How  appetite is regulated in our Brain

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I  want to apologize tor the technical details of this article.  There is a great deal of ongoing reseach in this field and our knowledge changes frequently.  In this article I will attempt to pull together different aspects of knowledge into one place. Don't feel bad if it is overwhelming, I  have to keep reading this stuff over and over to keep it clear in my own mind; even, then, it is difficult to put all the different parts in one coherent model.  Yet, these are the  mechanisms that increase or decrease appetite.  They can be targeted by medication.  They are the bases for the medications I use.

The hypothalmus is the area of the brain where appetite is controlled.  In order to control appetite, there needs to be a way for this structure to measure the current energy stores as well as the current energy needs.  There needs to be  a way for it to recognize the long term nutritional status of the body as well.  Once it is able to determine these factors, it needs to be able to modulate appetite and metabolism for the good of the person. 

In order to increase our appetite, it needs to connect with the motivational parts of the brain such as the Nucleus Accumbens.  Increased activity here will cause increased hunger.  It also can affect our metabolism through interconnections with the pituitary gland and the rest of the endocrine system.

One particular area of the hypothalmus, the arcuate nucleus, is in a unique position to both monitor the blood as well as the brain.  In this area, two opposing nerve groups are found.  Their names are quite the mouthful.  The first of these is the Cocaine and Amphetamine-related transcript/proopiomelanocortin  (CART) group, which secetes a neurotransmitter called melanocortin as well as endorphin, an opiod.  The second is the
NeuropeptideY/Agouti related protein (NPY) group.
These two tracts interconnect with each other in many ways, trying to inhibit and influence each other.  They also go to different areas within the hypothalmus where they have opposing effects on the target areas.

Easily, the more important tract is the CART.  Activity of this nerve group suppresses appetite.  Whenever these nerves have been inhibited in lab animals, a profound amount of weight is gained.  As detailed below, it is also able to increase metabolism.  The NPY neurons, on the other hand, increase our appetite and decrease our metabolism.  Abnormalities in this group do not result in as big a difference in weight as the CART.  Nevertheless, if we want to lose weight, we want the NPY tract to be less active.

Neurologic Connections

The CART neurons are influenced by several important  parts of the brain.  It is affected by connections originating from the Amygdala  and Vagus nerve.  The Amygdala modulates fear and stress and lets the hypothalmus know if there is danger.  The vagus nerve is able to monitor what the stomach and intestines are doing and sense the presence of food.  The vagus nerve can tell the hypothalmus if we have been fed.  The mechanics of  these connections are still  being studied.  

The CART neurons than go on to effect multiple areas of the hypothalmus and brain.  The destinations include the nucleus accumbens where it works to inhibit appetite. In addition to connecting to the Nucleus Accumbens, there are also connections from there as well, perhaps in some type of feedback loop.  This means our appetite can be affected by what is going on in the Nucleus Accumbens.  As explained in articles elsewhere in this website, the Nucleus Accumbens is the key target of all addictive substances and is dysfuctional in most diseases of addiction.    

It also connects to the area controlling the Vagus nerve and may have an effect on how the intestine handles food.  Likely, it slows down activity in the gut.  Perhaps this explains why stress may cause some people to have stomach upset.   

One easy way to remember all these effects is to realize that if we are in danger and need to react, what is known as the "fight or flight" reaction, increased activity of the CART neurons is crucial.  It receives alarm signals from the Amygdala.  It then suppresses hunger, turns off the gut and increases metabolic output to optimize the enrgy reserves for the muscles to act.

In contrast to the CART, NPY neurons increase appetite.  Its function seems less potent than the CART since abnormalities in its function have less inpact on weight gain or loss.  The connections of NPY neurons are more localized than those of the CART.  Most remain within different areas of the hypothalmus.  These areas are listed below.

In the paraventricular nucleus of the hypothalmus, input from POMC and the NPY are both received.  There, the two opposing forces duke it out..  The summation of these opposing stimulations effect metabolic rate.  One way that metabolic rate is affected is through increasing or decreasing thyroid activity. They also affect the ACTH/cortisol hormone axis. 

The NPY neurons also go to the Lateral hypothalmus.  There they stimulates neurons that contain orexin, a neurotransmitter that increases appetite.  These orexin neurons travel to the Nucleus accumbens and increases hunger.   This may be the most important cause of hunger we have. 

The lateral hypothalmus also has endocannibinoid receptors, the target of marijuana.  Activation of these receptors causes hunger, perhaps by increasing orexin.  This is one reason we get the munchies from smoking pot.

Orexin is also involved in sleep regulation ; low levels of this hormone is implicated in the cause of narcolepsy.  If we could devise a medication to reduce orexin activity, it would reduce appetite, cravings and promote sleep.  Although there are no medications yet to take advantage of this, I am told that some are in development. 

Localized effects within the Arcuate Nucleus

There are many neurologic connections within the Arcuate nucleus and because of this, there is a soup of chemicals which are known to be neurotransmiiters.  It is valuble to consider the effects of these chemicals without trying to trace them to specific neurologic influences.

It is  well known that seratonin affects appetite.  Redux, fenfluramine and meridia are all well known diet drugs that worked by increasing activity of seratonin.  It turns out that one type of seratonin receptor (the 5ht2c) increases activity of the CART.  Another receptor, the 5HT1a, reduces activity at the NPY neuron.  Much of the current research in anti-obesity treatment is focused on manipulating these receptors.

Other transmitters to consider are the opiods.  CART/POMC neurons are actually a major source of these endorphins within the limbic system- supplying them to the nucleus accumbens as well as other areas implicated in drug use.  When the CART neurons are more active they make more endorphins.  These endophins feeback on the CART to slow them down.  These endorphins also interact with the NPY neurons  to facilitate an increase in appetite. Therefore, opiate blockers will serve to reduce appetite by blocking both mechanisms.

Responses to hormones from other parts of the body

Both the POMC and NPY are able to respond to a variety of nutrients and hormones in the blood.  Abnormalities of these processes have been implicated in weight control issues.

Leptin was described some time ago.  It is made by the fat cells and is proportional to the bodies fat content.  Therefore, high Leptin tells the hypothalmus that fat stores are adequate.  Leptin directly increases CART activity.  Of course, this decreases appetite and increases metabolism.  In addition, Leptin reduces orexin activity in the lateral hypothalmus.

The CART also responds to blood sugar and insulin which are increased after eating; so insulin and higher sugars decrease our appetite by stimulating the CART.

Glucgagon Like Peptide (GLP) which comes from the gut also stimulates the CART.  GLP is increased after eating.  GLP  is already targeted by a number of medications that are used in treating diabetes.  These medications have lead to weight loss.

In addition to GLP, the Pancreas also secretes another hormone called Amylin.  This has multiple effects on suger metabolism but has also been demonstrated to decrease appette by stimulating the CART neurons.  This is important because a medication that mimics amylin, which was approved to treat diabetes, has been proven in a study to lead to weight loss even in a non-diabetic population.

Does an empty stomach make you hungry?  That is because an empty stomach secretes ghrelin which increases activity of NPY neurons.  However, after we eat,  peptide YY from the gut, and pancreatic polypeptide from the pancreas inhibit the NPY neurons and decreases appetite.

Cholycystokinin and oxyntomodulin from the gut will also reduce hunger after we eat.  They effect the Vagus Nerve, which in turn, affects the CART nerves

Stuart Wasser MD

November 2010

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