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Cravings and the Brain’s Reward Cascade

Now that we have a clearer connection between inflammation, stress, and weight gain, the final piece of the puzzle is how these factors tie into what we mentioned as a main obstacle in managing appetite and maintaining weight loss: the reward cascade, particularly the reward deficiency cascade syndrome.

The “reward deficiency cascade” is a term coined by Dr. Kenneth Blum, a neuropsychopharmacological and genetic researcher. According to his research on alcoholism and addiction, he concluded that addictive substances and behaviors have a genetic component to them and are therefore partly hereditary. He also outlined the brain’s reward cascade that lights up when an addiction is engaged in.

The brain systems involved include serotonin and dopamine levels. These levels are also important factors in the reward deficiency cascade system.

For example, dopamine receptors, especially the D2 receptor, are involved in functions like motivation, attention, and motor control. If the D2 receptors are not properly expressing, or if there are just not enough of them, then you become more likely to develop conditions like ADHD, OCD, addiction, and overeating. This lack in number or expression can be due to a genetic variant.

This may be why you see people who have managed to get sober from one addiction easily shifting to another addiction. This may also explain why those who quit smoking tend to eat more, and why managing appetite can lead to smoking more cigarettes or drinking more coffee. Low serotonergic and dopaminergic actions cause imbalances in the reward cascade and are drivers of craving behavior.

Add to these imbalances chronic stress and chronic inflammation, and you lose more serotonin. Serotonin helps you in calming down and is involved in the feelings of craving and satiety. The less serotonin, the more cravings you will experience and the harder time you’ll have in managing appetite.

Another issue that is shared among obese people is a variety of nutrient imbalances, triggered by stress and inflammation, which directly affect serotonin and dopamine. For example, obese people tend to have a low level of tryptophan, which is a precursor to serotonin.

Chronic immune activation and inflammation can create issues with tryptophan, such as:

The enzyme indoleamine 2,3-dioxygenase (IDO) degrades tryptophan to N-formyl kynurenine. So instead of tryptophan becoming serotonin, it goes through the IDO pathway and becomes kynurenine.
N-formyl kynurenine metabolizes to niacin
This process alters serotonin levels and changes mood
Low tryptophan is a trigger for comfort food
What’s interesting is that in overweight individuals who have lost weight, their tryptophan pools do not stabilize. So their cravings stay, making managing appetite very difficult to keep up.

Add to that stress, which perpetuates inflammation and the IDO pathway, and you keep losing more and more serotonin. And if you have a gene snip that affects your methylation process, such as MTHR, it will affect any addictions and cravings you have even more because serotonin is methylation-dependent.

The Link Between Serotonin and Dopamine
Another obstacle obese people face is that they suffer from congested livers. This has implications on the NEM’s detoxification response, on inflammation, and on dopamine and serotonin production.


A congested liver equals an increase in acid aldehyde, which is associated with high levels of uric acid. Acid aldehyde in the brain will block serotonin and dopamine production. As we already saw, low levels of serotonin will trigger cravings, especially for so-called comfort foods, which are usually high in carbohydrates, as well as some combination of fat, sugar, and salt.

As you read, obesity is a big factor in the lack of dopamine receptors. The higher the BMI, the lower the number of receptors. Insulin resistance can also interfere with dopamine clearance, and this may be one of the reasons that type 2 diabetics have weight issues.

But serotonin and dopamine also affect each other. Serotonergic activation influences D2 receptor function. So if you have enough serotonin, your dopamine is spared, but if you don’t, dopamine will down-regulate. As soon as that happens, your cravings come on strong.

When this neurotransmitter pool is blunted, you’ll have a hard time focusing and feeling at ease, so this pool needs to built back up first in order to deal with the cravings and reward behaviors, and eventually help you in managing appetite. Otherwise, there is a danger you will revert to old eating habits very quickly, and will-power alone will not suffice.

Of course, the question of supplementing will come up. The first warning that needs to be given is that taking a medication or supplement to balance dopamine in order to solve focus or reward issues may be a mistake for some, while a necessity for others. Usually, the better route is to fix the serotonin receptor issues first before the dopamine receptor issues. An exception, however, is for people with prefrontal lobe lapses and ADD. In those cases, you first deal with dopamine regulation before serotonin.

What about using appetite suppressants? Unfortunately, appetite suppressants can also deplete dopamine levels, so they’re not a particularly sustainable or pleasant way to lose weight.

One way to improve dopamine levels naturally is through moderate exercise. That’s because exercise up-regulates dopamine and increases nitric oxide levels. But you don’t want to do high intensity exercises, as these can actually lead to excess nitric oxide and a down-regulation of dopamine. Moderate exercise combined with eating nitric oxide rich foods, such as dark leafy greens, and using nitric oxide supplements, like beet products, can be useful.

The Reward Cascade, Managing Appetite and the Gut
You’ve probably heard about the gut-brain connection, and maybe how the gut is sometimes called “the second brain.” First of all, the majority of serotonin comes from the gut, and dopamine is also stored in the gut.

Also, the gastric stimulation that occurs when you eat comfort foods activates limbic and cortical regions in the brain. This is doubly so in those who are obese. These are the same regions in the brain that are activated when a drug-dependent person gets a craving for drug consumption.

This is why trying to address obesity simply as a lifestyle issue just doesn’t cut it for most people. The gut-brain connection has to be taken into consideration in managing appetite and in weight loss. Unless the reward deficiency is corrected, fixing the weight problem is a huge struggle that is likely to fail.


In addition to that, if you keep up a strict calorie restricted diet for a while, which is extremely difficult to maintain, you can lose lean muscle mass. And then, of course, the yo-yo back and forth is inevitable. Fix the brain issue first, and you have a much better chance.

Thankfully, because the brain is so intimately connected to the gut, the way to fix the reward imbalance may actually be through the gut. Instead of going down the calorie restriction path, you first can make a few simple changes that can get the rebalancing of the reward system started.

First, take a look at how much fat you’re consuming compared to how much fiber. An excess in dietary fat can lead to a diminishment in dopaminergic function, and a deficiency in dopamine will add to obesity because it will provoke compensatory overfeeding in order to try and restore the reward sensitivity.

High fat consumption will down-regulate oleoylethanolamine (OEA), which is a diet-derived gastrointestinal lipid that is also a satiety messenger, and which helps restore gut-stimulated dopamine release. OEA can also reduce motivation problems concerned with eating healthier foods by increasing their reward value, and it can reduce the craving for fatty foods.

Ketogenic diets are becoming very popular, and they do work for weight loss and other health issues. However, like all other strict diets, you need to stay aware of the possibility of a rebound effect, as the backlash can be very strong.

If you choose to try a high fat diet, you’ll need to make sure you are getting enough fiber from resistant starch like oatmeal or green bananas, so you can maintain the integrity of your microbiome, which is what gives you the gut-brain messengers.

Obese people tend to have imbalances in their microbiomes, a state called dysbiosis. And certain types of gut flora, when in excess, are more energy intensive, which triggers the need to eat more. Basically, the microbes in the gastrointestinal (GI) tract can manipulate their host’s eating behavior for the sake of their own survival and fitness. This illustrates how important gut flora balance is. An imbalance in gut flora will affect the neurotransmitters and enteroendocrine hormones released or stored in the gut.

Enteroendocrine hormones, secreted by specialized cells of the GI tract and pancreas, are intimately linked to the reward cascade. They regulate energy homeostasis, influence energy expenditure, are involved in food reward pathways, and can alter feeding behavior.

If the gut flora is out of balance and your microbiome is not getting enough resistant starch, it can’t make some of the important gut hormones involved in hunger and satiety. For example, it can’t regulate ghrelin, which is known as “the hunger hormone” because it stimulates appetite. This can make managing appetite an uphill battle.


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