. Zebrafish reportedly share some 70% of all human genes, making them a useful model for studying human biology.

Despite the genetic similarities, Kuperman stressed that “there is quite a distance” between humans and fish.

The new study therefore examined the Otp gene in mammals, focusing on its impact on the hypothalamus, the brain’s command center for fundamental functions such as hunger and stress.

Researchers used a mouse model and administered a drug that selectively shut down the Otp gene. Kuperman recalled that the mice responded “very fast” to the loss of Otp.

“They released extra corticosterone, which is a bona fide stress hormone, and showed depression-like behavior,” she explained.

Levkowitz noted that the mice’s resilience was also seriously eroded once Otp was switched off.

He explained that mice can usually swim in water “and when you put them in a small pool, normal mice will try to climb the walls of this pool and get out. But in the absence of Otp, the mice gave up.”

“It was like the mice had a feeling of helplessness,” Levkowitz assessed. “This was surprising,” he admitted.

The study also found that the mice accumulated a higher percentage of body fat in the absence of the Otp gene.

“In our model, the mice weren’t obese,” Kuperman said. “They didn’t eat more, but they had a higher percentage of body fat."

“When you lose Otp, you also get thyroid disturbances and heightened sensitivity to stress and depression,” Levkowitz explained.

“The results showed that a molecule we once thought of purely as a developmental regulator turned out to be a master regulator of physiological balance throughout life,” the professor argued.

“It’s not just building the system; it keeps it running,” he concluded, adding that “we need to have more basic science to understand all the connections.”

The researchers said additional studies will be needed to further understand the role of the Otp gene and determine whether the findings could eventually have implications for both male and female humans.

“This is necessary because otherwise you will develop drugs that will treat males and may act differently on females,” Levkowitz stated.