Molecule Shuts Down Food Intake and Turns on ‘Siesta Mode‘” is the headline from Howard Hughes Medical Institute. And, another headline from E!, “Oprah Packs on the Pounds. . . and the Guilt!”
Oprah, don’t feel guilty! It’s your N-acylphosphatidylethanolamine, a phospholipid released from the gut after a fatty meal that travels to your brain,and settles down for a nap in your hypothalamus, making you feel full and sleepy.
That’s only part of the story: These same blood lipid signaling molecules and their degradation products also affect mood, energy, pain, and fertility.
From HHMI:
. . .In studies with mice and rats, researchers [Dr. Shulman and colleagues] have found that a chemical messenger called NAPE is made in the small intestine after the animals ate a greasy meal. After eating, NAPE—N-acylphosphatidylethanolamine, a mouthful in itself—enters the blood and travels to the brain, where it quashes hunger signals. Rats treated with extra NAPE for five days ate less and lost weight, hinting that studying NAPE could help researchers design better appetite suppressants or obesity drugs.. . .
(Thank you for the heads-up, Eva-Christine http://www.evah.org/).
The link between appetite and fat has been studied for some time, at least since HHMI researchers hit upon leptin about 15 years ago or so. Leptin was the paradigm shift: as insulin is to sugar, leptin is to fat. It was tough to turn into a drug, though.
Identifying particular blood lipids as another gut-brain pathway signal is a feat — although as a drug, I wonder if it has delivery issues. The trouble with the circulating natural anti-obesity molecules is that they need to have a long half life and sufficient dose. Think about it — you can’t make a pill the size of a burger, and anyway, the effects would only last a couple of hours. Translate that into a dosing regime: people won’t inject 3 horse needles a day, not unless they’re near death. And injectables for weight loss are a tough sell, anyway, at least to otherwise healthy obese people. NAPEs apparently have a quick half life – the rats in the study got hungry about 2 hours after exogenous administration. Rats outfitted with little vests geared with a NAPE IV line, and dosed for 22 days, had a continual suppression of appetite. So. . .. derivatize for a longer serum half life ? Maybe, but it’s still an injectable. Pills are better. But, will you need a pill the size of a pizza? Perhaps the way to go is with a pharmaco-milkshake on this one. Or maybe NAPE-producing probiotic laced yogurt. I’d cut a deal with a yogurt maker, as it seems some yeasts (and probably bacteria) produce these lipid-like molecules. If the substances are GRAS, then you can skip FDA and go straight to the pharma-food (unless the dosing alters the GRAS status). Probably testing a lactobacillis will produce something close. (I’m guessing).
Plus, I’m not clear if the NAPE molecule is what travels to the brain, or if it degrades first. HHMI researchers detected NAPE in the hypothalamus. There is another paper which points to oleoylethanolamide, which is an enzyme break down of NAPE, see here and here.
There’s a lot to be said for the molecular structure. NAPE and some of the other ones are amphiphilic – basically being water soluble on one side and oil soluble on the other. This is common in bile acids, transferrins and other molecules that sit on top of a cell membrane and have an active role (where you have water on one side, and the cell membrane surface on the other). My favorite amphilic molecules are non-Newtonian. With amphilic molecules, formulation is tricky. With some of the bile acids, if you put pressure on them, they liquefy. They solidify by staying still.
Regardless, lipid schmipid, so what? I mean, eat a greasy burger, you get high blood lipids, and you’re not hungry. Big deal. Plus high blood lipid levels can be pathological.
Mais non, mon chou, the whole lipid signaling story is in the midst of being unraveled.
So, let’s talk munchies. Blood lipids and their degradation products also interact with the endocannabinoid system – one of the systems with a dials for mood, alertness, memory, hunger, drastically lowering your threshold of entertainment until you spend a productive day playing this — all the things that go south with cannibis use.
A fatty diet also causes the liver to produce anandamide — that binds to cannabinoid receptors (the same one activated with cannabis), and causes munchies. Anandamide is also produced when NAPEs break down. On the other hand, adding anandamide to the diet (so you get the munchies) increases your brain N-aceylethanolamines (that suppress appetite, here, although I don’t know about N-acylphosphotidylethanolamines, with the extra phosphotidyl moiety — and a precursor to N-acelethanolamine – so perhaps I’m missing something). Looks like a good feedback mechanism to me: anandamide binds to the pot receptor, causes munchies, and NAPEs show up and go to the hypothalamus to cut appetite. Yin and yang.
Plus, there’s a connection with mood in there, somewhere.
Some cannabinoid receptors live and work in the bikini area (here) – and these bind the lipid signaling molecules (or their break down products). Mood, hunger, lipids — is there a PMS connection here somewhere? If PMS is caused by cannabinoid receptors in the uterus outcompeting the brain for lipid signaling molecules, that would leave the brain receptors for cannabis and for hunger empty. Grumpy and hungry.
Perhaps there is an indirect dopamine effect for the NAPE->anandamide lipid signaling molecules. Some blood lipid signaling molecules that bind endocannabinoids also bind to vanilloid receptors. Vanilloid receptors are involved with body surface and internal temperature, skin perception of hot or cold, pain and numbness, depression and anxiety. Anandamide – apparently via a vanilloid receptor, rather than a cannabinoid receptor - makes mice have a bad attitude. Mice were given anandamide, and then trained to do a task to get a food pellet. The mice knew how to do the task, but didn’t want to – similar to disruption of dopamine effects via the vanilloid receptor. they weren’t hungry – or else they would have gotten the food pellet faster. Nor were they otherwise suddenly sedentary (as compared to an open field test where they ran around). Nope, they just weren’t motivated. (See the paper, here and also another abstract here). Does this cross reaction between the cannabinoid receptor and the vanilloid receptor (which may relate to anxiety) result in people on cannabis becoming paranoid instead of relaxed?
So, maybe all of this is acting on beloved Oprah. Hang in there Oprah, and add NAPE or oleoylethylamide to your diet, and don’t use cannabis (because you may get more paranoid and feel more defensive, if not guilty, and at least get hungry).
Cites and links after the jump
Gillum MP, Zhang D, Zhang XM, Erion DM, Jamison RA, Choi C, Dong J, Shanabrough M, Duenas HR, Frederick DW, Hsiao JJ, Horvath TL, Lo CM, Tso P, Cline GW, Shulman GI. “N-acylphosphatidylethanolamine, a Gut- Derived Circulating Factor Induced by Fat Ingestion, Inhibits Food Intake,” Cell 135: 813 - 824 
doi:10.1016/j.cell.2008.10.043
Guo Y, Wang H, Okamoto Y, Ueda N, Kingsley PJ, Marnett LJ, Schmid HH, Das SK, Dey SK.,”N-Acylphosphatidylethanolamine-hydrolyzing Phospholipase D Is an Important Determinant of Uterine Anandamide Levels during Implantation,” J. Biol. Chem., Vol. 280, Issue 25, 23429-23432, June 24, 2005doi:10.1074/jbc.C500168200
Fu J, Kim J, Oveisi F, Astarita G, Piomelli D., “Targeted enhancement of oleoylethanolamide production in proximal small intestine induces across-meal satiety in rats., Am J Physiol Regul Integr Comp Physiol. 2008 Jul;295(1):R45-50. Epub 2008 Apr 23. PMID: 18434444
Schwartz GJ, Fu J, Astarita G, Li X, Gaetani S, Campolongo P, Cuomo V, Piomelli D., The lipid messenger OEA links dietary fat intake to satiety. Cell Metab. 2008 Oct;8(4):281-8, PMID: 18840358 [PubMed - in process]
Panlilio et al., “Anandamide-induced behavioral disruption through a vanilloid-dependent mechanism in rat,” Psychopharmacology 10.1007/s00213-008-1399-x published on-line 11.18.08
Your post makes me want to make up a t-shirt that says the following:
It’s N-acylphosphatidylethanolamine*, stupid!
(* a phospholipid created in my small intestine)
Rats outfitted with little vests! Poor lab rats. I almost hate to read animal studies, especially pain studies. This one made me feel faint:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2497464
“Here we report a method for performing a chronic constriction injury (CCI) of the infraorbital nerve (ION) in the rat as a component of a chronic pain model. …”
Sandra aka “not Devin”
Ouch, there’s got to be a better mouse model than that for chronic pain. . .
Definitely an “ironic T-Shirt” theme here. . . you could excuse just about anything. How about, “Don’t blame me, I’m DRD4R7″
(http://neurologicalcorrelates.com/wordpress/2007/11/26/love-advice-for-the-ladies-watch-out-for-men-born-in-winter-especially-swedish-ones/)
Someone was making dopamine chem-draw necklaces, a perfect gift for your Valentine.
On the clothing theme . . . I was wondering about the little vests, whether they were 3-piece suit types, down bubble vests or perhaps a nice crocheted in granny squares? Nope, they’re clear plastic.