The Obesity Epidemic: is the Metabolic Syndrome a Nutritional Deficiency Disease?

by Stephanie Seneff

seneff@csail.mit.edu
October 9, 2009

French translation created by Vicky Rotarova

1. Introduction

The United States is currently facing an obesity epidemic across its population, affecting children and adults alike. It is now estimated that 30% of Americans are overweight [29], and the problem has been worsening over time.

Why does the US have this problem? Why are we the "leaders" in obesity and related health issues such as heart disease and diabetes, despite our incredibly high dollar investment in health care? What are we doing wrong?

My research, detailed in this essay, shows that in many cases the underlying cause of obesity lies with basic nutritional deficiencies, which can be corrected through simple dietary changes. These deficiencies are likely caused, in large part, by two ill-conceived, yet supposedly "healthy", modern day lifestyle choices: an excessively low-fat diet, and sun phobia. The modern preference of sugar-laden over calcium-rich foods also plays a role.

The solution to our problems, fortunately, is surprisingly simple. It involves making a conscious effort to consume foods rich in vitamin D, calcium and fats, and to spend more time outdoors on sunny days. While many researchers have come to suspect that vitamin D (Details) and calcium (Details) deficiencies play a causative role in obesity [2][4][5][10][20][22][24][35][37][38][41][42], the critical role played by insufficient dietary fats has been largely overlooked. I have previously argued that a deficiency in these three nutrients is a key contributor to the current epidemic in autism in America. I have also made a case for a role played by these deficiencies in increased susceptibility to infectious diseases such as swine flu . Here, I will develop an argument that explains why a person suffering from deficiencies in calcium, vitamin D, and dietary fat is likely to steadily gain weight throughout their life, and develop a host of associated health problems.

Excessive weight is often associated with what has been termed "the metabolic syndrome." This syndrome is manifested principally by excess fat deposited around the abdomen. It is usually associated with several other risk factors for diabetes and heart disease, including high blood pressure, high levels of triglycerides in the blood, elevated values for LDL (the "bad" cholesterol), reduced values for HDL (the "good" cholesterol), and high blood sugar [42].

The basic problem that a person with severe calcium and vitamin D deficiencies faces is an inability for the heart and muscles to effectively utilize glucose (sugar) for their energy needs [14][18][19]. Even when blood sugar levels are high, the heart and muscles are starved for energy. I am reminded of a ship lost at sea -- "water, water everywhere and not a drop to drink." However, there is an alternative energy source -- fats -- that would be readily available to them if the body could just maintain an adequate supply.

With a low-fat, high-carb diet, it is sugar rather than fat that is primarily available from food sources. Thus the body's fat cells are recruited to convert the sugar to fat so that the muscles and heart will be able to satisfy their energy needs. The fat cells are overburdened with this monumental task, and, to keep up with demand, they must become more abundant; i.e., the person gains weight.

The heart can never afford to be without energy supply. Hence, I argue that an additional step is taken to assure a private source of fat in very close proximity to the heart. Fat deposits begin to accumulate directly within the walls of the arteries supplying the heart. The familiar name for these fat deposits, placed there to fuel the heart, is "arteriosclerosis." Eventually, fat also accumulates in the body cavity encasing the heart -- i.e., "pericardial fat" [9]. Intriguingly, pericardial fat is distinct from abdominal fat or subcutaneous fat in that lipolysis (the breakdown and release into the blood as a fuel source) is more active [26]. Fat in the arteries of the heart is an easy target for bacteria and viruses, which can gain entry via the lungs, and conveniently find plenty of oxygen, along with a handy food supply from the fat deposits. I (and others [27][36]) believe that it is infection in the fats lining the coronary arteries that ultimately leads to heart attacks (Details) .

In the following sections, I will first explain why these deficiencies are widespread in America, and then present the argument at a somewhat technical level that explains in detail how the metabolic syndrome evolves. Finally, I will provide recommendations for modest lifestyle changes that will correct these deficiencies.

2. Why are These Deficiencies Present in America?

Vitamin D and calcium deficiencies are epidemic in America today. It has been estimated that 44 to 87 percent of Americans are deficient in calcium Calcium Deficiency in U.S.) . The best source of calcium is milk; however, people today largely prefer sugar-laden and other beverages over milk. Calcium is essential for building strong bones and teeth, and it also plays a critical role in food metabolism. A recent study showed an alarming increase in broken bones in today's children compared to those in the 1970's [17]. Rickets is now reappearing among children [12], and teenagers are being diagnosed with osteoporosis, something that was unheard of in the last two generations.

It is estimated that 70% of America's children are currently deficient in vitamin D [21] (Details) . This is not surprising, given current medical advice. The sunscreen industry lobby has convinced most Americans, including medical experts, that the sun should be aggressively avoided to prevent skin cancer. This advice is given in spite of the fact that the sun is an excellent source of vitamin D, allowing the skin to manufacture it directly from cholesterol. Moreover, vitamin D is protective against all cancers (Details) a characteristic which probably more than compensates for any extra skin cancer risk incurred by sunbathing. Vitamin D deficiency is also associated with an increased risk of high blood pressure and diabetes [37]. In order to obtain vitamin D from food, it is necessary to eat animal fats; animals manufacture vitamin D, a fat-soluble vitamin, and store it in their fat cells.

Vitamin D is also crucial to the absorption of calcium from the digestive tract into the blood stream, and both vitamin D and calcium are important catalysts in crucial biological processes. Fats also promote the uptake of calcium in the intestines, whereas dietary fiber, touted as being healthy, impedes it [40] (Details) .

In experiments where calcium supplements were provided to obese people, it was found, quite to the surprise of the research team, that the subjects lost a significant amount of weight without even trying to, as a consequence of the additional ingested calcium, particularly when it was provided in milk products as opposed to in tablet form [42]. The fat in milk likely aided absorption, and the additional calcium helped to correct the glucose utilization problem that had come about due to calcium deficiency.

These three nutrients, fats, vitamin D, and calcium, have intricate mutual dependencies that make it important to consume them together. Americans are deficient in these important nutrients largely because of their perceived need to pursue a low fat diet and avoid sun exposure.

Unfortunately, intuitive arguments can be made as to why sun exposure and fat consumption might be unhealthy: the sun's UV rays can cause cancer by introducing errors in DNA transcription; heart disease is strongly associated with fatty deposits in the coronary arteries, fatty acids in the blood, and obesity. It is too easy to imagine that these negative factors would likely be related to dietary fat consumption. The American medical establishment is heavily entrenched in the idea that dietary fat is unhealthy. People who adopt a low fat diet inevitably increase their intake of carbs and sugars, as much of the fat removed in foods is replaced with sugars to make them palatable. Many foods available today are also often highly processed and easily digested, leading to a rapid rise in blood sugar. Finally, foods containing vitamin D are avoided, due to their universally high fat content.

3. The Basic Problem: Impaired Glucose Uptake

Homeostasis is the process by which the body manages its energy needs, Energy management is a crucial component of all cell metabolism. Any work that a cell does consumes energy, and this energy is supplied by either fatty acids, in the form of triglycerides (derived from dietary fat or supplied by fat cells on the body) or from glucose (derived from carbohydrates and proteins or supplied from temporary stores in the liver). While muscle cells can typically store a small amount of fuel locally, these local stores are quickly depleted during intense exercise. New supplies of nutrients are then extracted from the blood stream. The levels of glucose and triglycerides in the blood are constantly monitored and adjusted based on complex chemical signaling, to maintain sufficient supplies to all the body's cells.

A person with metabolic syndrome suffers from an impairment of their muscle cells' ability to absorb glucose from the blood [13] (Details) . Critically, this includes the heart muscle. Glucose transport depends critically on insulin, which is supplied by the pancreas. Vitamin D [2][3][30] (Details) and calcium [29] are intimately involved in the process that allows the pancreas to release insulin into the blood. Insulin in turn stimulates glucose uptake in the muscle cells [7]. Calcium is also critical for the migration of the catalyst GLUT4 to the membrane of the muscle cell [22][38], where it orchestrates the transfer of glucose across the membrane, providing energy to the cell. Thus, calcium deficiency inhibits several inter-related metabolic processes, all of which affect glucose transport.

All of the body's cells depend upon an important biological substance called adenosine triphosphate (ATP) for energy generation. Through a chemical process, ATP is converted to adenosine monophosphate (AMP), and the energy that is released during this chemical reaction fuels muscle contraction. The cell's mitochondria are able to convert AMP back to ATP (to be recycled) by consuming either glucose or fat. When there is not enough fuel to convert AMP back to ATP, the ratio of AMP to ATP builds up. The ratio of AMP to ATP within the cell is a measure of its energy state, and is used by many different types of cells in the body to detect energy shortages and trigger corrective measures.

As the muscle cell exhausts its internal stores of energy, it attempts to absorb more glucose from the blood. An impaired glucose transport mechanism inhibits this process. As a consequence, the ratio of AMP to ATP in the cell steadily rises, activating a powerful regulating peptide secreted by the cell, known as AMPK. AMPK in the muscle cell promotes the movement of GLUT4 to the membrane, even in reduced insulin contexts [35]. With GLUT4 at the cell membrane the cell can now begin to absorb the glucose and insulin supplies in the blood, causing these levels to fall.

At this point, several things happen to counteract the falling level of blood glucose, which is detected by the pancreas and hypothalamus. They emit hormones and peptides that signal the body to replenish glucose levels in the blood. The alpha cells in the pancreas react by secreting glucagon, a hormone that triggers the liver to convert its stores of glycogen into glucose and release it into the blood stream. Similar glucose-sensing cells in the hypothalamus increase the appetite and stimulate the person to consume food, in order to replenish the supplies being drawn down in the liver.

Both of these glucose sensing mechanisms (in the hypothalamus and in the pancreas) are triggered by AMPK, and both involve a rush of calcium into the cell as part of their signaling cascade [29] (Details) . I hypothesize that deficiencies in calcium cause these glucose sensing mechanisms to detect low glucose levels internally even when glucose levels in the blood are still reasonably high. This is in fact an intelligent design, to tie their glucose-sensing mechanisms to those of the muscle cells, because, if the muscle cells can't absorb glucose efficiently, it is in some sense equivalent to having low blood glucose.

Thus, due to poor glucose uptake, the set point for the blood levels of glucose is maintained at an artificially high level. This is because poor uptake can be somewhat compensated for by elevating the concentration in the blood. Eating easily processed sugars and starches is the most effective way to quickly satisfy the cravings caused by poor glucose uptake. While the higher levels of glucose help to satisfy the muscles' needs, the glucose is also available to the fat cells, which feed on the excess sugars and store them as fats. Over time, sustained high blood sugar leads to chronic weight gain, diabetes, and heart disease.

Correcting the underlying glucose uptake problem will require long-term dietary changes which I will later describe. But first, I would like to explain some of the biological processes involved in food metabolism and weight, and show how the body tries to compensate for malfunctioning glucose uptake.

4. Fat Cells to the Rescue

The fat cells play a fascinating role in attempting to compensate for glucose uptake deficiencies. Fat cells are now considered by experts to be an essential part of the endocrine system, in that they can orchestrate energy management by many organs of the body by releasing hormones into the blood [8][11][28]. Fat cells are able to absorb excess sugar from the blood and convert it into fat. The fat will later be released into the blood stream as fatty acids and triglycerides, which offer an alternative energy source to the muscle cells (and most other cells of the body) - an alternative that does not suffer from the problem of membrane transport, which is specific to glucose.

In a situation where glucose transport is defective, the fat cells appear to: (1) program the muscle cells to consume fats rather than sugars, and (2) take upon themselves the task of converting as much of the incoming sugar as possible to stored fats. The fat cells accumulate fat whenever the blood sugar levels are high, and then release it into the blood stream whenever blood sugar levels are low enough. Thus they strive to maintain in the blood stream a steady supply of an alternative and more efficient source of fuel (fats) for the muscles to consume instead of sugar.

Through signaling involving a peptide released into the blood stream by fat cells, called leptin, fat cells are able to redirect the muscle cells to obtain most of their energy needs from fats instead of from glucose. However, as a consequence, the fat cells then become burdened with the task of of converting as much as possible of the incoming glucose to fats.

The fat cells must thus buffer up a reserve store of fats, and release fats into the blood to provide nutrition for the muscle cells during fasting conditions, when glucose is not available. After meals, when glucose levels are high, the fat cells are preoccupied with extracting glucose from the blood, and therefore are unable to release fats. Thus, they must provide additional triglycerides in advance of a meal, so that the muscle cells will continue to have food while the glucose is being taken up by the fat cells and converted to a renewed supply of fat. This safety buffer of triglycerides is what is responsible for the observed high fasting triglyceride levels of the obese.

If more dietary fats were consumed, fat from food sources would be available to the muscles while the fat cells are distracted with taking up glucose, and there would be correspondingly less glucose to convert. But because so much fat is needed to feed the muscles, and because so much excess sugar is going to waste, the fat cells find themselves unable to meet the demand, so they end up proliferating -- and the person becomes obese.

The fat cells also suffer from an impairment of glucose transport, as they rely on the same mechanism involving GLUT4 and insulin to transport sugar across their cell walls (Details) . Fat cells however are able to internally hoard both vitamin D [5] and calcium [42], so that they can improve somewhat their own abilities to transport glucose across their cell membrane. But this also leaves the muscles more vulnerable to glucose uptake inefficiencies, because it further depletes the availability of calcium and vitamin D in the blood. As long as the muscle cells use up fats as their energy source instead of glucose, and as long as the fat cells can maintain a good supply of fats in the blood, all will be well. This is the scheme that the fat cells are trying to perpetuate.

5. How does the Heart Cope?

The heart is the most fuel-consuming organ in the body. It must continue beating once or twice a second, with no breaks, day in and day out [16]. The heart is similar to the skeletal muscles in that it too faces glucose deprivation when calcium and vitamin D supplies are inadequate. Like the skeletal muscles, it can utilize both fat and sugar as fuel, and it uses the same GLUT4 peptide to usher the glucose across the cell walls [33]. As long as the fat cells in the rest of the body are able to release a steady stream of triglycerides into the blood stream, the heart can simply use these for most of its energy needs, and, in fact it prefers fats over glucose as a fuel source. It is likely that, especially after a high-carb, low-fat meal, with poor glucose absorption there will be intervals when the heart is fuel deficient.

In the face of inadequate fuel concentrations in the blood supply, I propose that the heart adopts two different coping mechanisms: (1) grow bigger, and (2) develop its own "private" supply of nutrients, in the form of fat deposits. By becoming enlarged, the heart is using the strategy of "strength in numbers." Imagine that six children are competing against three adults in a tug-of-war. The children may win, even though they are weaker, simply because there are more of them. Likewise, the heart, by increasing the number of muscle cells, may be able to beat as strongly as a smaller heart, but each independent muscle cell carries a lesser burden, and therefore can get by on a reduced fuel supply.

The second strategy, creating an internal supply of fats, begins with fatty deposits in the linings of the arteries supplying the heart, known familiarly as arteriosclerosis. These deposits, with time, become "hardened," i.e, associated with calcium deposits; calcium that has been hoarded by the fat cells over the years, just as is done in the abdominal fat cells. The calcium is hoarded because it enables the fat cells to absorb glucose and convert it into fats. As a further strategy, the heart develops a layer of "pericardial fat," [9] fatty deposits, typically just outside of the major arteries feeding into the heart. These deposits supply additional fats directly to the heart, to supplement those lining the artery walls.

One problem with encasing the heart with fats is that it becomes susceptible to bacterial infection. The highly oxygenated blood, coming directly from the lungs, may easily become contaminated with bacteria that have entered the body through the lungs. These bacteria may find it attractive to feed off of the fatty deposits lining the arterial walls. As a consequence, cholesterol must infiltrate the artery walls, as a first line of defense in the immune system, to attack the bacteria (Details) . The cholesterol also draws upon white blood cells to assist in the battle. Furthermore, the fat cells encasing the heart, as contrasted with fat cells elsewhere in the body, are especially primed to release cytokines [9], which are also infection-fighting agents. Thus the presence of fat in the heart's arterial walls and encasing the heart is associated with high levels of cholesterol and cytokines in the blood.

6. Hormones and Enzymes that Control Appetite

The fat cells are able to influence the muscles to preferentially take up fats rather than glucose by releasing certain hormones into the blood, hormones that also have a powerful influence over appetite. One of these hormones is leptin. While leptin influences the muscle cells indirectly through its signaling in the hypothalamus, it also stimulates the muscle cells directly, and influences them to oxidize fatty acids in their mitochondria [28]. Leptin also encourages the fat cells to release their fats through lipolysis [25]. All of these actions work in concert to redirect fuel usage away from glucose. The programming of the muscles to preferentially consume fats aligns well with the fat cells' infusion of fats into the blood and absorption of sugars through their fat-producing factories.

Leptin also has the effect, via the hypothalamus and pituitary gland, of suppressing appetite. Adiponectin is another hormone released by fat cells, and it is generally agreed that adiponectin induces hunger. Leptin and adiponectin levels would ordinarily fluctuate throughout the day, with leptin levels rising at night to encourage a switch from glucose-based to fat-based energy management. However, in the obese person, the leptin levels are typically high all the time, and the adiponectin levels are kept very low [43]. High levels of leptin in the blood signal to the appetite center in the brain a sense of being full [8], whereas high levels of adiponectin are hunger-inducing. This means that the obese are being informed both that they are full, and that they are not hungry. You would think that this would protect them from overeating. However, it is likely that the observed insensitivity to leptin as an appetite suppressant in the obese is also related to calcium depletion, because the signaling mechanisms that respond to leptin in both the hypothalamus (Details) and the pituitary gland (Details) depend on changes in internal calcium concentrations.

So, why does the obese person overeat? I have reached the almost inescapable conclusion that the culprit is over-sensitized AMPK, as is also suggested by several other researchers [15][18][19]. AMPK operates not only in muscle cells, but in just about all cells of the body [15]. In particular, it plays a critical role in sensors in specialized cells in the brain: in the hypothalamus and the pituitary gland. These cells release chemicals into the blood that influence the liver, the pancreas, and the appetite, in terms of turning on or turning off mechanisms that will provide further fuel into the system, in the form of either fats or glucose.

As was said before, whenever the muscles exert themselves for sustained periods, they soon reach a critical point where large amounts of ATP have been converted to AMP, in the process of releasing energy to drive muscle contraction. The AMP:ATP ratio rises sharply. This activates AMPK, which then reprograms the muscle to both increase the levels of calcium inside the cell and consume more sugar [32][34][39], a very bad idea since calcium and insulin are in short supply. Certain GI or "Glucose Inhibited" cells in the hypothalamus, as well as alpha cells in the pancreas, are programmed to respond to low glucose levels by instructing the liver to release more sugars and increasing the appetite for foods with a high glycemic index. They essentially broadcast the urgent message to the brain that more glucose is desperately needed. The person is compelled to consume sugars and carbs that will digest very quickly and further raise the already high blood sugar levels.

7. The Body Grows Larger

Ironically, the arguments made above suggest that aerobic exercise is ill-advised for those who suffer from this impaired glucose-uptake syndrome. While many have speculated that our more sedentary lifestyle is likely a contributing factor toward obesity, I believe that instead physical fatigue itself is a predictable outcome of defective glucose metabolism. The inability to obtain sufficient fuel from glucose on the part of both the muscles and the heart simply saps us of the energy to move around [23] (Details) .

The effect of sustained aerobic exercise is to switch the muscle back into a glucose-uptake modus operandi for energy acquisition, which, however, is malfunctioning due to calcium and insulin insufficiency. Exercise is able to induce GLUT4 to migrate to the membrane even in the absence of calcium [13] . The insulin/glucose levels fall to possibly dangerously low values, which induces the appetite center in the hypothalamus to sound the alarm bells. The subsequent appetite stimulation induced by AMPK in the hypothalamus overrules all of the other appetite regulating signals and compels the person to overeat the very foods they should be avoiding.

As a consequence of further increases in the already high levels of sugar in the blood, the fat cells are compelled to squirrel away as much of the excess sugar as they can. Particularly susceptible to this urge to make fats will be the abdominal fat, since it is situated in close proximity to both the pancreas and the liver. The higher blood concentrations of both insulin and glucose provide extra impetus to assimilate sugars and manufacture fats. Thus the abdominal fat cells are more efficient in storing food than the peripheral fat cells. They will also tend over time to increase in size and multiply, in order to distribute the task load among their neighbors and reduce the burden carried by each individual cell. The additional fat cells will further deplete the available calcium and vitamin D in the blood, leading to an even poorer ability on the part of the muscle cells to take up glucose.

Alongside the growth of fat cells, other cell types also need to become more abundant, to support the increased burden of a larger body size, combined with reduced energy supply. As already mentioned, the heart becomes enlarged. Muscles must increase in size both to be able to haul around the extra weight and because of their innate inefficiencies in fuel utilization [14]. Bones must grow bigger and stronger to support the excess weight. Blood supplies have to be extended to supply nutrients to all of these proliferating cells. All of this means that the body's overall nutritional needs continue to grow, which puts futher burdens on the fat cells, thus completing the vicious cycle. Over time the person with a severe deficiency in calcium, vitamin D, and fats grows steadily larger, eventually reaching a condition of morbid obesity.

8. The Metabolic Syndrome

A person with impaired glucose uptake as a consequence of calcium and vitamin D deficiencies ends up in a situation where both glucose and triglyceride levels in the blood are abnormally high. The heart and muscles are very poor at utilizing glucose, and hence they will depend to a large degree on fats (triglycerides) to supply their nutritional needs. The fat cells must release excess amounts of triglycerides during fasting conditions, such as at night, because they will not be able to release triglycerides once they are reassigned to the task of taking up excess glucose. After a meal, when glucose levels are high, the triglycerides will be steadily drawn down by the heart and muscles, while the fat cells absorb the glucose and begin the process of converting it into more fat.

Under conditions of aerobic exercise, the muscles and heart are reprogrammed to consume additional glucose, which causes glucose levels to plummet. This sets off alarm bells in the pancreas, which induces the liver to release more sugar, and in the hypothalamus, which stimulates the appetite for foods with a high glycemic index. The signalling mechanisms in the pancreas and the hypothalamus are likely also defective due to the calcium and insulin deficiencies [6][31] (Details) , and so they maintain a set point for glucose in the blood that is abnormally high. But the high glucose levels are in fact required, in order to compensate for the inefficient transport of glucose across the membrane of the muscle cells. The excess available glucose in the blood is taken up by the fat cells, the fat cells enlargen and multiply and the person becomes obese. Furthermore, the heart, a muscle, enlarges and becomes encased in fatty tissues, and its arteries become laden with fatty deposits, i.e., arteriosclerosis.

I believe the low HDL and high LDL can also be explained as follows. HDL is the carrier for cholesterol that is to be returned to the liver, where it can be disposed of via the gall bladder. It is dispensed by the gall bladder into the gut along with bile, and performs the very useful function of helping digest fats. Anyone who is consuming a low-fat diet requires less cholesterol for digesting the reduced dietary fat, and HDL levels fall. LDL is likely high because it is the carrier that transports cholesterol to the tissues. One of those tissues is the fatty deposits in the artery walls of the heart, that were placed there, according to my interpretation, to supply extra fuel to the heart. But these fatty deposits are also vulnerable to invasion by bacteria and viruses, entering through the lungs. High levels of cholesterol would need to be made available in the blood stream protect the fat deposits from oxidation and to help keep these invasive microbes under control.

Thus plausible outcomes of the calcium, vitamin D, and dietary fat deficiency are obesity, high blood sugar, arteriosclerosis, high levels of triglycerides, elevated LDL and low HDL, six key aspects of the metabolic syndrome (Details) .

9. The Solution

Most of the foods that contain vitamin D naturally have been taken off the menu of the American diet due to the belief that fats are harmful to your health. Since vitamin D is manufactured by animals, a strict vegetarian won't get any vitamin D from their food intake. Foods that are high in vitamin D are also very high in fat and cholesterol as well, and have therefore been for the most part "black-listed." These include pork lard, bacon, egg yolk, liver, caviar, butter, and raw milk. Americans have recently been responding to the claim that fats are healthy as long as they are omega-3 fats, which has fortunately brought fatty fish, such as sardines, salmon, and mackerel, back on the menu. A fantastic source of vitamin D is cod liver oil, which used to be routinely given as a natural vitamin supplement to children, and still is in many parts of Europe. But Americans seem to have unfortunately abandoned this practice. Several foods in the American diet have been fortified artificially with vitamin D, but many of these, such as cereals, orange juice, and non-fat milk, contain little or no fat, so it is mysterious to me how the fat-soluble vitamin D can possibly be properly distributed in the product or properly absorbed.

The lack of adequate dietary fat contributes to the metabolic syndrome in at least four ways: (1) vitamin D is only available in fatty food sources because it is a fat-soluble vitamin, (2) calcium uptake is more efficient when the calcium is consumed with dietary fats, (3) calcium uptake depends critically on the presence of vitamin D, which is deficient due to (1) above, and (4) the burden of fat cells to manufacture fatty acids from sugar is alleviated by the dietary availability of fats from ingested food sources.

By far the best way to acquire adequate vitamin D is through sun exposure. Possibly one of the most important components of a healthy lifestyle is to spend ample time outside in the sunlight. However, today's lifestyle in America often leaves little time for outdoor activities. Furthermore, Americans have been trained to fear rather than bask in the sun, mainly due to the aggressive ad campaigns of the sunscreen industry arguing that the sun causes cancer. Of course, one needs to avoid sunburn, but, building up exposure slowly by developing a tan in the spring affords natural protection from burning in the summer. This strategy is, in my view, far preferable to liberally applying sunscreen. Sunscreen at an SPF level of 8 or greater effectively wipes out any opportunity to manufacture vitamin D in the skin. The protection acquired from all cancers due to the vitamin D that is manufactured in the skin upon sun exposure more than compensates for any increased risk to skin cancer caused by sun exposure.

Another healthy choice is to eliminate 'empty carbs' as much as possible. This includes such foods as cookies, donuts, candies, and soft drinks. Switch from white to whole wheat bread, and from white rice to brown rice. When eating potato, be sure to put lots of butter and/or sour cream on it. Potato ingested with fat has a much lower glycemic index than potato ingested without fat. This practice will help prevent blood sugar levels from spiking, which is healthy in terms of combating diabetes and heart disease. However, fixing the metabolic syndrome caused by high blood sugar is only possible if, along with limiting consumption of empty carbs, you also repair your deficiencies in calcium and vitamin D.

I would also argue that one should make sure to consume adequate amounts of dietary fat, especially dairy fat [33]. Whole milk is particularly outstanding because it contains substantial amounts of calcium and vitamin D, and it contains the necessary fat to assure that these two elements will be well utilized rather than just passing through the digestive system unabsorbed. Animal fats such as bacon are good sources of vitamin D, while also supplying fatty acids to help with energy needs. Fatty fish such as salmon and sardines are particularly good because they contain both omega-3 fats and vitamin D. One should assiduously avoid the trans fats found in processed foods such as cookies, crackers, and margarine. Butter and eggs are also healthy choices. Egg yolk is particularly good because it contains both fats and vitamin D. Nuts, particularly walnuts, almonds, and macademia nuts, are also good sources of fat.

Finally, it is essential to get enough calcium. Ingest the calcium with dietary fats. If you're fond of milk and cheese, then you can probably supply all of your calcium needs through dairy products, as long as you choose ones that contain fat (i.e., avoid non-fat dairy products). If you don't like milk or are allergic to lactose, then bean curd is an excellent choice for calcium. Bean curd can be prepared in lots of ways, from raw soybeans to soy milk to Chinese tofu dishes. However, it's not standard fare in the American diet, so it might be preferable to go with the third option for calcium, which is to eat lots of leafy green vegetables such as spinach, broccoli, kale, and mustard greens. Again, these need to be eaten with fats to be properly absorbed, which means frying them in oil or liberally adding butter.

It has been amply demonstrated in research studies that most vitamins and minerals taken in pill form are far less effective than the forms found naturally in foods. In many cases, you may be just wasting money on something that passes through the digestive system unabsorbed, and also creates abnormal situations of anomalously high levels of concentrated nutrients in the gut, which seems intuitively to be a bad idea. However, sometimes due to lifestyle constraints, it may be impossible to get enough sun exposure, and a vitamin D suppplement would likely be beneficial in such situations. 10. Summary

For several decades now, Americans have come to believe that the following two practices are foundational in a healthy lifestyle: (1) eat a low-fat diet, and (2) stay away from the sun. I believe that, to solve the obesity epidemic, we need to abandon these two practices. Additionally, if people consume adequate amounts of calcium, then all three nutritional deficiencies that have led to obesity will be overcome: vitamin D, calcium, and dietary fat.

The result of these three deficiencies is defective glucose uptake in both muscle and fat cells. The obese person becomes trapped in an endless metabolic cycle of trying to supply the energy needed for a steadily increasing demand. The fat cells are at the center of the storm, because they are burdened with the arduous assignment of converting the excess consumed sugars and carbohydrates into fat. The fat cells must do this because the muscle cells are impaired with a malfunctioning ability to metabolise sugars. Even if the metabolic problem were not fixed, if the obese person simply ate more fat, and therefore consumed fewer carbs, the fat cells' burden would be greatly alleviated. In addition, getting plenty of vitamin D and calcium, either through diet or sun exposure, would alleviate the core problem of impaired glucose transport across the cell wall. Now that the heart and muscles can utilize sugars directly, the excessive burden on the fat cells to expand and proliferate is relieved, and the body fat will inevitably melt away.

11. What's Next?

Not all people who have deficiencies in dietary fats become obese. Whether the person accumulates excess body fat to compensate probably depends in part on genetic make-up. However, those who stay thin suffer consequences that are at least equal in severity, and perhaps exceed, the health issues associated with obesity.

In my coming blog posts, I plan to discuss how children who consume insufficient dietary fat may develop conditions such as ADHD. depression, and sleep disorders, as a consequence of inadequate fat supply to the brain. A case in point is Matthew Smith of Royal Oak, Michigan [1], a 14 year old child who fell off his skate board and died suddenly. Matthew had been diagnosed with ADHD when he was in first grade, and had been on Ritalin since then as treatment. Upon autopsy, his heart was found to be diffusely enlarged, scarred, and riddled with fat. The medical examiner blamed Ritalin for the heart damage, and certainly Ritalin may have aggravated the problem. I believe, however, that the fatty and enlarged heart and the ADHD are both a consequence of insufficient fats in the diet. It may be the case that Ritalin works by making the brain more efficient at utilizing fats, but this would be at the expense of the heart. The heart would then be compelled to further enhance its own private store, to satisfy its nutritional needs.

The brain is an extremely fatty organ. All of its nerve fibers are coated with a fatty myelin sheath that insulates them to keep their signals intact. The brain does not use fat for fuel. This would be extremley unwise, because it would be unable to avoid feeding off of itself. However, with inadequate fat supply, it is unable to build healthy nerve fibers, and this has dire consequences to mental health. The consequences are especially disturbing for children, whose immature brains are constantly integrating new knowledge, concepts, and experience, to make sense of the world they live in and their role in it.

References

[1] F. Baughman, Jr., MD, How Psychiatry Makes 'Patients' Out of Normal Children , Trafford Publishing, 2009.
[2] A. M. Borissova, T. Tankova, G. Kirilov, L. Dakovska, and R. Kovacheva, "The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients," Int J Clin Pract, Vol. 57, pp. 258 -- 261, 2003.
[3] B.J. Boucher, N. Mannan, K. Noonan, C.N. Hales, and S.J. Evans, "Glucose Intolerance and Impairment of Insulin Secretion in Relation to Vitamin D Deficiency in East London Asians,"Diabetologia Vol. 38, 1239-- 1245, 1995.
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[22] Y. Li, P. Wang, J. Xu, F. Gorelick, H. Yamazaki, N. Andrews, and G. Desir, "Regulation of Insulin Secretion and GLUT4 Tracking by the Calcium Sensor Synaptotagmin VII," Biochem Biophys Res Commun, Vol. 362, No. 3, pp. 658--664, October 26, 2007.
[23] W. Lim, MD; S. Hong, PhD; R. Nelesen, PhD; J.E. Dimsdale, MD, "The Association of Obesity, Cytokine Levels, and Depressive Symptoms With Diverse Measures of Fatigue in Healthy Subjects," Arch Intern Med. Vol. 165, pp. 910-915, 2005.
[24] S. Liu, Y. Song, E. Ford, J. E. Manson, J. E. Buring, and P. M. Ridker, "Dietary Calcium, Vitamin D, and the Prevalence of Metabolic Syndrome in Middle-Aged and Older U.S. Women,"
[25] A. Martia, F.J. Novob, E. Martinez-Ansoa, M. Zaratieguib, M. Aguadoa and J.A. Martineza, "Leptin Gene Transfer into Muscle Increases Lipolysis and Oxygen Consumption in White Fat Tissue inob/obMice" Biochemical and Biophysical Research Communications, Vol. 246, No. 3, 29 pp. 859-862, May 1998.
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[30] A.W. Norman, J.B. Frankel, A.M. Heldt, and G.M. Grodsky, "Vitamin D Deficiency Inhibits Pancreatic Secretion of Insulin," Science, Vol 209, Issue 4458, 823-825, 1980.
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[35] M. A. Pereira, D. R. Jacobs, Jr, L. Van Horn, M. L. Slattery, A. I. Kartashov, and D. S. Ludwig, "Dairy consumption, obesity, and the insulin resistance syndrome in young adults: the CARDIA Study." JAMA Vol. 287, pp. 2081 -- 2089, 2002.
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[37] J.P. Reis, D. von Muhlen,E.R. Miller, 3rd, E.D. Michos, and L.J. Appel, "Vitamin D Status and Cardiometabolic Risk Factors in the United States Adolescent Population," Pediatrics, August 3, 2009.
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[41] M. B. Zemel, and S.L. Miller, "Dietary Calcium and Dairy Modulation of Adiposity and Obesity Risk," Nutr Rev. Vol. 62, No. 4, pp. 125--131, April, 2004.
[42] M. B. Zemel, H. Shi, B. Greer, D. Dirienzo and P. C. Zemel, "Regulation of adiposity by dietary calcium," The FASEB Journal, Vol. 14, pp. 1132-1138, 2000.
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Supportive Scientific Evidence for Essay on Metabolic Syndrome

I have presented an argument here , on why I believe that nutritional deficiencies in vitamin D, calcium and fats may be the source of the obesity epidemic in America, and the related metabolic syndrome. In the essay, I tried to present the theory I have developed using as few technical terms as possible. While, to my knowledge, my theory taken as a whole is novel, others have certainly proposed some aspects of it, such as the idea that poor glucose metabolism by muscles may be a factor in obesity. Here, I will provide supportive evidence from the literature, by presenting a number of facts and scientific studies that back up various aspects of the theory.

1. Obesity and Fatigue

2. Vitamin D Deficiency and Metabolic Syndrome

3. Calcium, Fats, and Fiber

4. Calcium Deficiency and Obesity

5. Vitamin D and Obesity

6. Vitamin D and Insulin

7. Vitamin D Deficiency Epidemic in America

8. Calcium and Glucose Metabolism

9. Muscle Glucose Utilization and Obesity

10. AMPK and Hypothalamus and Appetite

11. Calcium and Insulin Stimulation in Hypothalamus

12. Leptin Resistance in the Hypothalamus

13. Pituitary, Leptin, and Calcium

1. Obesity and Fatigue An excellent study was recently conducted by Lim et al. [1] to measure correlations between fatigue and various factors that they suspected might be related to fatigue. They studied 70 subjects, and tabulated multiple dimensions of fatigue, such that they were able to tease apart "emotional fatigue" from "physical fatigue." The variables that they investigated were adiposity (degree of obesity), symptoms of depression, and circulating levels of certain cytokyines, such as IL-6, which are often high in obese people. They found that, while depression was associated with all types of fatigue, obesity itself was the best predictor of physical fatigue. The cytokyne levels appeared to be unrelated to fatigue.

Reference

[1] W. Lim, MD; S. Hong, PhD; R. Nelesen, PhD; J.E. Dimsdale, MD, "The Association of Obesity, Cytokine Levels, and Depressive Symptoms With Diverse Measures of Fatigue in Healthy Subjects," Arch Intern Med. Vol. 165, pp. 910-915, 2005.
2. Vitamin D Deficiency and Metabolic Syndrome

A recent study by Reis et al. [1] examined whether low serum vitamin D levels was associated with cardiovascular risk factors in adolescents in the United States. In a study involving 3577 adolescents, they found that low vitamin D levels are strongly associated with high blood pressure, high blood sugar, and high levels of triglycerides. This association was true regardless of the adolescent's body weight. This result strongly suggests that vitamin D deficiency is a main cause of metabolic disease, and it implies that obesity may not itself be a risk factor for cardiovascular disease, but rather a potential side effect of vitamin D deficiency.

References

[1] J.P. Reis, D. von Muhlen,E.R. Miller, 3rd, E.D. Michos, and L.J. Appel, "Vitamin D Status and Cardiometabolic Risk Factors in the United States Adolescent Population," Pediatrics, August 3, 2009.

3. Calcium, Fats, and Fiber A study on pre- and peri-menopausal women [1] examined the relationship between the women's ability to absorb calcium in the diet and their dietary habits. They found that the most significant factor that led to better absorption of calcium was dietary fat, with a highly significant P value of 0.001. A factor that negatively impacted calcium absorption was dietary fiber. So a high-fiber, low-fat diet, probably considered a healthy diet by many people, is particularly bad for calcium absorption. People who were overweight were also less efficient in absorbing calcium than people with a low body mass index. This is likely related to their low vitamin D status, since vitamin D plays an absolutely crucial role in promoting calcium transport.

Zemel et al. [2] claim that low calcium diets promote excess storage of fats in fat cells. They have observed, for obese people, a significant weight loss associated with augmented calcium ingestion, whether through calcium pills or via dietary adjustments. However, calcium obtained from dairy products was particularly effective as compared with other sources of calcium. They have confirmed in studies with rats as well as through both epidemiological and clinical trial data that high calcium intakes afford protection from obesity.

References

[1] R.L. Wolf, J.A. Cauley, C.E. Baker, R.E. Ferrell, "Factors Associated with Calcium Absorption Efficiency in Pre-and Perimenopausal Women," American Journal of Clinical Nutrition,, Vol. 72, pp. 466--471, August, 2000.

[2] M. B. Zemel, and S.L. Miller, "Dietary Calcium and Dairy Modulation of Adiposity and Obesity Risk," Nutr Rev. Vol. 62, No. 4, pp. 125--131, April, 2004.

4. Calcium Deficiency and Obesity

Zemel and his colleagues at the University of Tennessee stumbled upon an association between calcium deficiency and obesity when they conducted a clinical trial intended originally to investigate the relationship between calcium and hypertension. [4] Much to their suprise, they discovered, for a group of obese African-American men, that an increase in daily calcium intake (in the form of two cups of yogurt every day) resulted over the course of a year in a 5 kilogram reduction in body fat on average. The men were not consciously dieting, but simply seemed to lose the weight for inexplicable reasons. The researchers subsequently pursued further research on special breeds of mice to try to uncover the reason for this windfall weight loss. They found that these agouti mice became obese when they were fed a diet that was high in sucrose and low in calcium. They were led to the conclusion that, when calcium is deficient, fat cells tend to store internally both calcium and vitamin D, and concurrently are predisposed to store excess fat. Through their experiments, they verified that an increase in dietary calcium suppressed intracellular calcium retention in fat tissue and also attenuated obesity.

Several other papers have been published showing an inverse relationship between calcium and/or vitamin D on the one hand, and obesity/diabetes on the other. Borissova et al. [1] showed that vitamin D supplements improved insulin secretion. Pereira et al. [3], among others, have found an inverse relationship between dairy consumption and body weight, hypertension, glucose homeostasis, and type 2 diabetes, and it has been hypothesized that this is likely due to the calcium and vitamin D contained in dairy. In a study examining the association between dietary calcium and metabolic syndrome in middle-aged and older women in the United States, Liu et al. [2] found that "higher intakes of total, dietary, and supplemental calcium were significantly and inversely associated with the prevalence of metabolic syndrome." Their study involved over 10,000 women who participated in the Women's Healthy Study, and who were free of cardiovascular disease, cancer, or diabetes and had never used postmenopausal hormones.

References

[1] A. M. Borissova, T. Tankova, G. Kirilov, L. Dakovska, and R. Kovacheva, "The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients," Int J Clin Pract, Vol. 57, pp. 258 -- 261, 2003.

[2] S. Liu, Y. Song, E. Ford, J. E. Manson, J. E. Buring, and P. M. Ridker, "Dietary Calcium, Vitamin D, and the Prevalence of Metabolic Syndrome in Middle-Aged and Older U.S. Women,"

[3] M. A. Pereira, D. R. Jacobs, Jr, L. Van Horn, M. L. Slattery, A. I. Kartashov, and D. S. Ludwig, "Dairy consumption, obesity, and the insulin resistance syndrome in young adults: the CARDIA Study." JAMA 287 : 2081 -- 2089, 2002.

[4] M. B. Zemel, H. Shi, B. Greer, D. Dirienzo and P. C. Zemel, "Regulation of adiposity by dietary calcium," The FASEB Journal. Vol. 14, pp. 1132-1138, 2000.

5. Vitamin D and Obesity

Researchers have recently become aware of a strong correlation between vitamin D deficiency and obesity. A study reported in 2007 [1] investigated fasting blood concentrations of 25-hydroxyvitamin D, as well as lipid profiles, and glucose and insulin levels for 73 morbidly obese patients. Sixty one percent of those who were identified as having metabolic syndrome were also vitamin D deficient. Their triglyceride levels were also significantly higher than those of the patients who did not achieve the criteria for metabolic syndrome (163 vs 95 mg/dl.), which supports the model that triglycerides are needed in the blood to provide an alternative energy source besides glucose for the muscles, when glucose uptake is impaired.

It remains unclear whether, in the case of obesity, the fat cells have depleted the vitamin D from the blood supply through enhanced uptake or whether a vitamin D deficiency leads to obesity. In an interesting study which examined the vitamin D3 levels in fat tissues extracted through liposuction from 17 obese men [2], it was concluded that fat tissue is in fact a storage site for vitamin D, and, thus, it is expected that a larger number of fat cells would correlate with increased storage and therefore lead to deficiencies in the blood serum. However, a compelling epidemiological argument that vitamin D deficiency induces obesity can be made by observing that obesity is far more prevalent among African Americans than among Caucasians. Since the dark skin of African Americans greatly reduces their ability to manufacture vitamin D in the skin, it is plausible that their increased incidence of obesity is a consequence of their increased susceptibility to vitamin D deficiency. I would argue that it goes both ways: vitamin D deficiency leads to an increased number of fat cells, which further depletes the vitamin D in a downward cycle. This is in alignment with the idea that fat cells hoard vitamin D in order to more efficiently utilize calcium.

References

[1] J.I. Botella-Carretero, F. Alvarez-Blasco, J.J. Villafruela, J.A. Balsa, C. VNazquez, and H.F. Escobar-Morreale, "Vitamin D deficiency is associated with the metabolic syndrome in morbid obesity," Clin Nutr. Vol. 26 No. 5, pp. 573-80, Oct, 2007.

[2] M. Blum, B. Dawson-Hughes, G. Dolnikowski, E. Seyoum, and S. Harris, "Vitamin D3 in Fat Tissue," Endocrine Journal, Vol. 33, No. 1, March, 2008.

6. Vitamin D and Insulin

The idea that vitamin D deficiency inhibits insulin release from the pancreas was tested and confirmed in research conducted in the late 1970's [1]. Their experiments with vitamin D deficient rats demonstrated a 48 percent reduction in insulin secretion from the rats' extracted pancreases, compared to the secretions realized when the pancreases were replenished with vitamin D. Furthermore, they confirmed that there is a vitamin D-dependent calcium-binding protein and cytosol receptor for 1,25-dihydroxyvitamin D3, the active form of vitamin D, in the pancreas. These results, taken together, suggest strongly that vitamin D enhances the pancreas' ability to produce and release insulin.

References

[1] A.W. Norman, J.B. Frankel, A.M. Heldt, and G.M. Grodsky, "Vitamin D Deficiency Inhibits Pancreatic Secretion of Insulin," Science, Vol 209, Issue 4458, 823-825, 1980.

7. Vitamin D Deficiency Epidemic in America

In an epidemiological study investigating the vitamin D levels of 3,577 12- to 19-year-olds in the NHANES database, it was found that 7 out of every ten children in America have suboptimal levels of vitamin D, and one in ten has levels below the bottom of the normal range [1]. Blacks had the highest incidence of deficiency, and vitamin D deficiency was found to be correlated with excessive weight gain.

A recent study by a team of researchers led by Jared Reis [2] investigated the correlations between vitamin D levels, high blood pressure, and high blood sugar, in a population of teenagers. They found that those with the lowest levels of vitamin D were more than twice as likely to have high blood pressure and high blood sugar as the rest of the teenagers. They were also more than four times as likely to have metabolic syndrome; i.e., enlarged waist and high cholesterol in addition to high blood pressure and high blood sugar.

References

Dr. Joann Manson, who directs preventive medicine at Brigham and Women's Hospital, is one of the principal investigators for upcoming clinical trials. She has been quoted as saying [3], "What's particularly exciting is that vitamin D may have a role in reducing some of the health disparities that are seen in race and ethnicity, because it is known that African-Americans tend to have high risk of vitamin D deficiency, and they also have a higher frequency of diabetes, hypertension, heart failure and many other chronic health problems."

[1] Kumar, J. Pediatrics, September 2009; vol 124, published online ahead of print. Reis, J.P. Pediatrics, September 2009; Vol 124, published online ahead of print. News release, Albert Einstein College of Medicine.

[2] J.P. Reis, D. von MN|hlen,E.R. Miller, 3rd, E.D. Michos, and L.J. Appel, "Vitamin D Status and Cardiometabolic Risk Factors in the United States Adolescent Population," Pediatrics, August 3, 2009.

[3] Patti Neighmond,All Things Considered NPR News Radio Broadcast, August 3, 2009.

8. Calcium and Glucose Metabolism

An excellent article to read in order to understand the critical role of calcium in controlling insulin-mediated glucose uptake was published by Li et al. from Yale Universiy in October, 2007 [1]. The first sentence of their paper following the abstract states, "Intracellular calcium plays a key role in glucose metabolism with respect to insulin secretion and glucose uptake." That is to say, calcium plays an important role both in the release of insulin from the pancreas into the blood stream and in the insulin-stimulated transport of glucose into the cell that is trying to burn the glucose for its energy needs. In some elegant experiments based on genetically altered mice, they demonstrated a markedly abnormal insulin secretion in the pancreas as well as marked insulin resistance in the mice's fat tissues.

In pancreatic cells, a rise in intracellular calcium immediately precedes the fusion of vesicles containing insulin with the cell membrane, in preparation for the release of the insulin into the blood stream. A biologically important family of transmembrane proteins, called "synaptotagnins," coordinate intracellular changes in calcium during membrane fusion events, for a number of different biological processes throughout the body. One member of this family, termed "Syt VII," has been shown to play a critical role in both allowing insulin to be secreted by the pancreatic cells and allowing glucose to be taken up by fat cells. Mice that have been genetically manipulated to have defective genes encoding this protein were demonstrated in this study to exhibit a much weaker response to glucose stimulation, both in terms of insulin release and in terms of glucose uptake in fat cells.

These authors pointed out that insulin dependent migration of GLUT4 to the membrane, where it can mediate the flow of glucose into the fat cell, is clearly dependent on intracellular calcium. Furthermore, GLUT4 translocation in a skeletal muscle cell, triggered by contraction, is also dependent on calcium. They hypothesize, that Syt VII regulates GLUT4 migration by sensing changes in intracellular calcium. In addition to these in-vivo studies, in-vitro experiments performed on rat soleus muscle [2] demonstrated that both calcium and magnesium deficiency led to inhibition of insulin-stimulated glucose utilization in the muscle.

In summary, intracellular calcium levels play a key role in (1) the release of insulin from the pancreas, (2) the uptake of glucose in the fat cells, and (3) the GLUT4 migration in muscle cells to the cell membrane. It has also been demonstrated in in-vitro experiments that glucose utilization in muscles through direct insulin stimulation requires calcium.

References

[1] Y. Li, P. Wang, J. Xu, F. Gorelick, H. Yamazaki, N. Andrews, and G.V. Desirab, "Regulation of insulin secretion and GLUT4 tra3cking by the calcium sensor synaptotagmin VII," Biochem Biophys Res Commun. Vol. 362, No. 3, pp. 658--664, October 26, 2007. [2] K. StefNmkovNa, V. SpustovNa, K. SebekovNa, and R. DzNzrik, "Magnesium deficiency impairs rat soleus muscle glucose utilization and insulin sensitivity." Biomed Experts, 1992.
9. Muscle Glucose Utilization and Obesity

An ingenious experiment is described in [1] below, where the researchers compared several measures of muscle metabolism in femoral muscles of a group of obese men with those of control non-obese men. The experiments involved providing a steady supply of insulin intravenously, while the subjects, in a supine position, exercised only one leg. In this way they could compare the exercised muscle with the unexercised muscle to see how exercise impacts glucose uptake. They found that the femoral muscle glucose uptake was 64% lower in the obese than in the nonobese men. Exercise-stimulated glucose uptake was only 40% lower, i.e., was not as impaired as resting-state glucose uptake. This is in line with the hypothesis that AMPK, released when exercise depletes the ATP levels in the cell, can induce GLUT4 to migrate to the membrane to support glucose uptake even in the absence of sufficient calcium [2]. Another very relevant observation they made was that free fatty acids (FFA's) in blood serum were inversely correlated with rates of glucose uptake, "suggesting that the obese were using FFA instead of glucose as fuel both in resting and exercising leg during hyperinsulinemia." This supports the theory that muscle cells in the obese have been induced to favor fat metabolism over glucose metabolism due to their impaired ability to take up glucose. Other researchers (see [3] below) have also demonstrated that the obese have defects in insulin-stimulated glucose extraction by muscle cells.

References

[1] K. HNdllsten, H. Yki-JNdrvinen, P. Peltoniemi, V. Oikonen, T. Takala, J. Kemppainen, H. Laine, J. Bergman, G.B. BolliN', J. Knuuti and P. Nuutila, "Insulin- and Exercise-Stimulated Skeletal Muscle Blood Flow and Glucose Uptake in Obese Men," Obesity Research Vol. 11, pp. 257-265, 2003.

[2] W.T. Garvey, L. Maianu, J. Zhu, G. Brechtel-Hook, P. Wallace, and A.D. Baron, "Evidence for defect in the trafficking and translocation of GLUT4 transporters in skeletal muscle as cause of human insulin resistance," The Journal of Clinical Investigation, Vol. 101, pp. 2377-2386, 1998.

[3] C. Castillo, C. Bogardus, R. Bergman, P. Thuillez, S. Lillioja, "Interstitial insulin concentrations determine glucose uptake rates but not insulin resistance in lean and obese men. J Clin Invest Vol. 93, pp. 10-16, 1994.

10. AMPK and Hypothalamus and Appetite

It has been determined through extensive research over the past ten or more years that the hypothalamus, a key region of the brain, is the control center for regulating body weight and glucose levels in the blood. Researchers at University College London have been conducting extensive research investigating many aspects of regulation of appetite in the hypothalamus, with the hope of developing designer drugs to treat obesity [2] [3]. They have determined that the system is very complex, but they have zeroed in on AMPK as playing a central role in controlling both weight gain and weight loss. They have developed a series of elegant experiments to investigate the role AMPK plays in body weight, in part through methods that involve knocking out selected genes in mice so as to produce strains that are uniquely disabled in specific neuron types in the hypothalamus. They have found that mice that can't produce AMPK in AgRP neurons in the hypothalamus become thin, whereas if POMC neurons are defective in AMPK manufacture, the mice become obese. This suggests that AgRP neurons induce weight gain, by releasing AMPK, and POMC neurons induce weight loss. Furthermore, they deterimined that both types of neurons became insensitive to glucose levels when they were defective in AMPK. Their logical conclusion is that AMPK is essential for glucose sensing mechanisms that regulate weight in the hypothalamus.

In addition to these AMPK-producing AgRC neurons and POMC neurons, they have identified two different types of glucose-sensing neurons, which they have labelled as GI (glucose inhibited) and GE (glucose excited) neurons. They discovered that GI, but not GE, neurons are sensitive to changes in AMPK, so I believe that the GI neurons are a critical piece of the puzzle. POMC neurons (the ones that induce weight loss when active) are inhibited by reductions in glucose, whereas GI neurons, associated with AgRP neurons and weight gain, are excited by falling glucose levels. Thus, logically, AMPK levels rise in AgRP neurons in response to falling or low blood glucose levels, and this induces a reaction by the GI neurons which results in a powerful appetite stimulant to induce the person to ingest foods that would rapidly replenish the glucose levels.

The evidence is compelling that glucose transport is impeded in fat cells and muscle cells when calcium is insufficient, and also that pancreatic cells are defective in releasing insulin if there is inadequate calcium. A question to ask, then, is whether glucose transport into the glucose-sensing neurons in the hypothalamus is also defective. The answer is not immediately obvious, because the brain in general uses a different mechanism for glucose transport that is not dependent on either calcium or insulin, so it should not be vulnerable to these deficiencies. This is very fortunate with respect to brain metabolism, since the brain only metabolizes sugar and would not be able to switch over to fat metabolism as the muscle cells are able to do.

Some research has been conducted to try to understand the physiological mechanisms used by GI cells. In [4], it is hypothesized that the mechanisms controlling the GI cells' response to low glucose may be distinct from the normal mechanisms adopted by cells in the brain, and, in fact, may be very similar to the mechanism used by alpha cells in the pancreas to detect low glucose. This seems like intelligent design, since the purpose of both the GI cells and the alpha cells is to trigger responses that will increase glucose levels when they are depleted, and they should be reacting consistently. It has been determined that both mechanisms are dependent on AMPK, and both involve calcium transport across the cell membrane. Hence, it can be surmised that calcium deficiencies could cause them to take up glucose less efficiently, and therefore perceive the level of glucose in the blood as being lower than it actually is.

References

[1] Y. Li, P. Wang, J. Xu, F. Gorelick, H. Yamazaki, N. Andrews, and G. Desir, "Regulation of Insulin Secretion and GLUT4 Tracking by the Calcium Sensor Synaptotagmin VII," Biochem Biophys Res Commun, Vol. 362, No. 3, pp. 658--664, October 26, 2007.

[2] B. Kola, "Role of AMP-Activated Protein Kinase in the Control of Appetite," Journal of Neuroendocrinology, Vol. 20, No. 7, pp. 942--951, July, 2008.

[3] B. Kola, A. B. Grossman, and M. Korbonits, "The Role of AMP-Activated Protein Kinase in Obesity," Obesity and Metabolism, Korbonits M., Editor, Vol. 36, Front Horm Res. Basel, Karger, pp. 198--211, 2008.

[4] P.D. Mountjoy and G.A. Rutter, "Glucose Sensing by Hypothalamic Neurones and Pancreatic Islet Cells: AMPle Evidence for Common Mechanisms?," Experimental Physiology, December, 2006.

11. Calcium and Insulin Stimulation in Hypothalamus

Insulin is able to suppress food intake and glucose production by the liver by stimulating certain cells in the hypothalamus in the brain. Scientists are beginning to decode the biological processes by which this happens. Insulin receptor substrates (IRS's) are phosphorylated when stimulated by insulin. However, IGF-1 plays a critical role by binding to the receptor to trigger the phosphorylation. When extracellular calcium concentration is reduced to less than 0.3mM, IGF-I is unable to perform its function in phosphorylating insulin receptor substrates [1]. In [2], it was determined that insulin-stimulated phosphorylation of IRS's is decreased in obese rats compared to lean rats, and I would theorize that this is due to inadequate calcium in the external medium, which has the effect of suppressing the binding of IGF-1.

In [3], the researchers showed that a direct infusion of insulin into the hypothalamus inhibits endogenous glucose production. They argued that their results "reveal a new site of action of insulin on glucose production and suggest that hypothalamic insulin resistance can contribute to hyperglycemia in type 2 diabetes mellitus."

Thus, these three papers taken together support the theory that inadequate calcium in the environment of the hypothalamic cells results in an inability to respond to insulin, which in turn results in an increased production of glucose (i.e., in the liver), and this leads to excess sugar in the blood.

References

[1] I. Kojima and M. Nagasawa, "TRPV2: A Calcium-Permeable Cation Channel Regulated by Insulin-Like Growth Factors," Chapter 7 in TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades,, Taylor & Francis Group, LLC, 2009.

[2] J.B.C. Carvalheira, E.B. Ribeiro, E.P. Araujo, R.B. Guimaraes, M.M. Telles, M. Torsoni, J.A.R. Gontijo, L.A. Velloso, M.J.A. Saad, "Selective Impairment of Insulin Signalling in the Hypothalamus of Obese Zucker Rats," Diabetologia, Vol. 46, No. 12, pp. 1629-40, 2003.

[3] S Obici, BB Zhang, G Karkanias, and L Rossetti, "Hypothalamic insulin signaling is required for inhibition of glucose production." Nat Med Vol. 8, pp. 1376-82, 2002.

12. Leptin Resistance in the Hypothalamus

It is exciting that researchers are able to manipulate mouse genetics to produce abnormalities in very specific genes, and to then study the effects of the resulting impairment on the mouse's homeostatis. A nice example of this is described in [1], where mice were genetically engineered to have a defective gene for a specific receptor for leptin in cells in the arcuate nucleus of the hypothalamus. This is in a sense simulating the "leptin resistance" characteristic of obese people, in a very specific way.

It has been observed empirically that the obese typically have very high values of leptin in the blood most of the time, yet they seem to not respond to it appropriately, in that it does not induce a sense of satiety, as it would ordinarily do [2]. These genetically engineered mice, with a defective receptor for leptin in the hypothalamus, develop an associated condition that mimics remarkably well the metabolic syndrome: they are obese, they have abnormally high levels of glucose in the blood, and they are disinclined towards exercise (i.e., trying to conserve energy). They are in fact acting as if they have a deficiency in glucose uptake in the muscle cells. Researchers were also able to reactivate the leptin receptors, and when they did this the glucose levels in the blood dropped significantly and the mice became more active. In the abstract, they conclude that these results demonstrate that leptin signaling in the arcuate nucleus of the hypothalamus is "sufficient for mediating leptin's effects on glucose homeostasis and locomotor activity."

References

[1] R. Coppari, M. Ichinose, C.E. Lee, A.E. Pullen, C.D. Kenny, R.A. McGovern, V. Tang, S.M. Liu, T. Ludwig, S.C. Chua Jr, B.B. Lowell, and J.K. Elmquist. "The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity," Cell Metab. Vol. 1 No. 1, pp. 63-72, Jan, 2005.

[2] J.M. Zigman and J.K. Elmquist, "Minireview: From Anorexia to Obesity -- The Yin and Yang of Body Weight Control" Endocrinology Vol. 144, No. 9, pp. 3749-3756, 2003.

13. Pituitary, Leptin, and Calcium

It has been observed that obesity is associated with a condition that is referred to as "leptin resistance," meaning that, although serum leptin levels are usually very high in obese people, the normal response of being satiated is somehow not occurring. The pituitary gland, at the base of the brain, is considered the "master gland" of the endocrine system. While the mechanisms by which leptin influences appetite are not fully worked out, it has been shown that the pituitary responds to leptin both directly and indirectly, mediated by the hypothalamus, to which it is attached. In [1] below, it was demonstrated that specific cells isolated from the pituitary respond directly to exposure to leptin by increasing the intracellular concentrations of calcium. This analysis was done in vitro, working with cells that are known to promote growth, which were extracted from the anterior pituitary of pigs. The experiments involved exposing these cells to leptin and measuring their internal calcium concentrations. They noted that the stimulatory effect of leptin was blocked if the cells were suspended in a low-calcium saline solution, and was also blocked if calcium channel blockers were added to the medium. This strongly implies an important role for calcium in the process by which the pituitary detects the presence of leptin, and therefore could explain the leptin resistance in the pituitary as being a consequence of inadequate serum calcium.

References

[1] A. Glavaski-Joksimovica, E.W. Rowea, K.Jeftinijaa, C.G. Scanesa, L.L. Andersona,and S. Jeftinijaa, "Effects of Leptin on Intracellular Calcium Concentrations in Isolated Porcine Somatotropes," Neuroendocrinology Vol. 80, pp. 73-82, 2004.

Acknowledgement

I would like to express my deep appreciation to Jody Caraher who critically read early drafts of this document. It is much improved due to her efforts.

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The Obesity epidemic: is the Metabolic Syndrome a Nutritional Deficiency Disease? by Stephanie Seneff is licensed under a Creative Commons Attribution 3.0 United States License.