By Pesach Benson • August 26, 2026
Jerusalem, 26 August, 2026 (TPS-IL) — A gene long known for shaping the brain before birth functions as a central regulator of stress and metabolism in adulthood, Israeli scientists have found.
The findings could inform future research into disorders where stress and metabolism intersect, including anxiety, depression, obesity, diabetes and thyroid dysfunction.
The Weizmann Institute of Science study identifies a gene called Orthopedia, or Otp, as a link between biological systems often experienced together during stress. Otp helps regulate brain development before birth and controls the activity of cells involved in the body’s stress and hormonal systems. While earlier research established its role in brain development, its function in the adult brain had been largely unknown.
The new findings show that Otp does not simply build the brain and switch off.
“We found that the same genetic program that shapes the brain’s wiring during embryonic development continues to play a central role in regulating the organism’s stress response and energy balance throughout its lifetime,” said Prof. Gil Levkowitz, a member of Weizmann’s Molecular Cell Biology Department whose team conducted the study with Prof. Alon Chen’s laboratory.
The researchers focused on the hypothalamus, a small brain region that regulates hunger, sleep, reproduction, stress and metabolism through chemical messengers that act as hormones or neuropeptides. “We tend to call them hormones when they affect body organs, and neuropeptides when they act on the brain, but in both cases it’s the same molecule,” Levkowitz said.
Removing Otp from a mouse embryo is fatal. More than a decade ago, Levkowitz’s team found in zebrafish that disrupting Otp during development could impair stress responses in adulthood, and detected the Otp protein in adult fish brains, raising the question of whether the gene remained active later in life.
To answer that question, researchers switched off Otp in specific adult-mouse cell populations without affecting earlier brain development.
Beyond Brain Development
When Otp was disrupted, the mice’s stress systems became overactive, releasing excessive corticosterone and other stress hormones. Moreover the animals showed depression-like behavior, including withdrawal and reduced coping with challenges. Their metabolism was also disrupted: thyroid hormone levels fell, body temperature dropped and cholesterol rose. Although the mice ate normally and kept roughly the same body weight as controls, they accumulated more body fat and became less responsive to hunger signals.
“We found that Otp acts like a central control hub in the adult brain,” said the study’s co-author, Dr. Yael Kuperman. “It operates in stress-related cells and in cells that control the thyroid system, which affects metabolism throughout the body.”
Rather than controlling a single pathway, Otp appears to integrate signals from different systems and help keep them in balance. At the cellular level, it acts in the nucleus, translating incoming signals into changes in gene activity across multiple groups of hypothalamic cells — including populations with opposing roles in regulating hunger and energy expenditure.
The findings suggest a program that once built the brain’s architecture is later reused to manage the body’s changing demands. “A molecule we once thought of purely as a developmental regulator turns out to be a master regulator of physiological balance throughout life,” Levkowitz said. “It’s not just building the system — it keeps it running.”
The research could open new avenues for studying stress- and metabolism-related disorders, and whether some dysfunction originates in early development or reflects a breakdown in adult regulation.
Levkowitz stressed that in humans, psychological and metabolic disturbances can overlap — depression or anxiety sometimes accompany low thyroid hormone levels, which can also affect cholesterol and blood sugar. However, the study was conducted in mice and does not establish that Otp causes these conditions in humans.
The study was published in the peer-reviewed journal Endocrinology.
