Stress and appetite

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Introduction to Stress and the HPA axis

What is Stress?

Stress is an emotional and physiological response phenomenon which almost all of us have experienced at some point or another. Although stress is now commonly perceived as social and workplace pressures of modern living leading to increased incidence of illness, stress can actually be defined as anything that is potentially damaging to the internal homeostasis of an organism. These stressors can be both emotional and physical. Emotional stressors can be anything from a novel environment to potential embarrassment and involve the perception of the stimuli as being 'stressful' and are processed by the limbic forebrain. On the other hand, physical stressors, e.g. an immune attack or sudden change in temperature, pose a potential immediate physical threat and are processed quickly by the brainstem. The stereotypic stress response is elicited by a stressor. This activates the hypothalamic-pituitary-adrenal (HPA) axis directly, resulting in heightened vigilance, enhanced cognition and arousal of the autonomic system. These physiological responses help to protect both the body and the brain from any harmful effects of the stress stimuli, although chronic stress states have been shown to have detrimental effects on the brain.

The activation of the HPA axis plays a major role in moderating the stress response. This triggers a cascade which ultimately leads to the secretion of the glucocorticoid cortisol from the adrenal cortex. Cortisol acts on the cytoplasmic receptors of many cells to initiate gene transcription and eventually protein synthesis. Cortisol also results in an increase in calcium influx via voltage-gated ion channels, although the exact mechanism of this remains unknown. While a moderate increase in intracellular calcium increases a cell's excitability, calcium overloading lead to excitotoxicity and neuron death.

The HPA axis

The HPA axis is comprised of the hypothalamus, the pituitary and the adrenal gland. The hypothalamus acts as the control centre for most of the hormonal systems in the body, as can be seen in the figure below.

In response to a stressor, be it psychological or physiological, corticotropin-releasing factor (CRF) is secreted. CRF is a polypeptide hormone which is synthesised in the paraventricular nucleus (PVN) and released from the median eminance into capillaries that carry it to the pituitary gland (the hypopthalamo-hypophysial portal vessels). There, CRF induces corticotrope cells to secrete adrenocorticotrophic hormone (ACTH). In turn, ACTH acts on the adrenal glands to stimulate the release of adrenal glucocorticoid hormones, of which cortisol is the main one in humans. Cortisol is the 'stress hormone'. Its release triggers negative feedback to the hypothalamus and anterior pituitary, thus resulting in a drop of circulating ACTH. Cortisol also initiates metabolic effects which facilitate a return to homeostasis.

Neural mechanisms of appetite control and the interconnections to the HPA axis

Green indicates anorexigenic pathways/neurons and red indicates orexigenic pathways. This figure represents the basic neural mechanisms of appetite, with emphasis on the PVN and how it relates to the HPA axis

Several peptides circulating in the blood inform the brain about the body’s nutritional status. Insulin and leptin, (which both acts to suppress appetite) and ghrelin (which induces appetite) are all thought to be able to cross the blood-brain barrier at the arcuate nucleus, which is one important site of action. In the arcuate nucleus, there are populations of neurons which produce and release substances which have either orexigenic effects (induce feeding) or anorexigeninc effects (suppress feeding). The orexigenic neurons, which signal hunger, or a negative energy state, co-express two orexigenic peptides: neuropeptide Y (NPY), and Agouti-related Peptide (AgRP). These neurones are inhibited by increased levels of insulin and leptin. onversely, insulin and leptin have excitatory effects on anorexigenic neurons that express pro-opiomelanocortin (POMC) which releases pro-opiomelanocortin, which is cleaved into melanocortins. One of the key melanocortins is alpha-MSH, which acts at MC4 receptors to suppress feeding/hunger. AgRP is an inverse agonist at the MC4 receptor, thus increasing NPY/AgRP neurons orexigenic effect

Appetite-regulating neurons of the arcuate nucleus project to other parts of the hypothalamus, such as to the lateral hypothalamus (LH), and the paraventricular nucleus (PVN) where second-order signalling is postulated to take place. PVN stimulation causes inhibition of eating, whilst LH stimulation has the opposite effect. It is in the PVN we see the interconnection between feeding control and the HPA (stress) axis and it is here where the main activator of the HPA axis, corticotropin-releasing factor (CRF), is synthesised. NPY neurons have abundant projections here, and that they are in close proximity to CRF cell bodies NPY had a stimulatory effect on CRF release.

Studies by Jhanwar-Uniyal et al. (1993) demonstrated two important findings, first that PVN is indeed innervated by NPY neurons projecting from the ARC (shown by correlation of NPY levels in the PVN and ARC, this correlation did not exist for other hypothalamic areas) and secondly, they found that direct injection of NPY into the PVN potently affected eating behaviour, leading to an increase of ingestion of carbohydrate dense food (no increase was seen in ingestion of protein and fat). This preference for carbohydrate dense food when stressed; and the biological relevance, will be discussed further along.

The key area of connection between the HPA axis and regulation of feeding is the PVN. Here, there are innervating NPY neurons (Orexigenic) and CRF synthesis. CRF inhibits NPY neurones, thus initially it is anorexigenic, however, glucocorticoids (GCs) feedback to the brain to inhibit CRF expression. With sustained activation of the HPA axis, the less CRF inhibition of NPY neurones, resulting in a greater orexigenic drive.

The control of appetite is immensely complex and this section only offers a brief overview (please see references for more detail). As has been described, there are several mechanisms in which appetite and stress are related to each other, and the significance of this will be discussed further along. The aim behind most research done in this field is to offer a solution to the growing morbidity of our generation as a result of obesity. Stress-induced eating has been shown to play a part in the obesity epidemic and it is the main objective of this paper to discuss the impact of stress on eating.

Acute Stress and Appetite

Why do you reach for that extra double chocolate chip cookie after a stressful day?

Stress is known to affect every body system and contributes to many of the negative health behaviours which impact todays’ society, including cardiovascular disease, diabetes and hypertension. With obesity becoming the world-wide epidemic which underlies many of these life-threatening diseases, many researchers have chosen to study the connection between novel stressors and an individuals eating behaviour, for example amount of food eaten and choice of food. There appear to be two ways in which our bodies’ can respond to stress, either by over or under-eating; both of which are explained in this section.

Rodent Studies

HPA Axis – ‘Uncontrollable Stress’

Rodent studies into this area have illustrated a greater caloric intake during the recovery period from a novel stressor. An ‘uncontrollable stressor’ can lead to the activation of the HPA axis resulting in the immediate release of the appetite depressant CRH. As shown above, this hormone stimulates the release of cortisol, or corticosterone in rodents. Sapolsky’s perceives the increase in feeding in these individuals to be due to the appetite-stimulating effects of the residual cortisol in the blood-stream following an acute stressor. However, it is not known how cortisol triggers this over-eating; studies have shown that there is no direct effect of cortisol but it is suggested that it may influence other factors such as Leptin, NPY or certain cytokines which have a more direct effect on eating.

Sympathetic-Pituitary-Adrenal Axis – ‘Controllable Stress’

However, several studies have also shown a suppression of eating in response to acute stress. In certain stressful situations, sometimes termed ‘controllable’ stressors, the ‘Fight or Flight’ response is activated rather than the HPA axis. This mechanism, caused by the release of catecholamines from the adrenal glands, namely Adrenaline and Noradrenaline causes a range of physiological and behavioural changes to allow the individual to cope with the situation. One such change is a reduction in food intake in the short term through a slowed gastric emptying and shunting of the blood vessels to the gastrointestinal tract to allow the muscles an increased blood supply. (Do you want me to expand on this, effects on Nor and Adr??)

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Chronic Stress

Chronic stress is the brain’s response to unpleasant events over a long period of time (greater than 24 hours). Examples of chronics stress include job pressures or mental health diseases. While acute stress results in the inhibition of CRF and ACTH secretion by increased glucocorticoid levels, chronic stress changes this feedback inhibition changes and instead becomes excitatory. The continued elevation of CRF release leads to a sustained increase in plasma glucocorticoid levels. There are 3 main effects of chronically high concentration of glucocorticoids .

Firstly, there is an increased expression of Corticotrophin-releasing factor (CRF) mRNA in the amygdala’s central which enables the expression of the “Chronic stress-response network”. This results in an increase in ACTH and therefore corticosterone. There is also an increase in glutamate secretion by the paraventricular thalamus. These structures were identified using c-Fos immunoreactive cells comparisons which were higher for chronically stressed rats than controls.

Secondly, high GCs activate mechanisms of coping such as increasing the stimulating of pleasurable/compulsive activities such as eating sugary foods and fats. An example of this is the urge to consume “comfort foods”.

Thirdly, the combination of “comfort foods”, high insulin levels and high GC levels increases abdominal fat depots. This inhibits CRF mRNA expression in hypothalamic neurons and reduces HPA activity. This increased ingestion of “comfort foods” such as fatty and high sugar content foods and increased abdominal fat are strongly associated with obesity,

Chronic stress can also lead to an overall decrease in the HPA axis’ ability to control hormone levels.

In rats severe chronic stress resulted in reduced intake of food. Moderate chronic also resulted in reduced food intake. It was shown that as CRF increases, there is a reduction in food ingestion. This reduced body weight.

Studies on the effect of chronic stress on appetite have been extremely limited. In humans, there tend to be two possible reactions, either body weight gain through increased calorific intake or body weight loss through decreased calorific intake. 158 male and female subjects were asked to complete a daily record of stress. This was done over 84 days and the results showed subjects increased or decreased eating in response to stress. Other tests have been equally inconclusive.

Elevated glucocorticoids of exogenous or endogenous nature for extended periods of time can lead to the disease Cushing’s syndrome (CS). In this instant the endogenous effects of increased GC concentration from chronic stress could cause the onset of CS. Experiments on rats suggest that the effects of an increase in corticosterone leads to increase in ingestion of foods with high fat and sugar contents. This causes systems such as upper body obesity and increased neck and arm fat. As well as Cushing’s syndrome, there are a variety of other diseases that may be caused including hypertension, type 2 diabetes and cardiovascular diseases.

The psychology behind the link between stress and eating

Stress can influence eating behaviours in two ways; it can either cause under or over eating. Most people change their eating patterns in stressful situations, for example an individual who is under extreme pressure at work would be more likely to choose to eat food high in sugar and fat, which in the long term could lead to weight gain. Similarly, one study demonstrated that people in a sad state were more inclined to eat high sugar and fat food whereas people who ate during a happy state were more likely to eat healthier food such as dried fruit. It is also thought that people who are already overweight or obese put on even more weight when they are under stress.

In recent years there has been much interest and research into the physiology behind eating behaviours but it has become obvious that both internal and external factors can have an effect on an individual’s feelings and any consequences which arise due to this.

Glucocorticoids play a major role in eating behaviours and also in learning, memory and habit formation. Stress-induced increases in glucocorticoid secretion have an intensifying effect on emotions and motivation and it also appears to increase calorie intake. As glucocorticoids increase so does insulin secretion which is a key feature of type 2 diabetes which can occur as a result of obesity. Insulin is thought to have a role in the selection of food, whilst glucocorticoids increase the motivation for choosing a particular food.

There is a relationship between individuals who are feeling stressed prior to eating and then feeling better after they have eaten highly palatable foods. Infrequent eating of pleasurable foods when under stress will not lead to obesity but eating pleasurable foods more often will develop habits to try to relieve the stress and in the long term this can lead to weight gain and obesity.

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