Some of us lose our appetites when under stress, whereas some of us might overeat. Whichever tendency we show, when the pressure is on we’re likely to pick high-sugar, high-fat “comfort” foods. Rodent studies led by Herbert Herzog, PhD, head of the Eating Disorders laboratory at the Garvan Institute of Medical Research, have now shown that animals put on more weight when fed a high-fat diet (HFD) and subjected to stress, than they do eating the same amount of high-fat food, without the added stress.

The findings suggest that the additional weight gain is triggered by activation of a molecular pathway in the brain that is controlled by insulin, and which results in reduced energy expenditure, so the body doesn’t use up as many calories. “This study indicates that we have to be much more conscious about what we’re eating when we’re stressed, to avoid a faster development of obesity,” Herzog said. The researchers reported their findings in Cell Metabolism, in a paper titled, “Amygdala NPY Circuits Promote the Development of Accelerated Obesity Under Chronic Stress Conditions.”

Our bodies adapt to physiological and psychological stressors to maintain homeostasis. However, chronic stress can have detrimental effects on many organ systems and change our eating habits, weight, and fat distribution, the authors noted. And while animal studies have shown that stress tends to be associated with a decrease in food intake, rats under stress will preferentially pick and increase their intake of high-fat, high-sugar foods.

Humans also tend to adopt one of two eating patterns when they are stressed. Some will respond by eating less and losing weight, but most report increasing food intake, the team commented. And whether the tendency is to reduce or increase how much we eat, stress also commonly results in us choosing foods with higher fat and sugar content, the authors continued. “… during times of stress, most people report an increase in the intake of highly palatable foods, independent of overall hyperphagia or hypophagia.”

Signaling between the hypothalamus, pituitary, and adrenal glands (the HPA axis) is implicated in feeding behaviors during stress, and is “tightly intertwined” with hormonal systems that are involved in appetite regulation, they explained. Studies have also suggested that energy balance is in part regulated by HPY activated feedback loops involving the hormones insulin and leptin, glucocorticoids, and neuropeptide Y (NPY).

NPY is an anxiolytic peptide that is expressed in different areas of the amygdala, and has also been implicated in the regulation of “emotional eating,” because of its role in the response to stress in psychiatric disorders, the team commented. “Therefore, dynamic changes in Npy expression levels in the amygdala in response to stress may be an important biochemical signal underlying stress-dependent eating.” However, the investigators noted, while the role of amygdala-derived NPY in regulating fear and anxiety has been well studied, “the part it plays in regard to the regulation of feeding and energy homeostasis is largely unknown.”

Through a series of studies in mice fed either normal, or high-fat diets, and under either stressed, or non-stressed conditions, the researchers have now identified a previously unknown feeding stimulatory pathway that is activated during times of stress, when combined with the availability of high-calorie foods. Their results found that under these conditions, NPY neurons in the central amygdala (CeA) region of the brain play a critical role in increasing food intake and decreasing energy expenditure, and so mice under stress and with access to high-fat foods put on more weight than those given the same diet but without the stress. The studies showed that chronic stress effectively activated the NPY system, “reinforcing food consummatory behavior and also inducing a stress-dependent energy conservation state leading to an exacerbated development of obesity,” they wrote.

This is a fluorescence microscopy image of nerve cells in the medial nuclei of the central amygdala (CeM), which produce the molecule NPY (red) in response to stress. [Garvan Institute/published in Cell Metabolism]
“Our study showed that when stressed over an extended period and high-calorie food was available, mice became obese more quickly than those that consumed the same high-fat food in a stress-free environment,” commented Kenny Chi Kin Ip, PhD, lead author of the study.

NPY is produced by the brain naturally in response to stress, to stimulate eating in humans and in mice. The team’s studies in the rodents showed that chemogenetically activating NPY neurons in the amygdala triggered increased feeding that was dependent on the presence of NPY. “… even when only a normal chow diet is provided, the acute specific activation of CeA NPY neurons by chemogenetic tools is sufficient to increase food intake and lower EE, the authors stated. Conversely, blocking NPY production had the opposite effect. “We discovered that when we switched off the production of NPY in the amygdala weight gain was reduced,” lp said. “Without NPY, the weight gain on a high-fat diet with stress was the same as weight gain in the stress-free environment. This shows a clear link between stress, obesity, and NPY.”

Herbert Herzog and Kenny Chi Kin Ip [Garvan Institute]
Further investigations showed that NYP neurons harbor insulin receptors, and while chronic stress raised test animals’ blood insulin levels modestly, the combination of stress and a high-calorie diet boosted insulin levels 10-fold compared with blood levels of insulin in animals on a stress-free, normal diet.

Prolonged high levels of insulin in the amygdala of the HFD, stressed animals effectively caused the NPY neurons to become desensitized to the hormone. The desensitized neurons then further increased NPY levels, which triggered the mice to eat more, but also had the effect of reducing their bodies’ energy expenditure. In contrast, overeating by HFD mice under non-stressed led to an increase in energy expenditure in response to increased food intake, “in an attempt to maintain the original homeostatic set point,” the team wrote.

Interestingly, knocking out insulin receptors specifically in the amygdala NPY neurons of experimental mice had the same effect as the combination of stress and high-fat diet, leading to increased body weight compared with control animals. “… our data suggest that loss of regulatory function of insulin signaling specifically on CeA Npy expression is a key contributor to the accelerated obese phenotype seen under chronic stress.”

Herzog said the findings have uncovered “a vicious cycle,” in which prolonged high insulin levels driven by stress and a high-calorie diet promoted more and more eating. “This really reinforced the idea that while it’s bad to eat junk food, eating high-calorie foods under stress is a double whammy that drives obesity,” he stated … “We were surprised that insulin had such a significant impact on the amygdala. It’s becoming more and more clear that insulin doesn’t only impact peripheral regions of the body, but that it regulates functions in the brain. We’re hoping to explore these effects further in the future.”

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