Wednesday, February 2, 2011

Appetite Regulation and the Brain

Before we get back to sleeping, there's a bit of brain signaling that it is important to get a handle on.  Most of this information is derived from rodent studies, but I have no reason to believe their brain signaling about appetite and whatnot would be much different from our own.  I want to go over this bit about satiety and hunger pathways in the brain because they overlap with the sleep pathways that we will cover next. 

The center of appetite is in the hypothalamus of the brain.  The most important part of the hypothalamus with respect to appetite is the arcuate nucleus.  (When we talk about neurons, a nucleus is generally a collection of neuron cell bodies with long branches called axons that spread out to different brain regions, spreading signals along the way).

Now it is time to introduce some players.  Bear with me, as there are a few too many.  Within the arcuate nucleus,  one set of neurons makes CART and POMC.  POMC is cut up into a neurotransmitter called alpha melanocyte-stimulating hormone.  This critter acts on various areas of the hypothalamus to reduce appetite.  Another set of neurons in the arcuate nucleus makes appetite-increasing neurotransmitters and sends axons to the same areas of the brain as the POMC (appetite reducing) neurons.  The appetite increasing chemicals are AgRP and neuropeptide Y.

Quick recap - arcuate nucleus of the hypothalamus is the nerve center for appetite regulation.  It is responsible for sending out appetite reducing neurotransmitters (alpha melanocyte-stimulating hormone) and appetite increasing neurotransmitters (AgRP and neuropeptide Y).

Now, these things are always beautifully regulated via negative feedback loops.  The POMC neurons and the AgRP and neuropeptide Y neurons project signal to an area of the brain called the paraventricular nucleus.  (Don't let all the long names blow your mind.  They are just names.  Maybe we should rename them Robb Wolf, Mark Sisson, Melissa McEwen, or Richard Nikoley to make them more friendly.)

The paraventricular nucleus synthesizes and secretes two appetite-reducing neuropeptides (corticotropin-releasing hormone - yes, that corticotropin releasing hormone - and oxytocin) in response to the stimulus by the appetite increasing neurotransmitters.  The arcuate nucleus also sends projections to the lateral hypothalamus to stimulate the appetite increasing hormones melanin-concentrating hormone (MCH) and the orexins.  It is these last two appetite-increasing hormones that have a lot of overlap with sleep regulation, and even mood.  I'll get to them in a few days.

Phew.  Now let's get a bit more big picture.  The arcuate nucleus is the epicenter of appetite control and receives a lot of signals from outside players.  The presence of glucose, and also long chain fatty acids such as oleic acid (the primary component of olive oil, but also a major component of most animal fats) in the arcuate nucleus will inhibit feeding behavior and peripheral glucose production.

And remember those CART/POMC (appetite reducing) and AgRP/neuropeptide Y (appetite increasing) cell bodies in the arcuate nucleus?  Turns out they are the major site of action in the hypothalamus of the hormones leptin and insulin.  Both those hormones will tend to reduce appetite by suppressing the AgRP/neuropeptide Y neurons. 

Have I lost everyone yet?  There is a slew of wondrous basic science research into appetite regulation in the hypothalamus.  One of the cooler things to do is to infect the hypothalamus with various genetically modified adenoviruses* (I know, it does sound like the first act of a zombie movie).  If the adenovirus carries a gene that activates the signal of "low energy availability" (for biochem geeks, this is AMP kinase), the mice increase food intake and gain weight (maybe they will be hungry for BRAINS).  If the virus signal suppresses the low energy signal, the mice will stop eating and get a bit too slender.  Our "food is aplenty" hormones insulin and leptin will decrease the "low energy available - so EAT" signal, whereas known bingey hormones cannabis and ghrelin will increase the appetite signal and lead you to eat. 

So for many, many years, researchers have known that glucose and insulin seem to decrease appetite.  (BUT BUT BUT what about diabetes and gaining weight and too much insulin and glucose!!!!  Yes, in that case the negative feedback is broken, likely through inflammation and damage in the hypothalamus - so you need more and more glucose and more and more insulin to give the signal to cut off the appetite, and protuberant bellies and sales of "Sweatin' to the Oldies" increase accordingly).  I think this basic science, in combination with a false sense of security about high carb diets causing increased insulin sensitivity in the periphery (as opposed to low carb diets, which will physiologically increase insulin resistance in the skeletal muscle), is what led to the misguided advice for diabetics to consume carbohydrate-rich diets all these years.  It was only recently (well, 2002) that oleic acid, for example, was found to significantly reduce appetite also.  (And that basic science finding pretty much coincides with the massive enthusiasm for olive oil and the Mediterranean Diet).

Um, I hope I still have a few readers by the end of this post!  Go out there and eat healthy and get some sleep.  Your hypothalamus will thank you, as will your less protuberant belly.

As always, a big thanks to Jamie Scott, who has sent me the major reference article for today's post.

*there was a recent study showing that kids who had previous infection with adenovirus-36 were much more likely to obese than kids with no previous infection.  No, I doubt it is the mutant strain that escaped the lab.  Antibodies to adenovirus-36 are also found in 30% of obese adults.**

**get some sunshine to boost your vitamin D to ramp up antiviral immunity.  


  1. On the subject of the brain and appetite, I'd love to hear your thoughts re the endocannabinoid system and appetite. I recently came across this senior resident's presentation (PPT: and got practically giddy thinking about the possible chain of dietary omega 6s -> arachidonic acid -> anandamide -> increased appetite.

    I'm a lay person and haven't looked into this at any depth, but it appears like research into pharmaceutical ECS antagonists haven't been successful, because of side-effects. But I want to look and see whether anyone is making the connection between increased omega 6s in our diet and ECS agonists and increased appetite.

    Here are a couple of other links I've bookmarked for looking interesting:

  2. Great stuff! I just stumbled upon your blog today and, as luck would have it, I'm writing a review of antipsychotic-induced weight gain. So reading about your cast of characters (and a few twists here and there) was indeed refreshing.

    I find the whole leptin resistance concept fascinating. One theory is that leptin is prevented from crossing the blood-brain barrier by the accumulation of triglycerides in the bloodstream. Another argument is that leptin resistance is not necessarily the result of elevated leptin, but of the lack of fluctuations in serum leptin.

    Evolutionarily, we were lucky if we had fat stores and when we did (e.g., during summertime), it was important to conserve them and we could afford not to eat. But during the wintertime leptin levels decreased and our appetite returned. Some say that humans have rapidly converted to a "continuous summer" state, thanks to the abundance of food available, but without the lack of seasonal fluctuations are required for normal leptin sensitivity.

    For another great review, check out: this article from Annual Review of Psychology.

  3. There's definite promise in the use of cannabinoids to treat autism. I use them myself (aspergers) but that's just anecdotal.

  4. Hey Emily

    How are u doing ?

    I red that u said that B polar type 2 don't respond well to antidepressant contrary to atypical depression

    So hypothetically !! What other treatment can we think about for this condition?

    By thy way does the Okinawa high carb diet does not contradict low carb diet?

    Thanks and enjoy the winter


  5. What do you say to someone who feels no sense of satiety despite eating low carb? Perfect bloodwork, multiple endocrinologist visits, no help.

    It sure is difficult to get by without a sense of 'fullness' if you know what I mean!

  6. Hi Vortex - the only thing that comes to mind is making sure you are eating enough protein, and making sure you have all your nutrients tip top. Paul Jaminet over at Perfect Health Diet describes ravenous hunger when he developed scurvy on a zero carb paleo diet. He supplemented with vitamin C and it went away. I don't know if that is the case with you, but it seems worthwhile to plug your daily eats into FitDay to see if something is missing.

  7. Shay - Bipolar II is, in my opinion, overdiagnosed, as symptoms overlap with ADHD + anxiety, borderline personality disorder, and a ton of people with resistant depression get labeled bipolar II just because therapy and antidepressant meds don't work great. I can't tell you how many times I get someone in my office with a diagnosis of bipolar II (they seem to always walk in on abilify - antipsychotic, lamictal - mood stabilizer, and a benzo for sleep, and sometimes an antidepressant), but if you really ask all the right questions, you figure out that something else is going on. So, no, I couldn't tell you what I would do hypothetically, because each case is very individual. I'm not sure what you mean by the Okinawa question - didn't translate well.

    Jules, Beth - cannabis is an extremely interesting compound. It apparently has powerful nerve growth properties - this can be actually quite toxic to young brains but there is actual promise for future treatments of dementia. I've seen too many young men walk in completely psychotic and paranoid after toking it up every day to be in favor of pot or even look the other way about it (as some of my colleagues who came of age in the 60s are wont to do sometimes). I've also seen too many middle-aged men who can barely put a sentence together after smoking a ton of pot daily for 30 years. I've also seen too many people come in with weight gain, lack of motivation, lack of concentration, and evening anxiety and insomnia... who happen to smoke pot every day. That doesn't mean that therapeutic options aren't interesting. But it does mean one must be careful not to rot one's brain with it (and MRIs of long-term heavy pot users do show shrunken areas of the frontal lobe). But I will definitely look at more of the appetite regulation links. The cannabis blocker won't be approved in the US due to side effects. It had modest weight loss effects.

    Pj1280 - neat - hopefully you cover zyprexa zydis which is the same medicine as olanzapine but is dissolved in the mouth and partially absorbed in the oral mucosa and doesn't seem to have nearly the metabolic issues as the olanzapine pill that you swallow. If you get a solid line on why that happens - let me know. Solid evidence of a gut absorption issue there, I would think, or maybe liver. There is also histamine and the brain, but still...

  8. Dr Deans,

    I just wanted to say thanks for writing such accessible, relevant posts. I'm curious to see what you have to say about sleep and hunger regulation, as I've done a fair amount of reading on that recently, and published a basic article on sleep in this month's Performance Menu ( PM is a athletic performance-oriented publication, so I addressed sleep as an ergogenic aid (again, in basic terms). We're going to start linking to you in our handouts for our nutrition workshops - in case you cared :) Anyway, thanks, and keep up the awesome stuff.


    Dallas Hartwig

  9. Thanks Dallas! Always an honor to be linked in a nutrition workshop. I'll be headed back to the sleep posts next week - but so many new exciting articles came out this week I had to jump around.

  10. What are your thoughts about urocortin? I just happened on a study addressing this neuropeptide, started reading on PubMed, and now am very interested in learning more.

    Front Neuroendocrinol. 2007 Apr;28(1):1-27. Epub 2006 Nov 2.

    Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs.

    Fekete EM, Zorrilla EP.


    Urocortins, three paralogs of the stress-related peptide corticotropin-releasing factor (CRF) found in bony fish, amphibians, birds, and mammals, have unique phylogenies, pharmacologies, and tissue distributions. As a result and despite a structural family resemblance, the natural functions of urocortins and CRF in mammalian homeostatic responses differ substantially. Endogenous urocortins are neither simply counterpoints nor mimics of endogenous CRF action. In their own right, urocortins may be clinically relevant molecules in the pathogenesis or management of many conditions, including congestive heart failure, hypertension, gastrointestinal and inflammatory disorders (irritable bowel syndrome, active gastritis, gastroparesis, and rheumatoid arthritis), atopic/allergic disorders (dermatitis, urticaria, and asthma), pregnancy and parturition (preeclampsia, spontaneous abortion, onset, and maintenance of effective labor), major depression and obesity (emphasis mine). Safety trials for intravenous urocortin treatment have already begun for the treatment of congestive heart failure. Further understanding the unique functions of urocortin 1, urocortin 2, and urocortin 3 action may uncover other therapeutic opportunities.

  11. Love what you have to say about pot. It gets way to much of a free pass if you ask me. I'm generally persuaded by the "legalize it" papers that my Freshman Comp students hand me, but I also let them know that the studies about long term daily use are in (Pubmed)don't look real promising.
    On Grehlin and never feeling full - look at Prader-Willi syndrome. It's fascinating. It's not my field but I like genetics.


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