Research Points to Fat-to-Brain Signaling Network Regulating Stress

CINCINNATI—The human body’s response to stressful situations is commonly thought to be a neuronal process, regulated entirely by the brain. But new research from the University of Cincinnati (UC) points to a fat-to-brain signaling network that serves to regulate not just homeostatic energy balance but also responses to psychological stimuli.

Results of the study are published online ahead of print in Psychoneuroendocrinology, the official journal of the International Society of Psychoneuroendocrinology. James Herman, PhD, a professor in the Department of Psychiatry and Behavioral Neuroscience in the UC College of Medicine and director of the Neurobiology Research Center of the UC Neuroscience Institute, is the senior author.

"It’s long been known that there are metabolic factors coming from fat,” says Herman, who also holds the Donald C. Harrison Endowed Chair in Medicine. "But this is essentially a factor that’s telling the brain how to regulate its stress response—literally sending a message from the fat into the brain to control how stressed out we are.”

When the body is under stress, it secretes glucocorticoids—hormones that produce an array of effects in response to the stress. Herman and his team studied the connection between glucocorticoid receptor (GR) signaling originating in fat with the brain control of both stress and metabolism in a mouse model with the receptors deleted in fat cells.

The researchers found that in the absence of glucocorticoid receptors in fat, mice were hyper-responsive to stress, indicating that the fat cells had been playing a major role in stress response signaling in normal mice.

"In other words,” Herman says, "the fat was reading stress hormone signals and sending a message to the brain that was modulating the brain activity relevant to stress response.

"If you want to think of it as a signaling pathway, the glucocorticoids were reaching the fat cells and releasing a substance that was then going into the brain as a messenger to tell the brain how to regulate a neural function.

"So rather than being totally a brain process, stress is also subject to control from other parts of the body. Messages from your fat can dictate how stressed out you are, depending on how the hormones are being processed in your fat compartments.”

The researchers note that the underlying mechanisms connecting the systems that regulate energy storage in fat cells and those that regulate the hypothalamic-pituitary-adrenal (HPA) axis, a major part of the neuroendocrine system that controls reactions to stress, are not clear and merit continued research. A member of Herman’s team, Yvonne Ulrich-Lai, PhD, has previously reported that the ingestion of comfort foods during stress exposure suppresses HPA axis activity by stimulating reward circuitry in the brain.

In the current study, the researchers note that the existence of glucocorticoid receptors in fat tissue raises the possibility of reciprocal body-to-brain feedback signals that link metabolic and neural processing in the regulation of key stress responses. This pathway, they add, may represent an important link between obesity and psychopathology—a link that could become an important factor in drug discovery.  

"The big picture implications of this research are that you are going to have to consider that anything you’re doing to modify metabolism, including modulation of fat, is going to have repercussions in the Central Nervous System. If you block the signaling in the fat, you may have traded one problem for another.”

The study was funded by grants from the National Institutes of Health.