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

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.

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.

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 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.

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.

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.

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.

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.

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.

[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.
[4] J.I. Botella-Carretero, F. Alvarez-Blasco, J.J. Villafruela, J.A. Balsa, C. Vazquez, 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.
[5] 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] 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.
[7] 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.
[8] 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.
[9] J. Ding, S. Kritchevsky, T.B. Harris, G.L. Burke, R.C. Detrano, M. Szklo, and J.J. Carr, "The Association of Pericardial Fat with Calcified Coronary Plaque," Obesity, Vol. 16, No. 8, pp. 1914--1919, 2008.
[10] Foss Y.J.,"Vitamin D deficiency is the cause of common obesity," Med Hypotheses, Mar;72(3):314-21, 2009.
[11] 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.
[12] L.M. Gartner, MD and F.R. Greer, MD, "Prevention of Rickets and Vitamin D Deficiency: New Guidelines for Vitamin D Intake," Pediatrics Vol. 111, No. 4, pp. 908-910, April 2003,
[13] W.T. Garvey, L. Maianu, J. Zhu, G. Brechtel-Hook, P. Wallace, and A.D. Baron, "Evidence for defect in the trafficking translocation of GLUT4 transporters in skeletal muscle as cause of human insulin resistance," The Journal of Clinical Investigation, Vol. 101, pp. 2377-2386, 1998.
[14] 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.
[15] D G Hardie, "AMPK: a Key Regulator of Energy Balance in the Single Cell and the Whole Organism," International Journal of Obesity Vol. 32, pp. 7-12, 2008.
[16] J.S. Ingwall, "On Substrate Selection for ATP Synthesis in the Failing Human Myocardium," Am J Physiol Heart Circ Physiol Vol. 293, H3225-H3226, 2007. [17] S. Khosla, MD; L.J. Melton III, MD; M.B. Dekutoski, MD; S.J. Achenbach, MS; A.L. Oberg, PhD; B.L. Riggs, MD, "Incidence of Childhood Distal Forearm Fractures Over 30 Years: A Population-Based Study," JAMA. Vol. 290, pp. 1479-1485, 2003.
[18] 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.
[19] 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.
[20] 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.
[21] J. Kumar, P. Muntner, F.J. Kaskel, S.M. Hailpern, and M.L. Melamed, "Prevalence and Associations of 25-Hydroxyvitamin D Deficiency in US Children: NHANES 2001-2004," Pediatrics, Vol. 124, pp. 362-370, 2009.
[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.
[26] J.M. Marchington, C.A. Mattacks and C.M. Pond, "Adipose tissue in the mammalian heart and pericardium: structure, foetal development and biochemical properties," Comp Biochem Physiol B (1989) Vol. 94, pp. 225- 232.
[27] L. Maximilian Buja, MD, "Does Atherosclerosis Have an Infectious Etiology?", Circulation 94:872-873, 1996.
[28] Y. Minokoshi, Y.B. Kim, O.D. Peroni, L.G. Fryer, C. Muller, D. Carling, and B.B. Kahn, "Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase," Nature. Vol. 17, pp. 339-43, Jan. 2002.
[29] 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.
[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.
[31] 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.
[32] E.O. Ojuka, T.E. Jones, L.A. Nolte, M. Chen, B.R. Wamhoff, M. Sturek, and J.O. Holloszy, "Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca2+," Am J Physiol Endocrinol Metab Vol. 282, NO. 5, May 2002.
[33] A.L. Olson and J. E. Pessin, "Structure, function, and regulation of Mammalian facilitative glucose transporter gene family," Annual Reviews Nutrition, Vol. 16, pp. 235-256, 1996.
[34] S. Park, T.L. Scheffler, A.M. Gunawan, H. Shi, C. Zeng, K.M. Hannon, A.L. Grant, and D.E. Gerrard, "Chronic elevated calcium blocks AMPK-induced GLUT-4 expression in skeletal muscle," Am J Physiol Cell Physiol Vol. 296,pp. C106-C115, 2009.
[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.
[36] U. Ravnskov, Fat and Cholesterol are Good for You! G.B. Publishing, Sweden, 2009.
[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.
[38] K. Stefikova, V. Spustova, K. Sebekova, and R. Dzurik, "Magnesium deficiency impairs rat soleus muscle glucose utilization and insulin sensitivity." Biomed Experts, 1992.
[39] W.W. Winder, "Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle," J Appl Physiol.Vol. 91, No. 3, pp. 1017-1028, Sep., 2001.
[40] 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.
[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.
[43] 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.

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

Reference

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.