Since I published the ROS theory of obesity, one of the most common questions I’ve gotten is, “What about monounsaturated fat(MUFA)?” My answer is it depends on whether it is dietary MUFA or derived in fat or liver cells from production of SCD1. We’ve already seen that when saturated fat is produced through de novo lipogenesis (when the body makes saturated fat from starch), some SCD1 is produced to unsaturate it, leading to a balance of saturates and unsaturates.
If you ate something very high in monounsaturated fat, the expectation should be that the body saturates it to get it to the same place of balance. Except that we lack an enzyme that can turn MUFA into saturated fat. Instead what happens is that a signalling molecule called oleoylethanolimide (OEA) is produced by our small intestine from ingested oleic acid, the most common dietary MUFA famously found in olive oil. OEA sets in motion a chain of events which saturates our dietary fat! It does this by cranking up saturated fat production in the liver and increasing the movement of fat throughout the organism.
The Caveman Pantry
For at least 400,000 years humans have been using bone marrow as a storage form of calories, leaving it in the whole bone for as many as nine weeks before cracking apart the bone and eating it.1 It appears to be the original pantry item. Another pantry item: at least 170,000 years ago modern humans were roasting high starch, low fiber, potato like tubers in a cave in Africa2, well proceeding the fully modern human diaspora from Africa3. Tubers store well in caves, especially when buried in sand or ash.
I find it likely that on rainy days in Africa 170,000 years ago, humans were roasting marrow bones and potatoes in their caves and eating them together. Many bone fragments have been found in the same cave where the roasted tubers were found.4 It may come as a surprise to some that bone marrow fat is one of the richest sources of monounsaturated fat (MUFA) on the planet, even rivaling olive oil at times!5 This is only surprising because of the culturally common but completely inaccurate assumption that all fat from animal sources is highly saturated. The cave dwellers were in my opinion the predecessors to modern Mediterranean people eating pasta with olive oil.
|Deer Bone Marrow||66%||23||6||54|
If you’ve already read The SCD1 Theory of Obesity Part 1 and Part 2, you’ll already see the problem here. Stored monounsaturated fat seems to be sufficient to cause fat accumulation in mammals. Furthermore, if a cave dweller were to simply store enough of the MUFA rich bone marrow fat as bodyfat, they might lose the ability to do leptin induced thermogensis in the fat cells and wind up with a post-obese metabolism.
Summary of the SCD1 Theory of Obesity
Fat cells release a hormone called leptin. The more fat mass you have, the more circulating leptin. If you have sufficiently saturated fat – both from diet and stored body fat – you respond to leptin by upregulating genes involved in thermogenesis, the process of burning off calories as heat. If your fat becomes too unsaturated, you lose the ability to do leptin induced thermogenesis. Your body temperature drops and you become prone to obesity.
SCD1 is an enzyme that converts saturated fat (SFA) to monounsaturated fat (MUFA). Obese humans make a lot of SCD1 and have highly unsaturated bodyfat. Overexpressing SCD1 is sufficient to cause heart muscle cells to store fat. Mice lacking SCD1 are largely protected from leptin-deficiency induced obesity.
Leptin is supposed to work by increasing fat burning in the fat cells (fat cells both produce leptin and have leptin receptors) which produces Reactive Oxygen Species (ROS) in the mitochondria which is a signal to both decrease SCD1 and turn on thermogenesis. If stored fat becomes too unsaturated, insufficient ROS are generated in response to leptin leading to a nasty cycle of ever increasing SCD1 and decreasing fat saturation levels, leading to lowered body temperature and obesity.
The Body Seeks Balance
We know humans can create ONLY saturated fat from starch through a process called de novo lipogenesis. Humans cannot exist on pure saturated fat so they upregulate SCD1 a bit in response to starch consumption. Conversely, if humans eat highly unsaturated sources of fat – such as bone marrow – they reduce SCD1. Either way the human body is trying to achieve the correct balance of monounsaturated and saturated fats that will allow for an appropriate response to leptin.
But what happens when the amount of dietary MUFA is enough to overwhelm the system? Reducing SCD1 can’t INCREASE saturation level of dietary fat, it can only prevent a further decrease.
Thanks to Tucker Goodrich for initially turning me onto a molecule called oleoylethanolamide (OEA). OEA is produced in our small intestine from oleic acid – the 18 carbon MUFA which is the primary component of both bone marrow and olive oil. We know that it’s important in energy regulation because it has been evolutionarily conserved for a very long time. The mammalian response to OEA presumably evolved in a common ancestor before mammals split off of the tree of life. That was over 178 million years ago.6 Remember that small mammals and dinosaurs co-existed! Due to the deeply conserved evolutionary nature of OEA signalling, OEA both combats obesity in rats7 and reduces non-alcoholic fatty liver disease (NAFLD) symptoms in humans.8
As a signalling molecule, OEA has several mechanisms of action:
- It suppresses appetite9
- It upregulates PPAR alpha, a master fat metabolism up-regulator9
- It downregulates SCD17
This is very clever.
The first thing is to minimize the amount of incoming MUFA. That’s straight forward enough. OEA decreases appetite through a mechanism that requires PPAR alpha. Consuming MUFA leads to a cessation in consuming MUFA.
PPAR alpha is a transcription factor that turns on all facets of fat metabolism: fat oxidation rates in the mitochondria, fat transport by increasing lipolysis in fat cells and export from the liver and fat production in the liver10. It also increases SCD111 leading to an appropriately saturated/unsaturated fat blend coming out of the liver. At least that is what happens when PPAR alpha is stimulated by a “normal” activator, such as the fibrate drugs11, which have been known to improve blood lipids (according to the traditional model) since the 1960’s.12
But in the specific case of OEA stimulation, PPAR alpha has all of those same effects except that the liver is now cranking out saturated fat in the absence of SCD1. Of course the bone marrow consumer is getting other specific inhibitors of SCD1 from the bone marrow – palmitoleic acid and CLA, among others – but the olive oil consumer has to rely on OEA alone.
OEA sets in motion a series of events which saturates incoming dietary MUFA by limiting the amount consumed, increasing fat oxidation rates to burn the MUFA off and increasing saturated fat production and export from the liver.
A Dynamic System
Let’s think a little more about what’s happening if you are the cave dweller who has just eaten bone marrow and potatoes.
Your insulin level will rise in response to the starch. Your fat cells will be relatively insulin sensitive, so insulin will reduce lipolysis but this will be somewhat countered by OEAs effect on PPAR alpha, which increases lipolysis.
MUFA from the marrow will be absorbed and released from your small intestine in floating “boats” (as Dave Feldman calls them) called chylomicrons, which are ultimately transported in the bloodstream. These chylomicrons will “dock” at tissues that express something called LPL (lipoprotein lipase) – predominantly your fat cells – where they unload their cargo. Much of the fat will be transported into your fat cells but much will also be “spilled” in the bloodstream, becoming free fatty acids.13 Since your fat metabolism is turned up due to PPAR alpha, much of the MUFA that enters the fat cells will be metabolized immediately.
Your liver, also jolted into action by the PPAR alpha, will be very busy: taking in these Free Fatty Acids that were spilled, using the blood glucose provided by the potatoes as raw material to build saturated fat by de novo lipogenesis, then re-esterifying it all together into triglycerides that it will pack into VLDL and release into the bloodstream. The VLDL, much like the chylomicrons, dock at tissues expressing LPL to unload their cargo. Some of this will also be spilled, making its way back to the liver to get up-satuaretd again before being packed into VLDL and returned to the blood.
All of this happens quite quickly. After a large meal, your intestine can continue to release dietary fat for several hours. The half-life of a chylomicron is typically under an hour. The half-life of VLDL is 30-60 minutes.14 So dietary MUFA can get up-saturated through several cycles after a large fatty meal.
Two hours post meal, the effect of insulin begins to wane and from there on out lipolysis from fat cells rapidly increases. Again, this behavior is spurred on by the up-regulated PPAR alpha due to OEA being released by the small intestine. The effect of PPAR up-regulation is to increase fat flux through the whole system. The recently stored MUFA rapidly re-enter the pool of circulating free fatty acids and head to the liver to get up-saturated.
The difference between dietary monounsaturated fat (MUFA) and MUFA created in fat cells by SCD1 is that dietary MUFA leads to the production of OEA. OEA blunts appetite, upregulates PPAR alpha and downregulates SCD1. This leads to increased fat oxidation, increased fat flux through the system and steadily increasing saturation levels of circulating fat in the hours after a meal. Ultimately, in cultures that are metabolically healthy, this seems to lead to fat saturation levels reaching an acceptable level before being stored.
Would I recommend olive oil if you’re trying to lose weight? I wouldn’t.
I’ll leave you with a thought question and I don’t know the answer. If I figure out the answer it’ll make a fun post. Feel free to comment. The question is this: If a healthy person eats JUST bone marrow, is there a tissue where PPAR alpha activation combined with SCD1 suppression leads to MUFA being broken down into acetyl-CoA which is then rebuilt into saturated fat before being exported or stored?
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