A few months ago a couple of people in my Fast/Feast support group spoke about how they were feeling less anxious and overcoming previous fears after having implemented intermittent fasting into their life. It was clear from previous conversations that their health had improved and physiological signals, such as hunger and satiety, had normalised. I wondered about the connection with anxiety and fear and it led me down a bit of a rabbit hole…

Leptin and ghrelin are two hormones associated with multiple physiological functions, especially energy balance. Leptin is a hormone secreted by adipocytes (fat cells) and tells our body when we are full (satiated). Ghrelin is a peptide hormone, which is produced and secreted in the stomach and tells our body when we are hungry. A number of studies, however, have indicated that these hormones could also be associated with different types of mood disorders.

Leptin

Leptin is our satiety hormone. When we feel full it is because leptin is released by the fat cells, sending a signal to the brain to tell us that we do not need any more food. It controls our appetite (or it should if working properly) so that we do not constantly crave and seek out more food. When leptin is low our hunger is increased and our metabolic rate is decreased, and when it is high our hunger is decreased and metabolic rate increased. This is due to the relationship between leptin and the thyroid. As leptin levels rise, hunger is stopped and the thyroid releases hormones to increase metabolism.

That is what SHOULD happen.

However, leptin resistance can occur alongside weight gain, resulting in obesity. Although there is plenty of leptin in the body, the brain stops responding to the signal, and therefore the body is no longer being told that it is full and to stop eating. Leptin and insulin (I will be discussing insulin in the next blog post) are closely interconnected, so when the body cannot release fat for energy (because insulin levels are high), the brain thinks that the body is starving and so it keeps signalling to eat more. It also reduces the metabolism to conserve energy, believing the body to be in a starvation type mode. This creates lethargy, fatigue and a disinclination to move, which can lead to further weight gain. As you can see, it becomes a vicious cycle.

Leptin resistance can be reversed however by implementing all, or some, of the following:

• Removing processed foods, which contribute to inflammation and gut dysbiosis, and do not provide the body with proper nutrients.
• Reducing carbohydrate intake – particularly refined carbohydrates, but also starchy carbs if you are overweight.
• Eating healthy fats, which help to reset hormone activity.
• Including vigorous daily exercise into your life
• Improving sleep habits – sleep and recovery is very important for the body to cleanse and reset itself each day.
• Eliminating sugar from the diet – including fructose if your fruit consumption is high.
• Including adequate amounts if protein to ensure the building blocks for growth, repair and renewal are in place.
• Implementing intermittent fasting/time restricted feeding into your daily or weekly routine. It helps fight inflammation, lower blood triglycerides (fat) and helps to resolve both leptin and insulin resistance.

Ghrelin

We all know that familiar feeling, and growling noise when we are hungry – it’s as though our stomach is literally talking to us! This is the hormone ghrelin sending a signal to the brain telling us to eat, that we need energy coming in to the body. Normally ghrelin levels peak just before eating and are lowest about one hour after eating. However, in overweight and obese individuals, ghrelin levels only decrease a little bit, which results in the signal not being received, with overeating being the consequence.

Reducing consumption of processed carbohydrates is an effective way to combat ghrelin issues, particularly foods with added fructose as this has been shown to have no effect on lowering ghrelin levels, thus exacerbating the hunger signal. Fructose can also interfere with leptin signalling, and so both of these damaged mechanisms can result in overeating.

Eating less often, in a practice known as intermittent fasting (IF), means that we have larger amounts of ghrelin present in the body, and, because it has the ability to stimulate human growth hormone (HGH), it means that HGH rises. Combining exercise at this time will cause HGH to rise even further. This is why fasted workouts can be extremely beneficial for health. HGH helps healing, growth and repair in the body and is a natural anti-aging hormone. It is also associated with longevity. Lower levels of ghrelin found in overweight and obese individuals means that they are less able to release HGH, which may contribute to continued inflammation. Ghrelin also appears to be responsive to acute doses of protein intake, improving satiety and fat oxidation, indicating that a high protein diet may be beneficial for those wishing to lose weight.

Resisting the signal to eat for a period of time during the day can invoke benefits for the brain, resulting in improved learning and memory. Once the body adapts to not eating all day, ghrelin levels begin to normalise and start to lower. The side effects of hunger pangs become less of an issue and the subsequent increase in HGH brings a higher mental clarity and sharper focus. The metabolism also starts to rise creating more energy and the ability to start utilising stored body fat for energy. A study looking at early time restricted feeding (eating early in the day and then fasting for the rest of the day) resulted in a decrease in fasting levels of ghrelin.

Depression and Anxiety – What’s The Connection to Leptin & Ghrelin?

The hypothalamic-pituitary-adrenal axis (HPA area of the brain is associated with mood disorders. Dysregulation of the HPA axis is connected with major depressive disorder (MDD) and many studies have shown that obesity and MDs are related, with approximately 25% in mood and anxiety disorders, with depression reported as a major risk factor for developing obesity, particularly amongst females. Stress induced overeating affects levels of hormones such as leptin and ghrelin, creating resistance and possible dysregulation of the HPA axis as a result.

Studies on rodent models have indicated that leptin might modulate HPA function, specifically with regard to symptoms of depression. There are now some human studies that are consistent with the animal studies, demonstrating that leptin can reduce symptoms of depression and have anti-anxiety effects.

Similarly, ghrelin’s role in the body is not only as a hunger signal but one that is also involved in reward, motivation and signalling pathways. It is through these mechanisms that it is being linked with stress, anxiety disorders and depression.

Investigations into ghrelin’s effects on anxiety-like behaviours have shown that increasing circulating ghrelin levels by calorie restricting mice for ten days, or by high level dosage of ghrelin to ad lib-fed mice, produces anxiolytic-like responses (reduction of anxiety/anti-depressive) in a maze test. Increasing circulating ghrelin levels by 10 days of calorie restriction, or by high level dosage, also resulted in anti-depressant-like responses in forced swim tests. However, mice that were lacking ghrelin receptors did not experience these responses when calorie restricted. This would suggest that interference with ghrelin signalling negates the antidepressant-like behaviours associated with calorie restriction.

Various studies have reported that administering acute ghrelin acts as an anti-depressant, significantly relieving symptoms of chronic stress and depression-like behaviours. An improvement of depressive symptoms was found in men with MDD after they were administrated with ghrelin.

It has been demonstrated that rises in ghrelin occur not only during periods of energy insufficiency but also following either acute or chronic stress. These raised ghrelin levels may help to minimize the deleterious, depression-like behaviours often associated with stress. It has been suggested that activation of ghrelin signalling pathways in response to chronic stress may be a homeostatic adaptation that helps individuals cope with stress. Ghrelin appears to have a positive effect on sleep, making it better quality and also has an effect on the synaptic plasticity in the zones of the brain involved with memory, improving memory capacity. Administering ghrelin as a treatment demonstrates an anti-depressant effect, but resistant patients retain high levels, leading to the hypothesis that ghrelin resistant individuals may be more susceptible to depression.

Future studies are needed to examine ghrelin’s effects on anxiety-like behaviours, as these have been shown by different groups to be either anxiogenic (inducing anxiety/depression) or anxiolytic (anti-depressive), but with more evidence suggesting anti-depressant effects.

Leptin was initially identified as an anti-obesity hormone, acting as a feedback signal to controlling storage in adipose tissue and controlling homeostasis. Low levels of leptin have been found to be associated with depressive behaviours in rodents and humans. Pharmacological studies indicate that leptin has antidepressant-like qualities. Findings of low circulating leptin levels in animal models of depression has led to the hypothesis that leptin insufficiency may underlie depression-like behavioural deficits. However it is important to note that both leptin insufficiency and leptin resistance may contribute to symptoms of depression.

While acute stress had no effect on levels of leptin, rats exposed to chronic unpredictable stress or chronic social defeat stress showed decreased basal levels of leptin in plasma. And even more interestingly, prior experience of chronic stress appears to sensitise the response of leptin secretion to acute stress. Rats that were subjected to two weeks of chronic unpredictable stress thereafter displayed a rapid fall in plasma leptin levels in response to acute stress. Leptin appears to elicit anxiolytic-like (anti-anxiety) effects when administered acutely, suggesting that leptin has both anti-depressant-like and anxiolytic-like properties.

A recent study showed that streptozotocin-induced diabetic mice had low circulating leptin levels and exhibited depression-like behaviour in the Tail Suspension Test, and that treatment with leptin resulted in reversal of this behaviour.

The sites of actions for leptin on depressive behaviours are thought to be located in the limbic structures. An increase in leptin expression in the hippocampus was observed in rats that received systemic injection with leptin and exhibited anti-depressive behaviour in the Forced Swim Test. Direct activation of the leptin receptor in the hippocampus by microinjection of leptin into this region elicited antidepressant-like behavioural effects.

Two human studies found that plasma leptin levels were higher in depressed patients particularly in in female patients. 

Other reports found that low leptin and low cholesterol levels were associated with depression.

In larger studies, two research groups demonstrated that plasma leptin levels were decreased in patients with major depression, independent of weight. Also, lower levels of leptin in cerebrospinal fluid were found in suicide attempters with depression than those without depression. Decreased levels of leptin in plasma were also observed in patients with bipolar disorder and obsessive-compulsive disorder with co-morbid major depression. When looked at in total, these clinical observations suggest a link between reduced leptin levels and major depression.

Obesity and Depression – What Is The Connection?

What is really interesting, and still needs to be addressed, is the association between obesity and depression. Typically, obesity is commonly characterised by high, not low, levels of leptin, and it has been reported that obese people are approximately 20% more likely to have depressive disorders than non-obese people. The high leptin levels associated with obesity are thought to be caused by leptin resistance, (similar to the fact that type 2 diabetic patients are resistant to insulin, and these could both be linked to the same pathways). Leptin treatment is ineffective on reducing food intake and increasing energy expenditure in obese people, whereas administration of leptin in people with normal weight leads to reduction in adipose tissue and weight loss. It is well documented that leptin resistance is caused by defects in the leptin signalling pathway possibly at several levels, including impaired transport of leptin across the blood-brain-barrier, reduced function of the leptin receptor and defects in leptin signal transduction. It has, therefore, been suggested that leptin resistance may contribute to the higher rate for depression in obese people. This could also help to interpret some of the conflicting results obtained in relation to circulating leptin levels in depressed patients.

There is more evidence suggesting that leptin has neurotrophic effects, increasing the grey matter concentration in the anterior cingulate gyrus, a region located in the medial frontal lobe. This area is involved with functions such as emotional processing, vocalisation of emotions and speech production. A study was conducted with 3 morbidly obese adult humans who were leptin deficient, to ascertain whether leptin replacement therapy would have significant effects on altering brain tissue and therefore stimulate weight loss. MRIs were taken of the brains at 6 months and 18 months after treatment started. Increases in the grey matter in the anterior cingulate gyrus, the inferior parietal lobule and the cerebellum were detected at 6 months and a dramatic weight loss was also noted. The authors concluded “Our findings suggest that leptin can have sustained effects on tissue composition in the human brain and broaden the potential spectrum of leptin’s influence beyond feeding behaviour and endocrine function”.

So, although there are some contradictions within the research, my thoughts are that these are possibly due to the hormonal imbalances that can be experienced when individuals eat all day long without a break. Also, the correlation between high carbohydrate diets and obesity, type 2 diabetes and hormone disregulation likely plays a part because this disrupts leptin and ghrelin signalling. Like the mice with no ghrelin receptors, poor diet and constant eating throughout the day would result in interference with ghrelin signalling, and those who suffer from obesity are often leptin resistant.

If you would like to find out more about intermittent fasting/time restricted feeding please  schedule a consultation.