Thursday, July 5, 2012

About free fatty acid/opioid receptor gene family

Free fatty acid receptors (FFAR) show at least 20% identity with many receptors including opioid receptors which may explain why people are willing to use fatty foods even if they know how bad it can be for them. Also serotonin, cannabinoid and dopamine receptors showed up in this family which may explain enjoyment of fatty food plus link between normal addiction to feel good. 
Seems little bit like opiates "hitchhiked" pleasure pathway that usually comes from fatty food.

Also many results overlapped when comparing fruit flies and humans making it look like this huge receptor family started when common ancestor of humans and flies lived or even before that.

Similar genes may start due to gene duplication that creates several copies of same gene. That may happen during sexual mating. Sometimes child get gene from mother, sometimes from father and sometimes from both parents. As time goes by these copies can mutate differently and get new functions.

I compared proteins with BLAST search. All receptors are proteins so by searching receptors here. After clicking on protein `run  BLAST` option shows up to the right. Search setting are fine with default settings although search could be limited there to proteins from 1 specie. These searches can show how much nature has recycled genes with small changes. It also shows that same thing could have many names but by comparing them sometimes becomes visible what unites them.

Comparison of FFAR1 with human receptors. Longer lines mean larger difference in proteins. Chemokine receptors attract white blood cells to source of chemokines. Small group from OPRL1 to delta opioid receptors and all between are opioid receptors. Lysophosphatidic receptor can cause cell division and stimulate cells electric activity by releasing calcium. Upper 2 cause blood coagulation.  

Human FFAR compared to fruit fly proteins. Rhodopsin and opsin are involved in vision as light sensing proteins. Gonatropin-releasing hormone receptor stimulates sexual development and most other are neurotransmitters that stimulate neurons (acethylcholine, dopamine, CCK, corazonin, octopamine). For example octopamine is similar to noradrenaline and that receptor is to invertebrates what noradrenaline and adrenaline receptors are to vertebrates.

On this image i did BLAST search for cannabinoid receptor GPR55 marked with yellow and that seems to have almost identical results to searches with FFAR or opioid receptors. Some things that unite cannabinoids and opioids is that they cause hunger, dry skin/mouth and euphoria but during withdrawals also somewhat similar symptoms like nausea, sweaty/oily skin, shivers, diarrhea and restlessness with tiredness.

Blood vessels were regulated by some of these receptors. Bradykinin widens blood vessels lowering blood pressure and angiotensin has opposite effects to bradykinin. Thrombin and platelet activating factor receptor cause blood coagulation. Possible that during some ancient era these receptors were more similar to FFAR and they all are probably able to lose sensitivity if something over activates them. For example if blood gets fatty it make it more viscose and likelier to spread slower but if FFAR senses too much fat it could widen blood vessels or block blood coagulation to minimize viscosity. For example omega-3 polyunsaturated acid inhibits blood coagulation. Another free fatty acid also widened blood vessel in heart.  

Uncaring pleasure that fatty food gives (most likely animal product like meat, milk, cheese etc) motivates animals to keep eating other animals or risk hunger and all the emotional suffering it gives. This enjoyment may also make animals willing to keep on eating cute little animals even if they suspect they suffer when they wiggle in the mouth.
Similar uncaring attitude applies to almost any meaty food. I know well that sausage is greasy sliced up animal leftover stuck in intestines but if i eat it i still get pleasant warm buzz through my body and mind that makes me happy i ate it. As extra experiment during the day i wrote this i drank about 1 gram of sunflower oil. I drank i slowly and cautiously but within seconds i got intense and pleasant calm. Contact with tongue seemed enough to start this feeling and it lasted strongly for about 5 minutes. Possible that naturally oily skin in animals is enough to start predatory eating frenzy by giving very pleasant mood.   
Dairy products are also very fatty and they feel good even if people know this lactose could give them stomach pains, nausea and diarrhea.
Fat is quite addictive which becomes obvious if you skip fatty foods for even 1 day. By afternoon this could reach the point of being tired, grumpy, restless and angry over many things but these symptoms disappear after greasy food.
This addiction is probably reason why people willingly eat themselves fat knowing well that they will shorten their life, cause joint pains, become worse looking, cause deaths of more animals in slaughterhouses, lose attractiveness and more likely to stay single/lonely but still they keep on eating like heroin addicts willing to risk HIV infections through needle sharing or prostitution.  

Mu-opioid receptor activators cause appetite for fattier foods if they are injected into nucleus accumbens.

Opiate withdrawals cause muscle pains similarly to drugs that lower concentration of fats in blood. For example several lipid lowering drugs listed in Wikipedia mention muscle pains.

Opiates cause constipation and inhibited gag reflex but during withdrawals vomiting and defecating become much likelier. Possible that this is also side effect of old function FFAR had. If FFAR is throughout gastrointestinal tract then it could sense how much fatty food is left to absorb. If this receptor notices much fat left in digested food then it may constrict intestinal smooth muscles so they would not let food out yet. If they also reduce release of mucus and gastric acids then intestines may become less slimy and nutrients may pass more easily. Blocked gag reflex can motivate animals to keep on eating animals that could wiggle in their throat.
But as usual in body receptors adjust their amount and sensitivity to work in certain limits so long term opiate use may cause very active smooth muscles that force food out from any passage it could. Maybe this nausea started as warning mechanism that stops animals from eating too much fat. 


THCV. Fats have usually long carbohydrate chain and THC happens to have long carbohydrate chain. While THC activates cannabinoid receptors THCV has bit shorter chain as only structural difference and this gives it almost opposite effects to THC (binds to receptors but doesn`t activate them). Looks like having cannabinoid receptors related to FFAR receptors makes them activate if they bind with something similar to fatty acid chain.
Anandamide above is produced by human body. It looks mostly like fat molecule but it activates cannabinoid receptors. Even artificial cannabinoids found in "spice" mixes have long (at least 4 carbon long) fatty chains. Shorter chains seem to bind weakly or just block cannabinoid receptors.

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