Posted by: Joseph Dixon | June 3, 2014

Science: Unintended Consequences; Ancel Keys, Cholesterol, and the Transition to an Obese Society; Part XVII, So What Is The Truth About Fat?

In the last chapter I discussed how fatty acids (the body’s gasoline) are mobilized from adipose in order to be used for energy by tissues like the heart. But it turns out that fatty acids and other lipid species are used in cells for many other purposes than just energy.

Just like all the different pieces that one finds in a box of Lego® bricks, all the different lipids in the cell can be used in intertwining ways to build any structure needed. One of my favorite lipids is found in the inner membrane of the mitochondrion. This membrane contains a relatively large quantity of an interesting lipid called cardiolipin, which is not enriched in any other membrane. The inner mitochondrial membrane is involved in producing ATP for the cell and it needs to be impermeable to hydrogen ions. Therefore, cardiolipin is what I call the electrical tape of the inner mitochondrial membrane. It is highly stable molecule that deflects both hydrogen ions and electrons well. Of course, biology would develop such a useful building block by utilizing the perfect lipid for this specific function.

If proteins are the houses and factories of the cell, and cholesterol is what makes membranes much stronger, then lipids are the stones that make up the walls and roadways of the cell, like the stones used in the following picture.

Rock Wall and Path 6-2014

A more conventional picture of how lipids form the cell membrane and surround a cell completely is shown in the following figure.

Screen shot 2014-06-03 at 3.52.52 PM

The diversity and utility of lipids

Scientists who study lipidomics, a specific field in lipid metabolism that relates to the vast diversity of lipids in biological systems, have discovered that there are over 10,000 distinct lipid species within a cell. But it is quite possible that there are many more lipid species than this. The fact that there are so many different lipids in cells leads to the basic concept that the more types of lipids that are present in the diet the better, because the lipids in our food, especially a large cornucopia of fatty acids, can be used in many different ways.

Therefore, in addition to providing energy, a wide variety of lipids are used for Structure and Communication.

The Backdrop

Omega 3 and Omega 6 Fatty Acids, Structural Components of the Brain, Role in Brain Development

There are a wide variety of lipids that probably contributed to human development. Valuable information about who we are today, and what kind of diet may be most suited for optimal health and maintenance of body weight, can be obtained from studies of the development of early humans.

Research performed in the last 10-15 years has documented that all humans living today are descendants from a small group of humans who lived and developed in Africa.   This particular group of modern humans possibly lived on the coast of southern Africa 190,000 to 100,000 years ago.

In an article in Scientific American, Curtis Marean, a professor at the School of Human Evolution and Social Change at Arizona State University, addressed the observation that modern humans display very low genetic diversity compared to other species, a fact that suggests that there was a population “crash in early H. sapiens.”   In 1991 Dr. Marean began to investigate caves that may have supported early H. sapiens during a long glacial period that lasted until about 120,000 years ago.

Curtis Marean, “When the Sea Saved Humanity,” Scientific American, August 2010, pages 53 – 61

Scientific Am Cover

Dr. Marean discovered an interesting cave, called PP13B, near Mossel Bay, South Africa. He found evidence that this cave was used by Homo sapiens from between 164,000 and 35,000 years ago. While other small groups of Homo sapiens may have died out in other parts of Africa due to the cold and adverse conditions brought about by the return of cold weather and glaciers between 195,000 and 123,000 years ago, this group of humans obviously survived. One advantage this group of humans had was that they had quick access to rich seafood because the cave looked out over the ocean. Also, they lived close to a diverse population of plants, including those that contain tubers, bulbs and corms with rich stores of carbohydrates. In the sediments of the cave, Dr. Marean discovered a diverse group of shells from shellfish harvested from the ocean. He also discovered a multitude of stone tools.

Cave in South Africa 6-2014

Dr. Marean has proposed that the genetic, fossil and archaeological data indicate that this cave, and other caves near by, may have been the site where modern humans survived the return of the glaciers and developed before leaving Africa around 50,000 years ago. Also, because these humans consumed seafood as a major source of high quality protein, they also consumed omega 3 fatty acids that are present in seafood. Over this entire period of time, it is quite possible that the brains of these early humans were developing and becoming more capable of advanced thought.

The development of the human brain in a geographical location that provided a source of rich high quality protein and omega 3 fatty acids may explain the fatty acid composition of our brains today.

The following table displays the fatty acid composition of human newborn adipose tissue and compares it to the fatty acid composition of human newborn brain. The differences in fatty acid content are startling!

The human brain has greatly increased concentrations of arachidonic (omega 6) and docosahexaenoic (omega 3) acids compared to adipose and other tissues such as liver and muscle. These are fatty acids that are highly unsaturated (contain multiple double bonds each). Obviously, as the brain is greatly enriched in these fatty acids over adipose tissue, there must be an important reason for this enrichment, and there also must be a mechanism that directs the enrichment of these fatty acids in brain.

Table adipose vs brain

Because to the best of our knowledge, omega 3 fatty acids were high in the diet when the human brain was developing and improving, there is a major hypothesis that a sufficient content of omega 3 fatty acids is required in our diet today in order to have the optimal mixture of fatty acids for brain development.

Benefits due to consumption of adequate amounts of omega 3 fatty acids

We can only speculate right now that because our brains have a very high content of arachidonic and docosahexaenoic acids, that these fatty acids play a special function in the brain. But if there was evidence that a deficiency of these fatty acids causes some kind of detrimental situation, and that increased consumption causes a positive effect, then this would strengthen arguments indicating that these fatty acids play an important role in brain. And in fact, there are now very strong epidemiological data that PUFA, especially those that are found in fish oils, are highly beneficial to human health in several important ways.

Omega 3 Fatty Acids and Depression

The health benefits of omega 3 fatty acids has been the subject of hundreds of articles in the scientific literature.   One interesting area studied is the effects of omega 3 intake on depression in different populations based upon easy access to fresh seafood. Studies have suggested that the consumption of fish on a regular basis is protective against depression.

A meta-analysis of 47 clinical research trials testing the efficacy of treating patients with various brain related disorders with different omega 3 fatty acid administration protocols was published in 2014. In the studies that specifically tested omega 3 fatty acids on clinically defined depression (11 studies), and in less rigorously defined depression (8 studies), a significant improvement in symptoms was noted in patients who consumed additional EPA compared to patients who received the placebo or DHA alone. This meta-analysis was more positive than the previous meta-analysis that was published. The authors stated that their study took advantage of several very recently conducted clinical trials that increased the total number of patients enrolled in the overall analysis.

The observation that treatment with EPA was effective whereas DHA was not effective is difficult to understand at this time as the biochemistry indicates that DHA is present in the brain at much higher concentrations than EPA. The authors of this meta-analysis suggested that it may be the anti-inflammatory properties of EPA that are protective, and not the role of omega 3 fatty acids as structural molecules in neurons. Also, the time of life when increased omega 3 fatty acid intake is required by humans may also be an important factor. DHA is known to be especially important for brain development during gestation and during the first several years of life.

Grosso G, Pajak A, Marventano S, Castellano S, Galvano F, Bucolo C, Drago F, Caraci F.  Role of omega-3 Fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials. PLoS One. 2014 May 7;9(5):e96905.

Summary: Omega 3 Fatty Acids and Depression

We are getting to the point where the data on the positive contributions of omega 3 fatty acid consumption to overall health is fairly convincing. There are areas where omega 3s are not as helpful as originally proposed, but certainly the studies that show improvement in depression show there are other areas where omega 3 fatty acids are required for specific physiological functions. With the availability of pharmacological omega 3 fatty acid products, we will soon have more information on the efficacy of omega 3 fatty acids.

Not All is Rosy Concerning Omega 3s. No Effects of Omega 3 Supplements on CHD

Whereas increased omega 3 intake was shown to be beneficial in depression, positive effects of omega 3s have not been observed with coronary heart disease (CHD). The most recent meta-analysis study showed that neither omega 3 intake, nor supplementation with omega 3 fatty acids, provided protection against CHD. In the same meta-analysis study, intake of saturated fat and monounsaturated fat were also not associated with CHD. This study suggests that there are other factors in the diet, beside fat content, that are responsible for the protection afforded against CHD by certain diets including the Mediterranean Diet.

The results indicating that fats did not influence the rates and outcomes of CHD at first are surprising, but we have to remember that most, if not all, of these epidemiological studies were performed after very, very high intakes of fat, such as those that occurred in Finland, had already come down!

ChowdhuryR, Warnakula S, Kunutsor S, Crowe F, Ward HA, Johnson L, Franco OH, Butterworth AS, Forouhi NG, Thompson SG, Khaw KT, Mozaffarian D, Danesh J, Di Angelantonio E. Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis. Ann Intern Med. 2014 Mar 18;160(6):398-406. doi: 10.7326/M13-1788.


Fatty Acids and Cell to Cell Communication – The Endocannabinoids

The endocannabinoids are lipid molecules that are used in the body to send signals from one cell to another.   In the brain, endocannabinoids usually transmit a chemical signal from one post-synaptic neuron to a near by pre-synaptic neuron.   Endocannabinoids are a family of molecules that are derivatives of fatty acids. The major endocannabinoids, N-arachidonoyl ethanolamine (anandamide) and 2-arachidonoyl glycerol (2-AG) have the polyunsaturated fatty acid, arachidonic acid, as a central part of their structures.

The story how the endocannabinoids were discovered is mind blowing.

Marijuana is one of the names given to the Cannabis sativa plant, which has been used for its mind altering properties. The physicochemical properties of marijuana include euphoria, heightened sensory perception, and increased appetite. The active ingredient in marijuana is tetrahydrocannabinol or THC. The many effects caused by marijuana and, THC, caused scientists to ask how it worked on so many systems. Biochemical studies found a membrane receptor (called CB1) on the surface of cells in the brain that THC tightly bound to after marijuana use. The scientists asked the question, if THC, an external substance, enters the brain and binds to CB1 receptors, which then causes many of its physicochemical effects, are there naturally occurring, endogenous compounds that normally bind to the CB1 receptor?

After about 20 years of looking for a needle in a haystack, scientists reported that they discovered the endogenous compounds that bind to the CB1 receptor, and they called these compounds, endocannabinoids. The following figure shows the structure of tetrahydrocannabinol (THC) and the structure of the endocannabinoid, N-arachidonoyl ethanolamine (anandamide).

THC Endocannabinoids Figure

The Brain reward system first occurs in the Arcuate nucleus, where signals (especially those related to food) from different areas of the body are received (See following Figure). Then signals are sent from the Arcuate nucleus to the Nucleus accumbens, where positive neurotransmitters like dopamine are secreted. Soon afterwards, other signals may be sent to the prefrontal cortex, where conscious actions are initiated (for example- go get another slice of pizza).

Originally (in early evolution) the brain reward system was used to give pleasurable feedback for when something nutritious was being eaten or when something good happened in everyday activities. Later on in evolution, this system was co-opted and is now involved in addictions and other negative activities.

Brain Reward Center NEJM 2008

How Lipids Signal From One Cell To Another Cell

The following Figure shows how endocannabinoid molecules, which are lipids, are transferred from one cell membrane to another cell membrane in order to continue a signal down a nerve tract. Anandamide or 2-AG are synthesized using arachidonic acid molecules that are part of the phospholipids that make up the cell membrane of neurons. When the endocannabinoids are released from the post-synaptic neuron into the space between the two neurons, they bind to the endocannabinoid receptors that are on the pre-synaptic neuron. Next, the receptors initiate signals within the cytoplasm and the pre-synaptic neuron continues moving the signal down the nerve.

Endocannabinoid Signaling at Membrane

So What Fats Should Americans Eat?

The answer to this question will be found in the chapter where the Mediterranean diet is discussed. A recent study has been published that has shown that the Mediterranean diet can be protective against CHD. Of course, Ancel Keys discovered this in the “Seven Countries” study, and wrote about it. Ancel Keys and his biochemist wife, Margaret, wrote the cook book, “Eat Well and Stay Well the Mediterranean Way,” which was published in 1975. Later, Dr. Keys and his wife moved to southern Italy and practiced the Mediterranean diet up close and personnel. In several articles written after his retirement to Italy, Dr. Keys provided insights into the Mediterranean diet and how it was changing as European countries were recovering their wealth in the period after World War II. But this part of the story will be presented in a later chapter.




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