When you’re stressed, do you lose your appetite or overeat? If so, it probably comes as no surprise to you that the mind and metabolism are deeply connected.
A new study from the Weizmann Institute of Science, published recently in Endocrinology, reveals a previously unknown biological link between mental and physiological stress responses. It turns out they are orchestrated by a single “mastermind” gene, a kind of master switch that is active in the brain even before birth.
This gene, called Orthopedia (or Otp), long known to play a key role in building the developing brain, remains active into adulthood, helping regulate key hormonal systems that determine how the brain controls stress, metabolism, and even behavior.
Says Prof. Gil Levkowitz, whose team conducted the study in collaboration with the lab of Prof. Alon Chen, “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.”
The Otp gene, which acts within the cell nucleus, is so essential that when it is removed from a mouse embryo, the mouse will not survive. In this new study, the team focused on the animal’s hypothalamus, which keeps basic survival functions like hunger and stress in balance. It does this by releasing chemical messengers that act both within the brain and throughout the body. “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 explains.
The team engineered a genetic tool that allowed them to selectively switch off Otp in specific cell groups, without disturbing brain development. In a series of experiments, they asked a fundamental question: Does this gene still matter in the adult brain?
The answer was a resounding yes. When Otp was disrupted, the mice’s stress systems went into overdrive. They released extra corticosterone and other stress hormones and showed depression-like behavior, developed poor stress-coping behaviors, seemed to withdraw, and quickly gave up in the face of stressful challenges.
At the same time, their metabolism went off balance. Their thyroid hormone levels fell and, as a result, body temperature dropped and cholesterol levels increased. The mice ate normally and weighed about the same as controls, yet they accumulated more body fat and their response to hunger signals weakened.
“We found that Otp acts like a central control hub in the adult brain,” says Kuperman. “It operates in stress-related cells and in cells that control the thyroid system, which affects metabolism throughout the body.”
In humans, Levkowitz notes, these systems often go hand in hand. “Depression or anxiety can look purely psychological, but in some cases, a blood test reveals low thyroid hormone levels. That can influence stress, but also cholesterol, blood sugar, and overall metabolism.”
At the cellular level, Otp works like a switchboard operator. It picks up signals arriving from the body and from the outside world and routes them to DNA, deciding which hormonal systems to activate and how to respond to changing conditions.
From an evolutionary point of view, the findings reveal remarkable efficiency. During development, Otp controls the production of substances that help brain cells specialize. Later in life, the same machinery is repurposed to deal with daily challenges, from stress to shifts in energy balance.
At the same time, the study revealed a great level of complexity, showing that Otp helps preserve a delicate balance among a multitude of components. It does not control a single pathway but several at once, sometimes producing opposing effects. In the hypothalamus, for example, it can stimulate the expression of peptides that drive hunger as well as those that call for energy expenditure, while maintaining the system’s equilibrium.
The study opens a new perspective on disorders of the brain and metabolism. It suggests examining them in light of a basic question: Are certain problems with stress resilience or metabolism rooted in early development, or do they result from a regulatory breakdown that emerges later in life?
Looking ahead, scientists may be able to target specific branches of the network controlled by Otp, rather than trying to fix the whole system at once. “We have identified a new master regulator of balance in the brain and body,” Levkowitz says. “Understanding in greater detail how it works may one day lead to more precise ways of treating different aspects of stress and metabolic dysfunction – not by shutting the system down when something is not working properly, but by nudging it back into balance.”
According to the World Health Organization, anxiety disorders affect some 359 million people, making them the most common mental health condition worldwide. Also according to the WHO, adult obesity has more than doubled since 1990; 1 in 8 people in the world currently live with obesity.
