Summary: Chronic stress combined with a high-calorie diet dramatically raises insulin in the amygdala of mice, causing insulin receptors on those neurons to become desensitized. Those insulin-resistant neurons increase production of neuropeptide Y (NPY), which drives overeating and reduces energy expenditure. This insulin–NPY pathway in the central amygdala helps explain why stress can trigger comfort-eating of calorie-dense foods and accelerate weight gain.
Source: Garvan Institute of Medical Research
Eating the wrong foods while stressed accelerates weight gain
Overeating calorie-dense foods harms health, but new research shows that stress magnifies that harm. Researchers at the Garvan Institute of Medical Research, led by Professor Herbert Herzog of the Eating Disorders Laboratory, found that when mice experienced chronic stress while having access to a high-calorie diet, they gained weight far faster than mice given the same food without stress. The team identified a specific brain pathway, regulated by insulin and involving neuropeptide Y (NPY) in the central amygdala, that drives this accelerated obesity.
Their results were published in Cell Metabolism on 25 April 2019.
“Our study suggests that what we eat during periods of stress has an outsized impact on body weight,” says Professor Herzog. “When stress and calorie-dense foods coincide, the brain’s response can create a feed-forward loop that accelerates obesity.”
The brain’s comfort-food center
While some people eat less under stress, most increase their intake—especially of foods high in sugar and fat. Food intake is primarily controlled by the hypothalamus, but emotional and anxiety-related responses engage the amygdala. The Garvan team explored how amygdala circuits contribute to stress-induced overeating.
Dr. Kenny Chi Kin Ip, the study’s lead author, explains: “When mice were chronically stressed and had access to a high-fat diet, they became obese more quickly than identical mice that ate the same diet without stress. That contrast pointed us to stress-responsive mechanisms in the amygdala.”
The key molecule identified was neuropeptide Y (NPY). NPY is produced in the brain during stress and stimulates appetite in both mice and humans. The researchers showed that blocking NPY production in the amygdala prevented the extra weight gain seen with the combined stress and high-fat diet. Without amygdala NPY, stressed mice on a high-fat diet gained weight at the same rate as unstressed controls, demonstrating a direct link among stress, amygdala NPY, and obesity.
How insulin in the amygdala drives a dangerous feedback loop
To understand what increased NPY production under stress, the researchers examined the NPY-producing neurons in the central amygdala and found they express insulin receptors. Under normal conditions, insulin is released after a meal to promote glucose uptake and convey “stop eating” signals to hypothalamic feeding centers. But the study revealed a different effect when stress and high-calorie food coincide.
The researchers measured insulin and found that chronic stress alone raised insulin slightly, but when stress was combined with a calorie-dense diet, insulin levels in the blood and the amygdala rose to roughly ten times those seen in unstressed, normal-diet mice. Sustained high insulin in the amygdala caused insulin receptors to become desensitized—these neurons lost their ability to respond to insulin. As a consequence, insulin-resistant amygdala neurons ramped up NPY production. Elevated NPY both increased food intake and suppressed energy expenditure (thermogenesis), promoting weight gain.
“We uncovered a vicious cycle,” Professor Herzog says. “Chronic high insulin driven by stress plus a high-calorie diet promotes NPY-driven eating and reduced calorie burning, which in turn fuels further overeating and obesity.”
Implications and next steps
Insulin imbalance is already central to many metabolic diseases, but this study highlights that insulin’s effects extend into emotional centers of the brain such as the amygdala. The findings suggest that preventing or reversing insulin resistance in stress-responsive brain areas could reduce stress-induced overeating and its contribution to obesity.
“We were surprised by how strongly insulin influenced amygdala circuits,” says Professor Herzog. “This work points to broader roles for insulin in brain function and motivates future studies to explore therapeutic strategies that target these pathways.”
Source:
Garvan Institute of Medical Research
Media contacts:
Viviane Richter – Garvan Institute of Medical Research
Image credit:
Garvan Institute / published in Cell Metabolism.
Original research: Closed access.
Title: “Amygdala NPY Circuits Promote the Development of Accelerated Obesity under Chronic Stress Conditions”
Herbert Herzog et al., Cell Metabolism. doi: 10.1016/j.cmet.2019.04.001
Abstract (summary):
Neuropeptide Y (NPY) powerfully stimulates feeding in the hypothalamus, but extra-hypothalamic NPY sources and their role in energy balance were unclear. The study identifies central amygdala NPY neurons as a stress-activated, feeding-stimulatory pathway that exacerbates obesity when combined with calorie-dense food. Overexpressing Npy in these neurons mimicked the obese phenotype, while selective removal of Npy prevented it. Activating central amygdala NPY neurons increased food intake and decreased energy expenditure. Mechanistically, diminished insulin signaling on these neurons under combined stress and high-fat-diet conditions drives the exaggerated development of obesity.