Is Low Blood Sugar Obesogenic? Hypoglycemic Episodes Characteristic of Weight Loss Plateaus & Weight Regain - What to Do? Diet, Sleep, Exercise & Mental Work Matter

Tip: Restore your muscle and liver glycogen after workouts and before long fasts to ensure a smooth transition from glucose to fat utilization.

In view of the diabetes pandemic it sounds stupid, when J-P Chaput and A Tremblay write that low blood sugar levels could contribute to the ever-increasing obesity rates in the US and other Western countries.

Their reasoning, however, is sound: An increase in blood glucose concentrations results in increased feelings of satiety whereas a drop in blood glucose concentrations has the opposite effect.

Chronically low levels of glucose, as well as the glucose excursions we see in the few (still) healthy people after shoveling down packages of twinkies and dingdongs, would thus precipitate overeating and eventually obesity and diabetes.

Use alternatives to sugar sweetened beverages if you want to stabilize your blood glucose!

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Compared to the way the hypothesis was originally formulated by Jean Mayer in the 1950s, the theory Chaput & Tremblay present in a 2009 review of the literature is significantly more complex (Mayer. 1953 & 1955. Chaput. 2009) and more of a glucose homeastasis hypothesis of obesity.

In contrast to the mainstream version of the "bad blood sugar spikes", Mayer and later Chaput and Tremblay focus on the role of the blood sugar troughs, we rarely think about. It all goes back to the classic glucostatic theory of food intake which postulates that

"that reduced glucose utilization in critical brain regions leads to perception and expression of hunger, and increased glucose utilization in these same glucosensitive sites leads to decreased hunger and cessation of eating." (Chaput. 2009)

In a state of decreased glucose utilization aka "metabolic hypoglycemia" (Mayer. 1955), there is a point at which the peripheral arteriovenous difference in blood glucose becomes negligible and glucose is no longer entering ‘metabolizing cells’ - this, according to Mayer, is the the signal for meal
initiation.

Does this mean that fasting is counter-indicated? For most of you probably not. If your liver gylcogen levels are well-stocked at the onset of the fast and assuming that you have a decent degree of metabolic flexibility, the transition into the fast will not put you at risk of metabolic (temporary glucose shortage at the cellular level) and / or full-blown hypoglycemia (really low blood glucose levels). So, fasting is ok, if you don't turn it into "starving" by extending the fast indefinitely and/or not restocking your glycogen levels in the feeding windows.

Interestingly, Mayer argued in his previously cited 1955 paper, already that the glucostatic theory would explain the short-term control of hunger and food intake, whereas a lipostatic mechanism would control the long-term regulation of body weight and energy balance.

There is nothing static about the glucostatic theory

Today, the role of glucose in the control of food intake is thought to be dynamic: it is a satiety factor and an initiation signal that has been associated with body fat by Chaput and Tremblay in two studies, which examined the effects of low glucose concentrations on long-term energy balance and weight gain in (Boulé. 2008)

Figure 1: Surprisingly linear increase in weight and body fat regain in prospective study and experimantal trial with lower blood glucose levels after OGGT (Boulé. 2008)

• 259 participants between 20 and 67 years of age involved in the Quebec Family Study - A study which revealed a closeassociation between glucose concentrations at the end of anoral glucose challenge and changes in body mass over the course of a 6-year follow up (Boulé . 2008).

• 44 obese participants on a 15-week weight-loss programme in either a drug therapy group or a placebo group coupled with energy intake restriction - A study which showed a higher propensity for weight regain over a follow up period of 83 weeks in those who had glucose levels below fasting values at the end of the oral glucose tolerance test during the weight loss intervention (Boulé. 2008)

In view of the fact that it would be easy to over-read the significance of these results: The researchers found that (1) lower glucose concentrations at the end of an OGTT were correlated with weight gain over time, that (2) large amounts of weight loss were associated with low glycemia at the end of an OGTT, and that (3) these low glucose concentrations were strong predictors of the amount of weight regained after weight loss.

The GI does matter - but only before and after you try to lose weight

Of these findings (2) is particularly interesting as it would support the notion that low glycemia can do both: It supports weight loss, when the energy intake is restricted and it increases the risk and extend of weight (re-)gain, when there is no energy restriction.

Figure 2: When the dietary energy intake is tightly controlled, there is hardly a difference in weight loss and body fat loss with high GI, low GI and high fat dieting in obese men & women (Raatz. 2005)

These observations would support previous evidence that a high glycemic index of foods, which would obviously be connected to higher glucose excursions after meals, figures large on ad-libitum (Alfenas. 2005), but only marginally on tightly controlled diets (Raatz. 2005).

It is thus no wonder that Chaput & Tremblay write in their latest review that their results are relevant only in phases without deliberate (significant) energy restriction. In these phases, the present research clearly suggests that weight-reduced obese individuals are at particular risk of weigh (re-)gain; an observation of which the scientists say that it is brought about by a destabilization of the "body homeostasis" that occurs, whenever the weight loss exceeds 10% of the initial body weight. And indeed: Tremblay et al. have observed in 1999, already that the mean glycemia of participants who had reached the point where their weight loss stagnated had reached an all-time low of 3.3 mmol/ l, of which studies by LeBlanc show that that it is significant enough to evoke a significant counter-regulatory hormonal response (LeBlanc. 1982; Tremblay. 1999).

Hypoglycemia and depression? The reduced glycemia could also be the underlying cause of diet induced increases in symptoms of depression as they were observed by Chaput et al. in a previous trial (2005), in the course of which their male volunteers became increasingly depressed, when they had surpassed the 10% weight loss margin (Chaput. 2007a). A direct association between low glycemia and depression in weight loss was confirmed in a follow up that used a low calorie diet (700kcal/day) + aerobic exercise. (Chaput. 2007b). Intriguingly, depression peaked, when the subjects finally hit a weight loss plateau in both studies.

These "significant counter-regulatory hormonal responses", which manifest in form of blunted growth hormone and epinephrine responses and appear to be controllable by regular exercise, are of particularly interest for those of you whose weight loss efforts have plateaued. A better glucose control with a focus on avoiding low glucose levels and regular physical activity could thus help you solve this problem... switching to a ketogenic diet which guarantees 100% glucose stability since the glucose is no longer used as a substrate, would be a another option.

Exercise to the rescue!

Another and eventually probably the most promising way of increasing glucose stability, facilitating further weight loss and forestalling future weight (re-)gain would be regular workouts.

"Physical exercise can be described as a stimulus contributing to optimal body functioning. This is discretely expressed at many levels of regulatory processes, be it by stimulating the effect of key enzymes, by increasing the sensitivity to hormones, by facilitating substrate transport through the membranes, by influencing cell receptors in a tissue-specific manner and probably many others.  The participation in regular physical activity has also been shown to prevent both hyperglycemia and hypoglycemia, which is concordant with the idea that exercise enhances the accuracy of substrate balance regulation." (Chaput. 2008)

It's thus not best to sit around all day to avoid your blood glucose levels from plummeting. On the contrary, individuals who are physically engaged in their daily schedule may expect a better control of both high and low glucose levels and better overall glucose homeostasis. And in fact, previous research also suggests that physically fit individuals are less likely to experience feelings of hunger associated with declines in blood glucose (Chaput. 2008).

The unbeatable benefits of exercise include both improved glucose control in the traditional sense of avoiding hyperglycemia and improved glucose control in the more comprehensive sense of avoiding both high and low glucose levels.

Chaput and Tremblay do yet add another factor to the discussion: Mental exercise! The glucose demands of our brain during cognitive activity are a commonly overlooked factor, when it comes to both glucose and energy control and that in spite of the fact that we all know that (with the exception of full ketosis) carbohydrate represents a critical energy substrate for the brain. Against that background,...

"the low capacity of the body to store carbohydrate might be perceived as a paradox of nature, particularly when cognitive activities are dominant in the daily activity schedule. This limitation is exacerbated by the inability of the body to synthesize glucose from free fatty acids." (Chaput. 2009)

It is thus not surprising that Cognitively and thus energetically demanding tasks will influence the ad-libitum meal intake, even if the measured energy expenditure during sitting at the desk doing nothing and performing a reading–writing task for 45 min is practically the same (13kj difference in Chaput. 2007c).

The brain may be your hungriest muscle

Figure 3: In contrast to both high (HIE) and low intensity exercise (LIE) 45 minutes of knowledge-based work will increase energy intake at a subsequent buffet (McCann. 1990)

In that the results presented in Figure 3 are not a statistical artifact. They agree with the results with the results of a study involving scientists from the University of Washington who increased their energy and fat intake at the time of the preparation of NIH grant applications (the additional influence of stress should be considered, here, as well | McCann. 1990)

In conjunction with the increase in the variability of glycemia, Chaput et al. observed in a 2008 follow up (Chaput. 2008), this may well explain the increased food intake the researchers observed in response to "cognitive work" in the broadest sense in all three studies.

Unquestionably, Chaput & Tremblay are right, when they warn that these observations raise the question as to whether other sedentary leisure activities (for example, video game playing, television viewing, chatting on internet) are also hyperphagic stimuli. In other words, whether they will make you overeat similar toknowledge-based work; and whether associations with glucose instability, as they were observed by Chaput et al. in 2008 exist for "texting", as well.  And even if that wasn't the case, the mere fact that knowledgebased work represents the main working modality in the current way of living, alone, would warrant further research in this direction.

Apropos "modern lifestyle", sleep or rather a lack thereof figures, as well

If you take a look at the data in Figure 4, you will realize that another feature of the modern way of living, i.e. a lack of sleep quantity and quality is associated with glucose excursions into hypoglycemia as well.

Figure 4: Mean glucose area below fasting glucose concentrations (GABF | higher values increase more severe / longer episodes of hypoglycemia) in men and women according to their habitual sleep duration (Chaput. 2007d)

The mean glucose area below fasting glucose concentrations (GABF) Chaput et al. measured in a yet another study they conducted in 2007 (Chaput. 2007d) clearly indicate that border line hypoglycemia is much less pronounced in long vs. short sleepers.

In that, it is interesting to see that the differences in mean glucose area below fasting glucose concentrations reflect the contemporary evidence of associations between sleep duration, obesity and type II diabetes - both sleeping too short (Xi. 2013) and too long is associated with increased risk of metabolic syndrome and/or type II diabetes (Ohkuma. 2014).

Bottom line: I doubt that hypoglycemia is the ultimate weight loss tool, but I hope you will agree that the previously presented evidence is significant enough to argue that you better keep an eye on both overtly high and overtly low glucose levels.

Table 1: Overview of factors that are believed to directly influence glucose homeostasis (Chaput. 2009)

As I've pointed out before, the latter damaging effects of low glucose levels are particularly pronounced, when you're not dieting. Yet even if you're calorically restricted, it's certainly a wise advise to keep the number and duration of episodes with borderline low glucose levels to a minimum to (a) reduce cravings, specifically for sweets, (b) minimize the negative long(er) term effects on the production of catecholamine and thyroid hormone (Leung. 1975), testosterone (Oltmanns. 2001) and the rest of the hormones the production of which depends on an intact hypothalamic signalling that is disrupted as a consequence of low glucose availability in the brain | Comment on Facebook!

References:

• Alfenas, Rita CG, and Richard D. Mattes. "Influence of glycemic index/load on glycemic response, appetite, and food intake in healthy humans." Diabetes Care 28.9 (2005): 2123-2129.
• Boulé NG, Chaput JP, Doucet E, Richard D, Despre´s JP, Bouchard Cet al. Glucose homeostasis predicts weight gain: prospective and clinical evidence.Diabetes Metab Res Rev 2008;24: 123–129. 
• Chaput, Jean-Philippe, et al. "Psychobiological impact of a progressive weight loss program in obese men." Physiology & behavior 86.1 (2005): 224-232.
• Chaput, Jean‐Philippe, et al. "Psychobiological effects observed in obese men experiencing body weight loss plateau." Depression and anxiety 24.7 (2007a): 518-521.
• Chaput, Jean-Philippe, et al. "Increase in depression symptoms with weight loss: association with glucose homeostasis and thyroid function." Applied Physiology, Nutrition, and Metabolism 33.1 (2007b): 86-92.
• Chaput, Jean-Philippe, and Angelo Tremblay. "Acute effects of knowledge-based work on feeding behavior and energy intake." Physiology & behavior 90.1 (2007c): 66-72. 
• Chaput, J-P., et al. "Association of sleep duration with type 2 diabetes and impaired glucose tolerance." Diabetologia 50.11 (2007d): 2298-2304.
• Chaput, Jean-Philippe, et al. "Glycemic instability and spontaneous energy intake: association with knowledge-based work." Psychosomatic medicine 70.7 (2008): 797-804. 
• Chaput, J. P., and A. Tremblay. "The glucostatic theory of appetite control and the risk of obesity and diabetes." International journal of obesity 33.1 (2008): 46-53.
• LeBlanc, J., et al. "Variations in plasma glucose, insulin, growth hormone and catecholamines in response to insulin in trained and non-trained subjects." Metabolism 31.5 (1982): 453-456.
• Leung, Yan, et al. "The effect of hypoglycemia on hypothalamic thyrotropin-releasing hormone (TRH) in the rat." Endocrinology 97.2 (1975): 380-384.
• Mayer J. Glucostatic mechanism of regulation of food intake. N Engl J Med1953;249: 13–16.
• Mayer J. Regulation of energy intake and the body weight, the glucostatic theory and the lipostatic hypothesis.Ann NY Acad Sci 1955;63: 15–43.
• McCann, Barbara S., G. Russell Warnick, and Robert H. Knopp. "Changes in plasma lipids and dietary intake accompanying shifts in perceived workload and stress." Psychosomatic medicine 52.1 (1990): 97-108. 
• Ohkuma, Toshiaki, et al. "U-shaped association of sleep duration with metabolic syndrome and insulin resistance in patients with type 2 diabetes: The Fukuoka Diabetes Registry." Metabolism 63.4 (2014): 484-491.
• Oltmanns, Kerstin M., et al. "Hypoglycemia, but not insulin, acutely decreases LH and T secretion in men." The Journal of Clinical Endocrinology & Metabolism 86.10 (2001): 4913-4919.
• Raatz, Susan K., et al. "Reduced glycemic index and glycemic load diets do not increase the effects of energy restriction on weight loss and insulin sensitivity in obese men and women." The Journal of nutrition 135.10 (2005): 2387-2391. 
• Tremblay, Angelo, et al. "Metabolic Fitness in Active Reduced‐Obese Individuals." Obesity research 7.6 (1999): 556-563. 
• Xi, Bo, et al. "Short sleep duration predicts risk of metabolic syndrome: A systematic review and meta-analysis." Sleep medicine reviews (2013).

Nasty Insights into the Yo-Yo-Effect: Lower Body Fat Sticks and From Fit2Fat There's no Easy Way Back! Plus: Why It's Easier to Get 6-Pack Abs Than Striated Glutes & Hams.

Image 1: The person in the middle was probably once morbidly obese. How I know? Lower body adipose tissue sticks.

After yesterday's first installment of "On Short Notice", which by the way appears to have pleased most of you (thanks for the feedback, everyone!), we are going back to an in-depth analysis of another cherry-picked study, today. Don't worry, though, I believe even those who are more into the "rumpy pumpy" news will like this one. After all, it could provide some more insights into why your upper body and lower body don't match each other and - what's even more important it puts another emphasis on the primer to never ever let yourself go for too long.

The fat you gain today, will not be gone tomorrow!

In the scientific version of "from fit2fat2fit" (click here to watch the ABC report on the "experiment"), Prachi Singh and his colleagues from the Mayo Clinic in Rochester, UK, fed 23 volunteers (15 men and 8 women; BMI 23.6 6kg/m², mean age 30y), who were sedentary, but normal-weight and free of chronic disease, standardized diets with a macronutrient composition of 20% protein, 40% carbs and 40% fat. In addition each of the participants, who were weighed at least 5x per week had to eat 1-3 of the following snacks

• ice-cream shake (402 kcal),
• chocolate bars (a king-size Snickers bar, 510 kcal), or
• an energy drink (Boost Plus, 360 kcal/8 oz)

in order to gain ~5% of body weight within the initial 8-week weight gain phase. By dropping the extra snacks, dietary counseling from and an increase in overall activity the participants had shed those extra pounds in a subsequent 8-week weight loss phase, again - and, somewhat to my surprise, this did actually work quite well, as the data in figure 1 goes to show you:

Figure 1: Body composition and fat depot weight at baseline and after weight gain and loss (based on Singh. 2012)

But despite the fact that it looks as if they were more or less exactly back to baseline a more detailed statistical analysis of the data revealed that only the total body weight, total fat mass and total fat free mass of the subjects (figure 1, left) , as well as their visceral and upper body subcutaneous (UBSQ) fat loss showed statistically significant correlations with the initial weight gain (p < 0.0001, p =0.001, respectively), or as a non-scientist would say it: Only for the aforementioned parameters everything was in fact back to baseline - the lower body fat gains, on the other hand stuck.

Figure 2: Correlation of changes in lower-body fat mass and femoral fat cell size (men: squares, women: circles; Singh. 2012)

Is lower body fat not a female problem? No, according to the study at hand which was however not not adequately powered to provide any definitive answers to this question, there were "no sex differences in fat distributions during weight gain and weight loss" (Singth. 2012). And while the actual actual data in figure 2 (taken directly from the original study) does confirm that, there is still a non-negligible difference in the total amount of body fat gained and lost, which reminds me of a previous post of mine on "Busting the 3,500kcal = 1lbs Weight Loss Myth! Plus: Women Need More, Men Less Than the Rule Predicts", it only confirms the scientists observation.

Due to the limited number of subjects and relative scarce data Singh et al. can only speculate about the exact underlying reasons for this phenomenon, stating that it is most likely related to the "differential triglyceride storage capacity or lipolysis rates of lower- and upper-body adipocytes". An assumption that does appear very likely, though, also because the reverse, i.e. the increased ability to rapidly store meal triglycerides of upper body fat cells (Marin. 1990; Jenson. 2003) and their overall increased susceptibility to to lipolytic stimuli (e.g. your average caffeine based lipolytic "fat burner") had been established in previous studies already (Gui. 1997; Martin. 1991; Nielsen. 2004).

Faster in faster out ain't the whole explanation, though.

Image 2: You can ask any bodybuilder, a six-pack is easier to get than striated glutes & hamstrings. And the difference between upper - and lower body fat storage could well explain this phenomenon!

Unfortunately, Singh et al.'s study does also suggest that the "faster in - faster out" mechanism is not the only physical / physiological reason for the persistence of lower body fat... when I come to think about it, you may yet well argue that it is in the end the reason that another phenomenon takes place. One, the scientists had observed in a previous study, already (Tchoukalova. 2010), namely that "UBSQ [upper body subcutaneous] and lower-body subcutaneous fat respond differently at the cellular level to accommodate increased energy storage" (Singh. 2012). While the former simply increases in size, the latter "reproduces", or to say it in medical terms:

• upper body subcutaneous fat mass increases (mainly) by cellular hypertrophy
• lower body subcutaneous fat mass increases (mainly) by cellular hyperplasia

You have encountered this difference in the "Intermittent Thoughts on Building Muscle" already (specifically in "Intermittent Thoughts on Building Muscle: The Skeletal Muscle Hypertrophy 101 - Part 1: What is Hypertrophy?") and may remember that it is essentially not much different from inflating a given number of balloons (hypertropy) vs. adding more balloons until the few large or the many small balloons eventually occupy the same total volume or, in this case, the fat depots (=sum of many small or few large fat cells) can hold the same amount of triglycerides.

Hypertophy vs. hyperplasia - the latter sticks!

In fact previous research suggests that as soon as the storage ability of the individual fat cells is exceeded, hyperplasia becomes the predominant way to increase the bodies fat storage capacities (usually this is also when the overflowing existing adipose tissue stores begin to "burn down" the house by releasing copious amounts of inflammatory cytokines; cf. Skurk. 2007). Consequently,

[a]fter weight loss, obese people have smaller adipocytes than do people with a similar percentage of body fat and stable weight [though] it is unknown whether those obese adults had more adipocytes before they became obese [...] evidence has suggested that postobese adults have a larger number of fat cells, which could be a long-term consequence of adult weight gain on adipose tissue cellularity. (Singh 2012)

And in fact, these changes in "adipose tissue cellularity" became obvious in the study at hand after no more than 8 weeks of weight gain and loss - life long body fat accumulation or weight gain in the double digit range may not even be necessary...

Limitations of the study: Taken on it's own the Singh study does yet fail to prove the hypothesis that weight gain is associated with increases in fat cell number while weight loss is not, simply because the scientists did take biopsies only at the end of the study - in my eyes a major design flaw, irrespective of the fact, whether the data they would have elucidated would have been "statistically non-significant", as they point out. I did therefore decide against plotting the respective data on adipocyte size and number because without appropriate knowledge of where the subjects were coming from it is worthless anyway.

In this context, it is also noteworthy that the amount of leptin that's released by a given fat cell appears to (non-linearly!) increase with it's size. Against that background the "adipocyte abundance" (many now almost empty fat cells with a very low leptin secretion) in formerly obese subjects could even explain why most of them are having a very hard time to keep the weight off, let alone shed those pounds that still cover their abs, buttocks, etc. After all, on the individual cell level, their body fat stores are in fact almost empty - regardless of the fact that these people still carry 20+ more pounds of body fat on their frame than someone who has not gotten obese in the first place.

Bottom line: NEVER go from fit2fat!

Video 1 (click here to watch): Don't do the "Drew Manning" - making money and becoming famous with being fat is not going to work out another time - after all, Ozzy has already had it on the show... well, maybe if you used Ozzy's Rasberry product (see previous post) to shed the weight again ;-)

Unless Spalding et al. are right and obese individuals must have developed their entire compliment of adipocytes before reaching adulthood (Spalding. 2008; studies such as Löfgren et al. suggest the exact difference, by the way) the results of this study do thus suggest that you better not do the Drew Manning (see video 1) - after all, your chances to cause a similar media stir like Drew (who by the way appears to be a nice guy), are invited by Dr. Oz and make it into the main news on almost all global television channels are close to zero. And with the profoundly reduced leptin expression, from your emptied fat cells you are going to have a very hard time to get rid of any of those new fat cells which may have formed while you were bulking (regardless of whether they are sitting in your upper or lower body), because an abundance of circulating leptin appears to be the crucial signal for your body to send those nasty storage cells into the fat cell nirvana (Della-Fera. 2001).

There are studies that suggest that supplements like CLA could help accelerate this process (Tsuboyama-Kasaoka. 2000). Unfortunately, the data comes from rodent studies, many human trials on the other hand did not elicit any beneficial results, in parts certainly due to lower dosages, which are however a safety measure to prevent side effects such as the profound insulin resistance and hyperinsulinemia Tsuboyma-Kasoaka et al. observed in their study. It appears only logical that the latter would be a direct consequence of the combination of triglyceride release profoundly reduced leptin levels in response to the sudden death of the fat cells, which was in fact so pronounced that the scientists do speak of "lipodystrophy", a medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue.

In the end, the only feasible option left appears - once again - to turn your life inside out and wait until the pendulum will have swung back into the right direction.

References:

1. Della-Fera MA, Qian H, Baile CA. Adipocyte apoptosis in the regulation of body fat mass by leptin. Diabetes Obes Metab. 2001 Oct;3(5):299-310.
2. Dilzer A, Park Y. Implication of conjugated linoleic acid (CLA) in human health. Crit Rev Food Sci Nutr. 2012;52(6):488-513.
3. Guo Z, Johnson CM, Jensen MD. Regional lipolytic responses to isoproterenol in women. Am J Physiol 1997;273:E108–12.
4. Jensen MD, Sarr MG, Dumesic DA, Southorn PA, Levine JA. Regional uptake of meal fatty acids in humans. Am J Physiol Endocrinol Metab 2003;285:E1282–8.
5. Löfgren P, Andersson I, Adolfsson B, Leijonhufvud B, Hertel K, Hoffstedt J, Arner P. Long-term prospective and controlled studies demonstrate adipose tissue hypercellularity and relative leptin deficiency in the postobese state. J Clin Endocrinol Metab 2005;90:6207–13.
6. Marin P, Rebuffe-Scrive M, Bjorntorp P. Uptake of triglyceride fatty acids in adipose tissue in vivo in man. Eur J Clin Invest 1990;20:158–65.
7. Martin ML, Jensen MD. Effects of body fat distribution on regional lipolysis in obesity. J Clin Invest 1991;88:609–13.
8. Nielsen S, Guo ZK, Johnson CM, Hensrud DD, Jensen MD. Splanchnic lipolysis in human obesity. J Clin Invest 2004;113:1582–8.
9. Skurk T, Alberti-Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab. 2007
10. Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Naslund E, Britton T, et al. Dynamics of fat cell turnover in humans. Nature 2008;453:783–7
11. Tchoukalova YD, Votruba SB, Tchkonia T, Giorgadze N, Kirkland JL, Jensen MD. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Proc Natl Acad Sci USA 2010;107: 18226–31.
12. Tsuboyama-Kasaoka N, Takahashi M, Tanemura K, Kim HJ, Tange T, Okuyama H, Kasai M, Ikemoto S, Ezaki O. Conjugated linoleic acid supplementation reduces adipose tissue by apoptosis and develops lipodystrophy in mice. Diabetes. 2000 Sep;49(9):1534-42.

Forgotten Dieting Aids: Choline, Carnitine, Caffeine and the Anti-Weight-Loss Plateau Effects of Sugar and Phosphates

I bet both Flex Wheeler (left) as well as Serge Nubret (right) still knew what choline is. Something you probably cannot say of many of today's gymrats.

In view of the fact that the brief "Oldie but Goldie" post on the efficiency of a stack of carnitine, choline and caffeine as a weight loss adjuvant on the SuppVersity Facebook Wall caught so much attention, I thought that especially those of you who have not yet "liked" the SuppVersity on Facebook and have thus missed this brief reminder of these "classic" fat loss helpers would appreciate if I devote a whole post to this issue as well as another "Oldie but Goldie", I came across recently: The anti-plateau effects of succrose (plain sugar) and phosphates during phases of (very) intense dieting.

ECA was yesterday and so was CCC ;-) 

Let's start with the CCC stack, though. In the year 2000, Hongu et al. published a paper describing a rodent experiment in which they were able to show that the combination of choline, carnitine and caffeine had similar beneficial effects on the body fat and leptin levels of sedentary rodents as exercise (Hongu. 2000).

Figure 1: Fat pad weight (in g) and serum glucose, lactate, triglycerides, free fatty acids and leptin levels expressed relative to sedentary rodents on standard chow (Hongu. 2000)

With statistically highly significant reductions in the weight of the epididymal, inguinal and perirenal fat tissue and corresponding decreases in leptin, the net fat (not simply weight!) loss the 7-wk-old male Sprague-Dawley rats exhibited in face of an unaltered basal energy intake at the end of the 5-weeks study period was yet so pronounced that the question, whether these results would be replicable and, more importantly, whether they could be reproduced in human beings should already be preying on your mind.

"So you are saying it's unlikely this will work in humans, right?"

For a follow up study, the scientists recruited 19 healthy non-obese women with no history of diabetes, or cardiovascular disease (18–54y; body weight, 47.5–92.7 kg; body mass index (BMI), 18.9–35.9kg/m²; body fat, 17.9–37.8%) and repeated the experiment (Hongu. 2003); yet with a slightly different design (see figure 2) that would allow the researchers to differentiate the individual effects of choline and carnitine - unfortunately, without the third "C", i.e. the caffeine.

Figure 2: Study design of the follow up human study three years later (Hongu. 2003).

In the absence of caffeine, the combination of choline and carnitine lost its congenial partner in crime, whose job it is to squeeze the lipids out of the fat cells (lipolysis). But that's not all, the dosages used in the human trial were also significantly lower than the human equivalents of those the rodents had coonsumed three years before (see infobox to the right of the next paragraph). With appropriately high doses, the caffeine may even not have been necessary to elicit the desired fat loss effects. What is unquestionable though is thatthe caffeine induced lipolysis would have amplified any existing effect, because you obviously need enough fatty acids to be transported to the mitochondria in order to make optimal use of the increase in oxidative capacity from the other "C"s in the CCC stack.

What we have here is not a fat loss study

What were the dosages of choline, carnitine and caffeine that were used in the studies? The human equivalent doses for the rodent study from 2000 were 98mg/kg choline, 52mg/kg carnitine and 1mg/kg caffeine. In the human study from 2003 the scientists used much lower dosages of 15mg/kg choline bitartrate and only 1mg/kg l-carnitine l-tartrate per day (!) no wonder the effects on the body composition were completely absent in the human trial.

Against that background the results of this follow up study are of greater theoretical than practical value for us, as they allow some insights into the underlying mechanisms which are responsible for the profound fat loss effects the researchers observed in the rodent trial. As far as this mechanism is concerned the researchers write in the discussion of their paper:

"The mild exercise routine enhanced fat utilization as energy substrate in both supplemented groups, but not in the placebo group [This went hand in hand with a 21–27%] loss of acylcarnitines in urine [that] has not been found in individuals subjected to low or high intensity exercise without supplement. [...] It may thus be argued that increased demand for energy by exercise in choline/carnitine-preloaded individuals increases rates of fatty acid oxidation, albeit incomplete, resulting in sustained loss of acyl groups in urine." (Hongu. 2003)

I willingly admit that this hardly sounds like an explanation, so let's briefly recap the main points.

Firstly, there is the increase in fat utilization in response to the ingestion of choline and carnitine. Secondly, therese there is the loss of acetylcarnitines, i.e. a complex of carnitine + the short-chain fatty acid acetyl in the urine of the women who participated in the study.

 "Choline promotes carnitine conservation and accretion by tissues that favor incomplete oxidation of fatty acids and disposal of fatty acid carbons in urine as acylcarnitines." (Hongu. 2003)

As the scientists point out, the reason for the latter is an incomplete oxidation of long(er)-chain fatty acids and the net result is a non-negligible loss of energy in the urine. With the addition of caffeine to the equation, the total amount of fat that is available for oxidation during exercise, but more importantly also at rest (not just during exercise) would have increased, the same would apply to the amount of fat that is shuttled into the mitochondria and the amount of fat that will leave the mitochondria only partially oxidized. And what happens if you use more stored fat and use it less efficiently? Correct! The fat depots on your hips, buttocks and abs and if you still have some, the nasty inter-organ fat will be gone faster than without the use of the "CCC" stack. Will it disappear magically overnight and without any dietary and lifestyle changes? Probably not overnight, but maybe over several weeks and months.

Add sugar & phosphate to ameliorate the downregulation of the metabolic rate on a diet

YoYo-Dieting or Constant Gluttony? What Happens During Weight Cycling? And Why Does Every Diet Make You Fatter? I have answered these and related questions in a previous blogpost, already (read more)

Sounds too good to be true? Well in a way it in fact is. After all, this requires a 100% constant food intake and presumes that your body does not adapt its caloric expenditure to achieve a new steady state. That the latter is not very realistic, is probably something many of you have already learned the hard way. after all, those new steady states are actually the underlying reasons of the nasty weight loss plateaus this 2nd part of today's SuppVersity post is dealing with.

"Sugar, orange juice, carrots, ..." does this ring a bell? Yeah, I see you have heard or read about this combination before on the Internet.  No idea yet? Well another hint, then: You usually complement those foods with egg shells, which are a good source of calcium, but not in the form of calcium phosphate, but rather as the simple white powdery calcium carnbonate and thus certainly not what the results of a 1996 study by Nazar et al. would suggest the sugars should be complemented with.

In the said study the results of which were published in the Journal of Physiology and Pharmacology 16 years ago, the researchers from the Polish Academy of Science write that the addition of a phosphate supplement containing non-disclosed amounts of calcium, potassium and sodium phosphate to a 1,000kcal, high viscose fiber diet ameliorated the diet induced reduction in basal metabolic rate in the 30 female overweight study participants (+15 / +19% depending on whether the supplement was taken from week 1-4 or week 5-8 of the 8-week dietary intervention). As Nazar et al. point out, the

"[p]hosphate supplementation ameliorated also a decrease in plasma triiodothyronine level and a decrease in thyroxine to triiodothyronine ratio. [While t]here were no differences between groups in the plasma insulin, catecholamine, growth hormone, cortisol and testosterone levels[,] plasma lipids or blood glucose concentration." (Nazar. 1996)

With the thyroid hormone concentration marking the only statistically significant hormonal difference between the supplementation and placebo phases of in the Nazar studies, the similarities to Dr. Ray Peat's previously alluded highly controversial "sugar for thyroid health protocol" should be obvious.

"Ok, but if it's phosphates instead of calcium, then it must be fat instead of sugar, right? "

Often a picture says more than 1000 words: Normal (left) and repeatedly hypoglycemic rodents (learn more about the obesogenic effects of hypoglycemia)

I bet the above question is now preying on the minds of some of you. "Sugar, really?" It may sound hilarious, but as I've pointed out several times before: An energy deficit, specifically a pronounced one, is a game changer. Things that would usually precipitate weight gain suddenly don't matter, when - at the end of the day - your body has used more energy than it has been able to acquire from the foods you  ate.

Unfortunately your body hates nothing more than having to fight to fulfill his acute energy demands by tapping into its body fat stores and will therefore after a couple of days start to save energy, this is particularly true, when your brain realizes that it's beloved glucose is becoming scarce and there is no abundance of ketone bodies to use instead.

Basically this is exactly the situation that arises on a HCG-like very low calorie (800kcal/day) high protein (95% protein, 4% fat, 1% carbohydrate) such as the one the obese women in a study by Hendler et al. were following at thne Yale Clinical Research Center in the late 1980s (Hendler. 1986). The exact study protocol was a bit complicated (and nonsensical ;-) with half of the patient starting out on what I would prefer to call a 'protein only' diet and not, as the scientists do a "high protein" diet, for 15 days followed by another 15 days on a "sucrose diet" with reversed macronutrient ratios, but identical energy content. The other half dieted for 15 days, only, on the sucrose regimen (I wonder why they did not switch those to the protein regimen afterwards...?!). And one miserable wretch "consumed the high-protein diet for 30 days to serve as a control for the sequential protein-sucrose diet"

HCG like dieting: Don't do this at home!

I guess, I don't have to mention that dietary interventions like these are meant to be used in clinical settings and in very obese individuals. So, don't be bamboozled by the 9kg of body weight the subjects lost within those 30 days and try something similarly stupid at home. Our interest in this study is merely related to the effects on the resting metabolic, which were (I will list the main effects and quote excerpts from the results):

• 

  Figure 3: Effect of the sequential protein-sucrose diet on resting metabolic rate (RMR), serum triiodothyronine (T3) and plasma norepinephrine concentra- tions (Hendler. 1986)

  significant reductions in resting metabolic rate during the protein phase: "After 15 days of the hypocaloric protein diet, resting metabolic rate decreased by 354 kcal/day, or 21 percent of control values (p < 0.01)"

• restorative effects of the sucrose diet in the subsequent 15 days: "Sucrose substitution significantly increased the resting metabolic rate (+228 kcal/day, p < 0.05) to values approaching those in the control period (p = NS)."

• metabolic shut-down in the poor wretch who followed the protein only diet for 30 days: "In contrast, the single patient given the protein diet continuously for 30 days showed a progressive decline in resting metabolic rate (2,165, 1,822, and 1,628 kilocalories per day at baseline and after 15 and 30 days of the protein diet, respectively)." 

• Plummeting levels of the active thyroid hormone T3 that were only partly restored in the sucrose phase: "Changes in serum triiodothyronine levels followed the pattern of diet-induced changes in resting metabolic rate. The serum triiodothyronine level fell by 41 percent (p < 0.02) after the protein diet and then rose (by 28 percent, p < 0.02) after sucrose substitution, reaching values intermediate between control and protein diet levels. 

• Significant correlations between the drop in T3 levels and the lowered metabolic rate: "There was a significant correlation between the changes in the serum triiodothyronine level and resting metabolic rate during the sequential diets (r = 0.701, p < 0.01).

• Only minimal signs of a reduced sympathetic tone in the protein phase, none in the succrose phase: "Supine norepinephrine concentrations were slightly, but not significantly, reduced by the protein diet (10 percent) and failed to change significantly when sucrose was substituted. 

• No correlation between epinephrine and the resting metabolic rate: "There was no correlation between changes in the supine norepinephrine concentration and resting metabolic rate."

Interestingly, no significant changes in any of the measured parameters, i.e. serum triiodothyronine (T3) levels, epinephrine and, most importantly, the reductions in metabolic rate were observed in the patients who followed the succrose diet.

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 Does it make sense to eat carbs on a lean bulk as well, or will they just make you fat *scary sound*? Learn more in a previous SuppVersity post.

So what's the take home message, here? Don't worry, as I've already pointed out, I am neither suggesting that you should follow a pure sugar nor a 800kcal diet. And you can be sure that the negative effects on the resting metabolic rate are "diet dose depend" (meaning the harder and imbalanced you diet, the more pronounced they will be). What I am suggesting is that there is reason I keep repeating my mantra "you cannot live on protein alone", both here, as well as on the SuppVersity Science Round-Up. So if you insist on going on a "low carb diet" you better do it right and turn to a  high fat diet (<15% protein), use regular really high carb (including sugar!) refeeds or periods of normal high(-ish) carb intake to keep your metabolism chugging along nicely.

A final note on a possible CCC protocol: I actually did not want to write that down, but I know you will be asking anyways. Please keep in mind though, that I cannot tell you the optimal dose and that I have more than just second thoughts about taking high amounts of choline (see potential side effects next to the respective bullet point below).

• Max. (!) 3g choline: Take the choline (bitartrate or citrate, no funky GPC or similar junk) with meals split across the day, but refrain from taking the human equivalents (HED) from the rodent study, I suppose 3g could already make you smell like a fish. Watch out for potential side effects, such as cramps, nausea, vomiting, dizziness, high blood pressure, or acne-like skin rash. Stop the supplement immediately, if you experience any of those. Also make sure to get adequate amounts of potassium and magnesium.
• 3-5g of carnitine: Stick to the l-tartrate or regular form of carnitine. Take the carnitine in 3 doses best on empty (learn more about in the Amino Acids for Super Humans Series). 
• 200mg sevings of caffeine: Use the caffeine whenever you are fasted for at least 90min or before you are working out. Don't take more than 400mg, max. 600mg per day and - needless to say - don't take it before bed.

Again keep an eye on side effects and don't expect any miracles! This is a supplement to help you lose fat, not to make you lose fat.

Once you've got these fundamentals right you may want to consider adding in the CCC stack and a phosphate supplement to promote - not to induce - fat loss.



References:

• Hendler RG, Walesky M, Sherwin RS. Sucrose substitution in prevention and reversal of the fall in metabolic rate accompanying hypocaloric diets. Am J Med. 1986 Aug;81(2):280-4.
• Hongu N, Sachan DS. Caffeine, carnitine and choline supplementation of rats decreases body fat and serum leptin concentration as does exercise. J Nutr. 2000 Feb;130(2):152-7.
• Hongu N, Sachan DS. Carnitine and choline supplementation with exercise alter carnitine profiles, biochemical markers of fat metabolism and serum leptin concentration in healthy women. J Nutr. 2003 Jan;133(1):84-9.
• Nazar K, Kaciuba-Uściłko H, Szczepanik J, Zemba AW, Kruk B, Chwalbińska-Moneta J, Titow-Stupnicka E, Bicz B, Krotkiewski M. Phosphate supplementation prevents a decrease of triiodothyronine and increases resting metabolic rate during low energy diet. J Physiol Pharmacol. 1996 Jun;47(2):373-83.