Biological Consequences of Specific Dietary Fatty Acids
Nutrition labels provide very limited information. Individual saturated and unsaturated fats can have distinct and even opposing biological effects.
Not medical advice.
More and more people are becoming metabolically unhealthy. For many, this is happening despite their active effort to eat less and exercise more. Why?
We have previously talked about the constellation of symptoms associated with metabolic syndrome. Obesity is just one of these. You can have metabolic syndrome without obesity, and be obese without having metabolic syndrome. (Important note: obesity is never healthy. Even in the absence of metabolic syndrome, obese people are at higher risk of multiple negative health outcomes).
An intriguing pattern was noted: although we’re eating way more calories today than our pre-industrial ancestors, caloric intake peaked and began declining somewhat near the year 2000. Obesity, diabetes, and metabolic syndrome have continued to rise despite this. We’re eating less and moving more than we were 1-2 decades ago, but metabolic health is worse (on average).
Uhh… what?
In “Decomposing Fats & Carbs,” we dissected different types of fats and carbohydrates, the two primary classes of dietary molecules we get energy from. A theme we emphasized: calories are not interchangeable. Your body reacts to different types of calories in different ways. We will build on that theme here, going into more detail on how different types of dietary fat have distinct effects in the body. Some fats are more obesogenic than others. As we will see in a later installments, there are even non-caloric obesogens—food and non-food components that promote obesity without providing us energy.
In “Eating Fat Like Never Before,” we took note of several striking patterns in modern Western fat consumption. Compared to our hunter-gatherer ancestors:
We eat more total fat. This trend has been going on for centuries but peaked and began declining somewhat by 2000;
We eat a higher ratio of unsaturated to saturated fats. Saturated fat availability remained quite flat from the early 1900s, while mono- and polyunsaturated fats became more prominent in the food supply;
The ratio of omega-6 (ω-6) to omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) has exploded. Americans today consume a ω-6:ω-3 ratio of 20:1 or more—much higher than the roughly 1:1 ratio of most hunter-gatherer diets.
For the average American today, more than 10% of total calories are coming from linoleic acid, a ω-6 polyunsaturated fatty acid (PUFA) found in seed oils. In traditional hunter-gatherer diets, ω-6 PUFAs are never more than 2% of calories.
These consumption trends and their correlation with obesity and metabolic dysfunction are striking, but don’t prove anything on their own. If these changes are significant drivers of “diseases of civilization”—obesity, diabetes, and other chronic conditions—then there should be a clear, mechanistic link between specific dietary fat profiles and these states of metabolic dysfunction. For example, what are the biological consequences of an ultra-high ω-6:ω-3 ratio? Does a diet high in linoleic acid actually drive weight gain, insulin resistance, or inflammation? How?
Because changes in the ω-6:ω-3 ratio is one of the most striking trends, we will start there. The vast majority of people in the industrialized world have a diet with ω-6:ω-3 ratio that’s way too high. For most, this is driven by overconsumption of ω-6 fats due to their ubiquity in processed foods. For people with specific diets (e.g. vegans), there’s also risk of ω-3 deficiency.
ω-6 PUFA overconsumption: a recipe for inflammation
Our consumption of cheap seed oils and processed foods has resulted in a dramatic increase in the ω-6:ω-3 ratio of our diet over time. The trend is striking and undeniable. If foods high in omega-6 (ω-6) fats like linoleic acid are as bad anti-seed oil crusaders say, then we should be able to find clear cause-and-effect evidence for how ω-6-rich diets drive metabolic dysfunction.
I recently did three different podcasts, each speaking to this from different angles:
In M&M #135, Dr. Orrin Devinsky walked me through diet trends in the US since the 1800s. There’s been a massive increase in cheap seed oils and general move away from animal-based fats over time. Mainstream medical institutions helped drive this trend through their myopic focus on blood cholesterol levels as a health marker.
In M&M #134, Dr. Artemis Simopoulos talked about how ω-6 fatty acids affect our biology compared to ω-3 PUFAs. ω-6s like linoleic acid generally have pro-inflammatory effects; ω-3 fatty acids are generally anti-inflammatory.
In M&M #136, Dr. Chris Knobbe dug into the health effects of ω-6s further: the much lower linoleic acid consumption among hunter-gatherers, how ω-6 overconsumption contributes to obesity and other forms of chronic illness, etc.
Dr. Simopoulos wrote a great review paper on the importance of the ω-6:ω-3 ratio for obesity. In short, despite their chemical similarity, ω-6 and ω-3 fatty acids are processed differently by the body.
Omega-6 and omega-3 fatty acids are not interconvertible, are metabolically and functionally distinct, and often have important opposing physiological effects, therefore their balance in the diet is important. —Simopoulos (2016)
ω-6 fatty acids serve as precursors to arachidonic acid, which gives rise to various pro-inflammatory signaling molecules. A high ω-6:ω-3 ratio is associated with higher levels of pro-inflammatory arachidonic acid derivatives. One example: prostaglandins, a group of fatty molecules with diverse, hormone-like effects in the body. They mediate inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin and ibuprofen antagonize the action of prostaglandins, as do corticosteroids and vitamins D3 and K2.
ω-6 and ω-3 fatty acids tend to have opposing effects on various aspects of physiology including adipogenesis (fat cell formation), inflammation, and insulin resistance. In general, ω-6 overconsumption will promote those things (bad), while a more balanced ω-6:ω-3 ratio will do the opposite (good).
It’s important to remember that biology is complicated. Things are rarely so clean-cut as, “Omega-6 = 100% bad, omega-3 = 100% good.” Both ω-6 and ω-3 fatty acids are necessary for the proper, adaptive functioning of our inflammatory mechanisms. As one physician-scientist told me:
If you didn’t have any omega-6s, you would be eaten by the maggots. They are part of your defense system against foreign invaders… So you need them. But you don't need too many of them. —Dr. Robert Lustig, M&M #140
We require inflammation to fight infection and repair tissue damage—it just needs to be restricted in space and time to minimize collateral damage. That’s why the balance ω-6 and ω-3 fatty acids is so important—it helps regulate where and when inflammation happens. When there’s an imbalance, inflammation “leaks” into inappropriate times and places. That’s chronic inflammation. It’s what an elevated ω-6:ω-3 ratio promotes, boosting your risk for all kinds of chronic diseases.
Does the scientific literature support this expectation? In my reading, yes. Here is a sampling of important observations in the literature, all from studies cited in this review paper and consistent with what four recent physician-researchers have shared on the podcast (see episodes #134, #135, #136, and #140)
High-fat diets rich in ω-6 PUFAs increase the risk of leptin resistance, diabetes, and obesity in both rodents and humans.
In rodent studies, “Western-like diets” (practically synonymous with a high ω-6:ω-3 ratio) not only drive obesity and excess insulin, but this effect is enhanced across generations: the offspring of mice on this diet look even worse than their parents even though they consume the same calories. Such transgenerational effects are consistent with human studies showing poor developmental outcomes in infants with skewed ω-6:ω-3 intake during the perinatal period. As discussed at the start of M&M #140, maternal diet can drive epigenetic changes that predispose infants to metabolic dysfunction later in life.
In rodents, elevating levels of the ω-6 PUFA linoleic acid causes greater weight gain compared to diets with less linoleic acid matched for total calories. Increasing linoleic acid content from 1% to 8% of calories increased the risk of obesity, even on a low-fat diet. (Recall: linoleic acid represents >10% of calories for many Westerners today, whereas traditional hunter-gatherer diets are <2%.)
The idea that an elevated ω-6:ω-3 promotes inflammation and chronic disease generally is further supported by work using genetically engineered mice that automatically convert specific fatty acids to or from ω-6 PUFAs. (Mammals cannot naturally convert excess ω-6 PUFAs into ω-3s, unlike other creatures). Scientists have compared two strains of engineered mice: One strain metabolizes ω-6 PUFAs into ω-3s, resulting in a lower ω-6:ω-3 ratio. Another strain produces ω-6s from monounsaturated fat, resulting in elevated ω-6 levels. What happens when you feed both strains the exact same diet?
Transgenic mice that overproduce ω-6 PUFAs, resulting in a skewed ω-6:ω-3 ratio similar to the typical American, show distinct metabolic profiles and health outcomes compared to mice with more balanced ratios (even when fed an identical diet). Overproduction of ω-6 PUFAs leads to elevated levels of markers for inflammation, liver disease, metabolic syndrome & type 2 diabetes, atherosclerosis, and liver cancer.
As we dissected in here, the ω-6 PUFAs are coming largely from seed oils, which are ubiquitous. Soybean oil is ω-6-rich and by far the most widely consumed seed oil. By contrast, coconut oil has very high saturated fat content and almost no PUFAs. In mice, a diet composed of both coconut and soybean oil drives more weight gain, adiposity, diabetes, glucose intolerance and insulin resistance than one containing coconut oil alone (matched for calories). The addition of soybean oil drives worse metabolic outcomes by leading to dysregulation of genes involved in liver metabolism, mitochondria function, inflammation, and more.
Results like this highlight why we shouldn’t think about diet in terms of calories alone. Different types of fats, such as the ω-6 PUFAs found in soybean oil vs. the saturated fatty acids found in coconut oil, have very different metabolic effects. They aren’t merely fuel—they can influence gene expression itself, which changes how our cells deal with the molecules we feed them.
The overall point: when there is a skewed ω-6:ω-3 ratio with an over-supply of ω-6 PUFAs, we observe poor health outcomes. A general increase in chronic inflammation is at the base of this, explaining why a high dietary ω-6:ω-3 ratio is associated with poor health generally. Cause-and-effect has been demonstrated for this in animal studies, with a clear mechanistic basis for why we should expect this in humans as well. It’s therefore likely that the consumption trends and associations we see between high ω-6 diets and poor health outcomes in humans are not merely statistical artifacts (“correlation without causation”).
But elevated ω-6 PUFA intake is only one side of the equation. If the issue is really ω-6:ω-3 balance, then we would expect ω-3 deficiency to also be problematic.
ω-3 deficiency: a recipe for brain dysfunction
The main driver of a high ω-6:ω-3 ratio is excess ω-6 intake, as virtually all ultra-processed foods and industrial seed oils contain high levels of ω-6s (e.g. linoleic acid). As Dr. Chris Knobbe pointed out, this has resulted in the average American today getting more than 10% of their calories solely from linoleic acid. Without knowing anything about biology, what are the odds that getting >10% of your calories from a single molecule is going to be good for your health? Consuming anything at that concentration is unlikely to be good.
The flip side of this equation is ω-3 deficiency. This is a special concern for people eating exclusively plant-based diets, like vegans. While certain plant foods (e.g. flax seeds, almonds) contain dietary ω-3s like ALA, its crucial for our bodies to have adequate levels of two others: EPA and DHA. These ω-3s are abundant in cold-water marine animals like salmon.
The body can convert ALA into EPA and DHA, but not efficiently. The conversion rate of ALA to DHA is especially low. This means you will have to consume a large mass of ALA-containing plant foods (i.e. eat more calories) to avoid EPA and DHA deficiency—not ideal if you’re trying to lose weight or reap the health benefits of caloric restriction.
To learn more about the topics covered in this essay, try these episodes of the Mind & Matter podcast:
M&M #134: Omega-6-9 Fats, Vegetable & Seed Oils, Sucrose, Processed Food, Metabolic Health & Dietary Origins of Chronic Inflammatory Disease | Artemis Simopoulos
M&M #132: Obesity Epidemic, Diet, Metabolism, Saturated Fat vs. PUFAs, Energy Expenditure, Weight Gain & Feeding Behavior | John Speakman
M&M #131: Dietary Fat, Cholesterol, Cardiovascular Health & Disease, Carbohydrates, Dietary Guidlines, Food Industry & Diet Research | Ronald Krauss
M&M #140: Obesogens, Oxidative Stress, Dietary Sugars & Fats, Statins, Diabetes & the True Causes of Metabolic Dysfunction & Chronic Disease | Robert Lustig
As Dr. Robert Lustig pointed out, DHA is critical for neuronal function. On a plant-based diet, supplementation is therefore crucial. The problem is that fish oil supplements can’t be consumed by true vegans. There are algal oil supplements but they contain mostly DHA, not EPA. It is therefore extremely difficult to get adequate levels of EPA and DHA on a strictly plant-based diet.
The ω-3 fatty acids ALA, EPA, and DHA all have positive health benefits, but not identical benefits. You can’t fulfill all of your ω-3-dependent biological functions with just one of them. In general, ω-3s are anti-inflammatory, with being DHA critical for proper brain function.
Here is a sampling of the literature on how brain function is impaired in animals with ω-3-deficiency:
When pregnant rats and their offspring are fed a ω-3 deficient diets during early brain maturation, offspring later show neuronal and behavioral deficits related to learning, memory and plasticity;
In mice, dietary ω-3 deficiency abolishes important forms of endocannabinoid-mediated neuroplasticity in the brain;
In rats, high sugar (fructose) intake induced metabolic dysfunction in the brain, including problems with insulin signaling and cognition. ω-3 deficiency makes this dysfunction worse, while ω-3 supplementation partially counteracts it;
When pregnant mice are fed a diet with high ω-6 and low ω-3 content (ω-6:ω-3 = 120), their offspring develop alterations in the brain’s dopamine ‘reward system’ and overeat palatable food (sucrose).
Animal studies give us a mechanistic basis to interpret the human literature, where ω-3-deficiency is linked to negative psychiatric conditions:
ω-3 deficiency and imbalanced ω-6:ω-3 ratios are implicated in negative psychiatric outcomes, such as major depression and suicide risk;
Early developmental deficiencies in ω-3s like DHA and EPA are linked to developmental abnormalities such as autonomic dysregulation and increased aggression.
DHA and EPA exert antidepressant, anti-inflammatory, and neuroprotective effects. Treatment of patients with major depression with EPA or DHA results in higher blood levels of their metabolites, which correlate with less severe symptoms.
The overall point: ω-3 PUFAs like DHA and EPA play a crucial role in the brain and a balanced ω-6:ω-3 profile is important for brain health. Diets with a high ω-6:ω-3 result in deficiencies in neuronal metabolism and plasticity in animal models, which can explain why they are linked to behavioral, cognitive, and emotional problems in humans. Everyone is at high risk of ω-6 overconsumption if they eat processed foods. Those who eat strictly plant-based diets are at risk of ω-3 deficiency without supplementation of fortification of foods with ω-3s (EPA and DHA in particular).
Saturated vs. Unsaturated Fat: Mainstream medicine’s culture of stubborn thinking
The demonization of saturated fat by the mainstream American medical establishment was a tragic product of 20th century culture. To this day many people believe saturated fats are “bad fats” and unsaturated fats are “healthy fats.” This popular belief has contributed to the meteoric rise in the consumption of “heart healthy” ω-6 PUFAs, among other dietary trends.
This rise in seed oil consumption, while other sources of fat and calories have stayed flat or even decreased, means that people are consuming a higher ratio of ω-6 PUFAs compared to other fats, including ω-3 PUFAs and saturated fats. We saw above what this did to mice in highly controlled experiments. Those results look suspiciously similar to what we’ve seen happen to human health for several decades.
In my conversation with physician-scientist Dr. Orrin Devinsky, he described many of these trends in detail, as well as factors that drove the widespread adoption of false or misleading beliefs about dietary fats. When I asked him how strong the evidence ever was that eating saturated fat is a major cause of heart disease, he said:
“This evidence has never been good. We are left with a relic. Unfortunately the American Heart Association probably represents the most die-hard advocate [of dietary saturated fat driving heart disease] and I think it would be wonderful if they would go back and do a deep-dive over the history.”
-Dr. Orrin Devinsky, M&M #135, ~0:12:10
In another conversation, Dr. Chris Knobbe walked me through ω-6 overconsumption and its detrimental impact on cardiovascular health. Why do mainstream medical institutions like the AMA label ω-6 PUFAs as “heart healthy?” This can’t simply be coming out of thin air. So why do they make this recommendation?
“One reason: they lower cholesterol. And that’s it… the American Medical Association, Harvard School of Public Health, Tufts University Nutrition department, Mayo Clinic’s nutrition department, Cleveland Clinic, American Heart Association… all recommend seed oils because they ‘improve our cholesterol,’ meaning they lower our cholesterol.”
-Dr. Chris Knobbe, M&M #136, ~0:56:50
These ideas are so deeply entrenched in mainstream institutions that they get baked directly into the algorithms generating the results of Tufts University’s Food Compass, which consistently ranks a variety of processed foods as better for our health than whole foods human beings were consuming for millennia prior to industrialization:
In these and other conversations, I asked where this myopic fixation on blood cholesterol comes from. The answer: because we have drugs that reliably lower blood cholesterol. Statins are one of the most widely prescribed and lucrative pharmaceuticals in history.
As it turns out, for most people, statins not nearly as effective at preventing mortality as we would hope. (For more detail, see M&M #140 ~0:43:46). Because they reliably lower blood cholesterol and mainstream medicine believes lower cholesterol is the key to cardiovascular health, statins are part of the “standard of care.” If your cholesterol levels are above some threshold, most doctors will reflexively prescribe a statin. (When something is the “standard of care,” it means you can’t sue your doctor later on, if something goes wrong as a result of the care you received).
The point for us here is that an entire system of official medical practices has been propped up by the strong, unending belief that dietary saturated fat is a major driver of cardiovascular disease.
The overall point: it’s silly to think about “saturated fat” as being good or bad for health because there are many different saturated fatty acids. They differ based on their overall length—ranging from short, medium, and long—and the placement of carbon-carbon single bonds long the molecule (e.g. strain- vs. branched-chains). These geometric differences mean that different saturated fatty acids have different physiological effects.
Saturated vs. Unsaturated Fat: Fatty acids with different shapes have different biological effects
In nutrition, fats are commonly classified based in the number of double bonds they contain—saturated (none), monounsaturated (one), and polyunsaturated (two or more). Nutrition labels capture this but obscure the fact that there’s a greater diversity of specific fatty acids. Here’s a cartoon illustrating fatty acid diversity in terms of both saturation level and length:
Chain length is the number of carbons bonded together along the main chain of a fatty acid molecule. Trying to memorize all of the different fatty acids and chain lengths is unwieldily. It’s convenient to think about chain length in simple buckets: short, medium, and long.
Fatty acids can also differ based on their branching pattern. Here are a few individual fatty acids with the same chain length but different branch patterns:
Odd- vs. Even-Chain Saturated Fatty Acids: Disease risk & food sources
It’s also useful to distinguish between odd- and even-chain fatty acids. In my conversation with Dr. Lustig, this was the primary distinction he made among saturated fats:
“There are two types of saturated fats. There’s ‘red meat saturated fats’ and then there’s ‘dairy saturated fats.’ They are not the same, even though dairy comes from an animal that also provides red meat.
Red meat is filled with even-chained saturated fatty acids, C:16 and C:18, and those are cardiovascularly neutral—neither good nor bad. Dairy saturated fat (e.g. milk) turns out to be odd-chain saturated fatty acids, C:15 and C:17… they turn out to be protective against cardiovascular disease.“
-Dr. Robert Lustig, M&M #140 ~0:39:18
Dairy and meat products each contain a mix of both odd- and even-chain saturated fatty acids. The distinctions quoted above are about relative abundance. For example, dairy products often contain higher absolute levels of even- than odd-chain saturated fats, but a higher proportion of odd-chain fat compared to meat (see chart below).
Here are a few studies and meta-analyses consistent with Dr. Lustig’s comments and contradicting the simplistic mainstream view that dietary saturated fat intake equates increased cardiometabolic disease risk:
A large meta-analysis of human clinical trials found no significant relationship (positive or negative) between total saturated fatty acids and coronary disease. The same analysis, when breaking down individual fatty acids, found a significantly lower relative risk of coronary disease for certain odd-chain saturated fatty acids (see graph below).
In another meta-analysis of human studies, higher levels of certain odd-chain saturated fatty acids were associated with lower cardiovascular disease risk.
Specific odd-chain saturated fatty acids interact with PPAR receptors and, in rodents, can have health benefits including lower risk of inflammation, cardiometabolic disease, and liver disease.
It would appear that specific saturated fatty acids (e.g. C:15), like specific unsaturated fatty acids (e.g. ω-3 PUFAs), are not merely energy sources for the body. They can act directly as or serve as precursors to signaling molecules—molecular messengers that influence how our cells behave. This is likely a reason why both C:15 saturated and ω-3 polyunsaturated fatty acids are associated with lower cardiovascular disease risk. Among other things, they seem to help dampen inflammation.
As should be clear by now, it’s not very useful to think about fats at the level of saturated vs. unsaturated. Within both fat classes, specific fatty acids can have distinct effects in the body. Some even have opposing effects, such as the pro- vs. anti-inflammatory effects of ω-6 vs. ω-3 PUFAs, respectively. It’s important to consider their relative abundance, both to each other and overall calories consumed.
Saturated fatty acid content varies widely between foods.
Even when we limit ourselves to long, even-chain saturated fats, comparing the fatty acid profile of different foods reveals striking diversity. Here’s a figure from this paper, highlighting the major even-chain saturated fatty acids found in a variety of foods and cooking oils:
Notice the broad patterns: foods differ in overall saturated fat level and the specific mixture of individual saturated fatty acids. For example, the majority of the fat content of butter and coconut oil comes from saturated fat, but each contains a distinct mix of saturated fatty acids. Proportionally, butter has much higher palmitic acid content; coconut oil has a lot more lauric acid.
Recall the trend in cooking oils we saw in here: consumption of vegetables oils high in ω-6 PUFAs has skyrocketed while oils high in saturated fat (e.g. butter, lard, tallow) are consumed much less than they once were:
This has been a major driver of the elevated unsaturated:saturated fat intake ratio for the average American. As with ω-6 vs. ω-3 PUFAs, it is important to consider the relative balance of saturated fatty acids. Not only has consumption of ω-6-rich vegetable oils exploded since the mid-1900s, this was paralleled by an already decreasing rate of butter and milk consumption.
It’s conceivable that the pro-inflammatory effects of increased ω-6 PUFA consumption have only been made worse by decreased consumption of dairy products containing odd-chain saturated fats with anti-inflammatory effects. Just consider the newfound popularity and aggressive mass marketing of plant-based dairy milk alternatives. The fat content is typically higher in ω-6 PUFAs and lower in saturated fat than dairy milk. What effect would we expect this to have on chronic inflammation, all other things being equal?
The overall point: all fatty foods contain a mixture of different fatty acids. Because fatty acids can actually change the way our cells behave, their metabolic consequences are often distinct. As a result, two different dietary mixtures of fatty acids, each containing the same calories, will likely produce different physiological outcomes. This can include weight and fat gain, as well as other markers of cardiometabolic health.
Beyond Fat…
As we’ve seen here, the relative ratio of different fatty acids is key. Over time, the ratio of different fats in the standard Western diet has changed dramatically:
Increases in the ω-6:ω-3 PUFA ratio (expected to be pro-inflammatory).
Increases in the overall ratio of unsaturated-to-saturated fats (less clear, but possibly also pro-inflammatory).
Macronutrient ratios are important both within and across the major macronutrient classes of fats, carbs, and protein. Diets high in both fats and carbohydrates can be more obesogenic and metabolically unhealthy than calorie-matched diets high in only one. Combinations of specific fats and specific carbs can be especially problematic.
To learn more about the topics covered in this essay, try these episodes of the Mind & Matter podcast:
M&M #134: Omega-6-9 Fats, Vegetable & Seed Oils, Sucrose, Processed Food, Metabolic Health & Dietary Origins of Chronic Inflammatory Disease | Artemis Simopoulos
M&M #132: Obesity Epidemic, Diet, Metabolism, Saturated Fat vs. PUFAs, Energy Expenditure, Weight Gain & Feeding Behavior | John Speakman
M&M #131: Dietary Fat, Cholesterol, Cardiovascular Health & Disease, Carbohydrates, Dietary Guidlines, Food Industry & Diet Research | Ronald Krauss
M&M #140: Obesogens, Oxidative Stress, Dietary Sugars & Fats, Statins, Diabetes & the True Causes of Metabolic Dysfunction & Chronic Disease | Robert Lustig
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