Monday, January 2, 2012


 I have never had an opportunity of conducting the laboratory investigations which are so necessary for a theoretical understanding of clinical observations, and I can only hope that those more fortunately placed will in time be able to fill this gap.”
– Dr. A.T.W. Simeons, Pounds & Inches

 By Robin Phipps Woodall, Author of Weight-Loss Apocalypse
HCG injections of between 100IU and 150IU might stimulate, from fat cells, sufficient amounts of leptin to prevent symptoms of starvation imposed by the very low-calorie protocol (VLCP), as described by Dr. Simeons. The controlled hCG/protocol environment should stimulate enough leptin to minimize hunger, to maintain a normal and healthy thyroid signal, and to prevent significant reductions in lean body mass by effectively maintaining energy homeostasis through fatty acid oxidation of leptin-sensitive fat stores.
The controlled demand imposed by participant adherence to the VLCP will prevent fat gain by offsetting the susceptibility to over-stimulate leptin. This controlled demand with optimized fat utilization should, with time and physical adaptation, up-regulate mitochondrial biogenesis. During the second phase, as energy demand on fat is significantly reduced, new smaller mitochondria might progressively increase oxidative power, measuring an increase in resting energy expenditure (calories, per pound of body weight, per day).
Using this hypothesis as the basis of future research might explain what is observed during the protocol.
The following material is meant only to start new discussion about how hCG might influence energy homeostasis when food is removed.
To start, let’s acknowledge the inherent difficulty of understanding the body’s integrated system of organs, each requiring its own nourishment and energy demands, in addition to understanding the systems of tissues dependent upon these organs. The energy needed to sustain our organs and tissues is a system that feeds and depletes. It gives and takes from one organ to the next, all while accommodating the complex influence from both physical activity and food. This balance of energy demand and energy sharing is called energy homeostasis, and maintaining homeostasis sustains these integrated systems during both feast and famine.
All systems integrate fuel and energy demands not only daily, but over a lifetime. This constant striving for homeostasis is what stimulates the feelings of hunger that prompt us to eat, and to stop eating when we’re satiated. Perhaps the most critical element in achieving homeostasis is maintaining a stable blood glucose level.
We are fed from many sources other than food; some sources of fuel are fat, muscle and liver glycogen, body protein, and blood glucose.  These “tissue” fuels are not stocked equally. Some have more reserves than others. Fat and body protein by far surpass the fleeting amount of energy reserves held in both glycogen and blood glucose. The total integration of these fuel systems for short and long-term metabolic homeostasis is vital to life, hourly, and over the period of our body’s life.
The energy our body captures is powered not only by food, but also by our tissue reserves. However, these substrates must be converted into what can be captured before the body can use it as energy. As you eat, the food you consume is not yet in a form that can be captured as energy, so tissue reserves are readily available to meet immediate demands. But for tissue reserves to be released, key hormones that determine when and how much energy is needed must be accessed.
Leptin is one of the most important energy-controlling hormones. Since its discovery in 1994, we more fully understand leptin’s key role as a fatty acid synthase (FAS) inhibitor, and most notably as an anorexigenic hormone affecting the signal of hunger, the function of the thyroid, and fat metabolism. 2 15
Similar to insulin, leptin levels fall and rise in coordination with blood glucose, signaling to the body and brain when and how much energy reserve is available. 3 Leptin helps maintain blood glucose levels by regulating fatty acid use in skeletal muscle for energy, and preserving blood glucose for other more important organs to use. 4
Leptin is primarily found in white and brown fat cells, but could also be produced in the mouth, placenta, ovaries, skeletal muscle, stomach, mammary cells, bone marrow, pituitary and liver. 5 6 The rise and fall of leptin levels influence hunger, thyroid stimulus, fat metabolism, and fat gain.  To successfully apply the modern science of leptin’s functions to Dr. Simeons’ protocol, I will discuss leptin as it relates to four areas; the hypothalamus, skeletal muscle, fat, and the thyroid.
As a diet begins, and food is restricted, blood glucose levels fall. As blood glucose levels drop in the body and brain, leptin also depletes. 7 12 As leptin levels fall, there is a reduction in malonyl-CoA, a recognized intermediate, in the hypothalamic-signaling pathway that controls feeding behavior and energy expenditure. 15 Recent evidence suggests that food deprivation, and the associated decrease in hypothalamic malonyl-CoA, increases the expression of neuropeptide Y (NPY) and agouti-related protein (AgRP), which produces the sensation of hunger. Conversely, as blood glucose and leptin levels rise after eating, the resulting increase in malonyl-CoA reduces the expression of NPY and AgRP, producing feelings of satiety when hunger is alleviated. 7 10
Studies have shown administration of a fatty acid synthase (FAS) inhibitor (such as leptin) to the central nervous system in obese mice, dramatically reduces feeding behavior, with the increase in hypothalamic malonyl-CoA concentrations.13 25 These findings show that during very low-calorie diets, a stimulant of a FAS inhibitor like leptin, would raise malonyl-CoA levels, and decrease the expression of NPY and AgRP. Theoretically, this should sustain feelings of satiation for longer periods of time with less food.
Leptin is primarily expressed and secreted by fat cells. As fat mass increases during energy surplus, blood leptin increases and interacts with its receptors in the central nervous system (CNS), leading to increased malonyl-CoA expression in the hypothalamus, and decreased hunger. 22 Although there could be fat loss due to lack of hunger with a FAS inhibitor, studies have shown central administration of FAS inhibitors transmitted to the skeletal muscle from the CNS, increases fatty acid oxidation and, with time, increases resting energy expenditure. 16 23 
As FAS inhibitors increase in skeletal muscle, the result is a decrease in muscle malonyl-CoA.  This outcome essentially determines whether or not fat is used for energy. 4 Muscle malonyl-CoA is a potent allosteric inhibitor of muscle carnitine palmitoyltransferase (CPT-1). CPT-1 is like a doorway on the mitochondrial membrane, opening or shutting access for fatty acids to enter and be converted into fuel for the body. When CPT-1 is deactivated by muscle malonyl-CoA, entry of fatty acids into mitochondria for β-oxidation is inhibited. 15
Muscular malonyl-CoA formation is catalyzed with increased activity in the enzyme Acetyl-CoA carboxylase (ACC). ACC is strongly inhibited by AMP-activated protein kinase (AMPK), which is stimulated by leptin. 11 So, as leptin levels decrease, AMPK is deactivated, which activates ACC. ACC creates malonyl-CoA, which inhibits CPT-1, and thus reduces fatty acid oxidation. 13 15
This happens as a response during starvation when blood glucose and leptin levels fall, preserving fat for longer periods of time, and forcing muscles to use other tissue substrates instead.12 However, eating has the opposite effect.
After eating, when blood glucose and blood leptin levels increase, the activation of AMPK deactivates ACC, which decreases muscular malonyl-CoA. As muscle malonyl-CoA declines, CPT-1 activates and opens access for fat into the mitochondria, where energy can be supplied through β-oxidation. 4 11 This might explain how eating food that is not yet in a form that can be captured as energy, stimulates the use of stored fuel for immediate use.
New science has shown that this system can be successfully manipulated, not only to counteract symptoms of starvation, but to improve metabolic rates. Centrally administered FAS inhibitors during food restriction, rapidly increases the expression of skeletal muscle peroxisome proliferator-activated receptor-α (PPARα), a transcriptional activator of fatty acid oxidizing enzymes, and uncoupling protein 3 (UPC3), a putative thermogenic mitochondrial uncoupling protein. 2315 Daily administration of FAS inhibitors over time increases the number of mitochondria in white and red skeletal muscle. This could explain why studies show increases in metabolisms tested through indirect calorimeter. 23 26 27 
This evidence shows that if there was a way to safely increase a FAS inhibitor such as leptin, as well as create energy demand with food restriction, the response over time should be to acclimate with more mitochondria, resulting in a higher caloric-burning capacity. But without a FAS inhibitor, one should expect with the same food restriction to see a slowed loss in fat, increased loss of lean tissue reserves, and a resulting decline in resting energy expenditure.
To prevent the natural decline in fat mobilization with a very low-calorie diet, there must be an alternative way to stimulate leptin to decrease muscular malonyl-CoA, This allows fatty acids to have continuous access into the mitochondria, where fat could provide substantial fuel for the body without significantly depleting blood glucose. This optimized fat utilization would prevent the need for the body to use lean tissue reserves during extreme caloric deficits and, over time, stimulate mitochondrial biogenesis, ultimately increasing the rate at which a person burns energy fuel at rest.
High levels of leptin in adipose tissue, without equally sufficient expenditure, have the opposite effect. Studies show that extremely high levels of leptin, similar to those seen in the obese, increase peroxisome proliferator-activated receptor-gamma (PPAR-gamma), which is the master control switch for fat storage.  21 22 14
PPAR-gamma activates a host of enzymes that promote the esterification of fatty acids to create triacylglycerides (TAG), and advances the formation of lipid droplets from these TAG.  When administered to mice, high levels of leptin increased the cellular expression of PPAR-gamma by 70-80%. 14 Leptin signals to the brain that there’s ample energy in storage, but also forewarns pre-adipocites to make room for more fat cells. 
The more fat a person has, the more leptin his or her body produces. 21 Essentially, if you were to compare two people who have the same exact metabolic rate, but extreme variance in body fat composition, their bodies would have a different response to the same food. If they ate the same exact amount and type of food, the more obese person would have much more blood leptin stimulated, due to their larger amount of body fat.
The excess amount of leptin, without equal excess energy expenditure, can cause an imbalance in energy homeostasis, making the body more sensitive to resulting fat gain as a need to recapture and compensate for the imbalance.  Leptin’s stimulus of PPAR-gamma would complement insulin as a survival mechanism to make room for more fat, aiding in the preparation for more energy storage cells as an adaptation for long-term energy homeostasis. A person with less fat would have less leptin, which might better compliment their metabolic energy balancing system, thus making him or her less sensitive to fat gain—even when eating the same exact meal as a more obese counterpart. Hence, fat gain and loss is not a linear function of calories eaten and expended because fat hormones, such as leptin, greatly influence energy homeostasis, and the body’s resulting compensations.
Both fat-preserving and fat-creating effects of leptin will function to conserve fat during starvation, and to form fat when food is excessive.  Leptin’s fat burning and storing/preserving relationships seem to follow an “inverted U” model. Leptin’s fat-conserving functions are maximum with high and low levels, and its fat-burning functions are optimal in the middle.
If leptin is stimulated by an outside influence, there might be less necessity for food and more sensitivity to over-stimulate leptin production. This excessive stimulus of leptin relative to expenditure would cause an expression of PPAR-gamma and an increase in fat when relatively small amounts of food are consumed.
Leptin’s elevation and depletion in the brain signals a fed or starved state, not only through hunger, but also through the metabolic suppression or stimulus from the thyroid. 8 When elevated, leptin stimulates thyrotropin-releasing hormone (TRH) that controls the release of thyroid stimulating hormone (TSH). TSH acts on receptors in the thyroid to promote synthesis and release of the thyroid hormones (T3 and T4), which increases the body’s basal metabolic rate. 8 As blood glucose levels fall with very low-calorie diets, the depletion of leptin in the brain inhibits this cascade affect, resulting in a weaker metabolic signal from the thyroid. 9
The natural drop in thyroid signal is an essential, life-sustaining mechanism that occurs during starvation. This mechanism slows down the rate at which the body needs fuel, thus preserving energy stores and life for a longer period of time. However, when leptin is administered during induced starvation, the thyroid signals stay strong. 10 If the thyroid signal stays strong, the body maintains a normal basal metabolic rate, and requires the same amount of fuel as if in a fed state.
To counteract the natural metabolic suppression of the thyroid, an energy-preserving survival mechanism, during sustained very low-calorie diets, an alternative stimulus of leptin would be needed.
Not only is there clear evidence that the placenta produces leptin, but there’s evidence that hCG might exert a negative feedback loop on trophoblastic release of leptin. 17 18 19 20 This means that specific quantities of hCG stimulate leptin production. If there were too much hCG, leptin levels would decline. If there were too little hCG, not enough leptin would be produced. 
Based on these findings, hCG could be a viable stimulant of leptin. But the question yet to be answered is, would injections of hCG with Simeons’ protocol:
·         Stimulate sufficient blood leptin levels to interact with its receptors in the participant’s central nervous system, acting as a potent FAS inhibitor in the hypothalamus, reducing hunger? In the hypothalamus to sufficiently stimulate the thyroid?
·         Stimulate enough leptin production in the skeletal muscle to increase fatty acid β-oxidation? The right amount of leptin in the fat cells to prevent fat storage?  And enough time and constraint for mitochondrial biogenesis to significantly increase resting energy expenditure?
·         Could other forms of hCG administration, including homeopathic hCG, do the same?
Simeons’ findings left many questions unanswered, and science uncharted by the refuting research of his protocol. Based on the evidence I’ve presented, hCG isn’t burning fat, it doesn’t directly reduce the appetite, and it doesn’t stimulate the metabolism. Rather, it is the energy demand of the protocol, combined with how hCG influences leptin, in the brain and body, that allows the body to metabolize fat and function as if fed, when food is not available. 

(1)       Lijesen, G.K.S., et al. 1995. The effect of human chorionic gonadotropin (HCG) in the treatment of obesity by means of the Simeons’ therapy: a criteria-based meta-analysis. The British Journal of Clinical Pharmacology. 40:237-243
(2)       Zhang, Y., et al. 1994. Positional cloning of the mouse obese gene and its human homologue. Nature. 372: 425-432
(3)       Morton, G.J. 2007. Hypothalamic leptin regulation of energy homeostasis and glucose metabolism. J Physiology. 583.2: 437-443
(4)       N.Y. Ann. 2002. Regulation of fat metabolism in skeletal muscle. National Academy of Sciences of the USA. 967:217-235
(5)       Margetic, S., et al. 2002. Leptin: a review of its peripheral actions and interactions. International Journal of Obesity. 26: 1407-1433
(6)       Groschl, M., et al. 2001. Identification of Leptin in Human Saliva. The Journal of Clinical Endocrinology & Metabolism. 86(11): 5234-5239
(7)       Mars, M., et al. 2006. Fasting leptin and appetite responses induced by a 4-day 65% energy-restricted diet. International Journal of Obesity. 30: 122-128
(8)       Rosenbaum, M., et al. 2002. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. The Journal of Clinical Endocrinology & Metabolism. 87:2391-2394
(9)       Flier, J.S., et al. 2000. Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring. The Journal of Clinical Investigation. 105(7): 859-861
(10)    Ahima, R.S., et al. 1996. Role of leptin in the neuroendocrine response to fasting. Nature. 382: 250-252
(11)    Kahn, M.Y. 2003. Role of AMP-activated protein kinase in leptin-induced fatty acid oxidation in muscle. Biochemical Social Transactions. 31(pt 1): 196-201
(12)    Flier, J.S. 1998. Clinical Review 94: What’s in a name? In search of leptin’s physiologic role. Journal of Clinical Endocrinology and Metabolism. 83(5):1407-1413
(13)    Wolfgang, M.J., et al. 2007. Regulation of hypothalamic malonyl-CoA by central glucose and leptin. The National Academy of Sciences of the USA. 104(49): 19285-19290
(14)    Qian, H., et al. 1998. Leptin regulation of peroxisome proliferator-activated receptor-gamma, tumornectrosis factor, and uncoupling protein-2 expression in adipose tissue. Biochemical and Biophysical Research Communications. 246(3): 660-667
(15)    Wolfgang, M.J., et al. 2008. Hypothalamic malonyl-CoA and the control of energy balance. Molecular Endocrinology. 22(9): 2012-2020
(16)    Orci, L., et al. 2003. Rapid transformation of white adipocytes into fat-oxidizing machines. The National Academy of Sciences of the USA. 101(7): 2058-2063
(17)    Islama, D., et al. 2003. Modulation of placental vascular endothelial growth factor by leptin and hCG. Molecular Human Reproduction. 9(7): 395-398
(18)    Maymo’, J.L., et al. 2009. Up-regulation of placental leptin by human chorionic gonadotropin. The Endocrine Society. 150(1): 304-313
(19)    Linnemann, K., et al. 2000. Leptin production and release in the dually in vitro perfused human placenta. The Journal of Clinical Endocrinology & Metabolism. 85(11): 4298-4302
(20)    Islami, D., et al. 2003. Possible interactions between leptin, gonadotrophin-releasing hormone and human chorionic gonadotrophin. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 110(2): 169-175
(21)    Considine, R.V., et al. 1996. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. The New England Journal of Medicine. 334(5): 292-295
(22)    Friedman J.M., et al. 1998. Leptin and the regulation of body weight in mammals. Nature. 395:763-770
(23)    Cha, S.H., et al. 2005. Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle. The National Academy of Sciences of the USA. 102: 14557-14562
(24)    Schwarts M.W., et al. 2006. Central nervous system control of food intake. Nature. 404: 661-671
(25)    Cha, S.H., et al. 2003. Hypothalamic malonyl-CoA as a mediator of feeding behavior. The National Academy of Sciences of the USA. 100: 12624-12629
(26)    Cha, S.H., et al. 2006. Hypothalamic malonyl-CoA triggers mitochondrial biogenesis and oxidative gene expression in skeletal muscle: role of PGC-1α.  The National Academy of Sciences of the USA. 103: 15410-15415
(27)    Thupari, J.N., et al. 2002. C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity. The National Academy of Sciences of the USA. 99: 9498-950
(28)    Lederman, S.A., et al. 1999. Maternal body fat, water during pregnancy: do they raise infant birth weight? American Journal of Obstetrics and Gynecology. 180: 235-240

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