Sucralose, Hazardous or Innocent? Part II: Appetite, Gut Health & Food Reward | Sucralose, Gluttony & Adiposity?

Plain mineral water is still the best thing to quench your thirst.

Today we are going to continue our thorough, educated reading of the recently published overview over the biological issues with sucrolase, a "popular" artificial sweetener most of you will probably know by its brand name Splenda. The focus of part I of this series was on the potential pro-diabetic effects of this agent that belongs to a class of molecules that has originally been hailed as a solution to the diabetes problem (it goes without saying that I am talking about artificial sweeteners here, right?). In a way we are thus only continuing the discussion, when we are trying to verify Schiffman's & Rother's argument that the consumption of sucralose is associated with an increase in obesity risk... or, put more simply that using sucralose is going to make you fat, not lean.

The good old "energy in" vs. "energy out" argument

As SuppVersity readers you are well aware that the oversimplified concept of an "energy balance" is fundamentally flawed. My recent post "Anorexia study suggests: Your body can easily reduce its resting metabolic rate by 10%" in the SuppVersity Facebook News is only one out of thousands of scientific papers you could quote to point out that replacing 420kcal of energy from pure sugar, i.e. three cans of regular coke, with its diet variety is not going to produce a net weight, let alone fat loss of 420g per week (suggested read: "Busting the 3,500kcal = 1lbs Weight Loss Myth!" | learn more).

This is part II of a multi-part series:

Sucralose, insulin, glucose, GLP-1

Appetite, Obesity & Gut Health

Cancer, Drug & Hormone Interact.

I know that Mark Sisson likes to says this, but this website is not written by a machine, but by a man who has the same "short" 24h days you have... basically, what I am trying to say is that I had to split this review of the review into a "trilogy" - and be honest, you wouldn't want an article thrice as long as this one, would you?

Thus being "in the know", you can only shake your head, when you read how Schiffman and Rother (ab-)use a recent study by Ruyter et al. (2012) to support the non-significant, not sufficiently differentiated data from epidemiological studies which inform us that obese people are more likely to consume artificial sweetened products than lean ones, to subliminally imply that artificial sweeteners would not help, in some cases even hinder weight loss.

"In an 18-mo trial with children, participants were randomly assigned to receive an 8-oz can per day of either a noncalorically sweetened or a sugarsweetened beverage that provided 104 kcal (de Ruyter et al., 2012). [...] The calorie consumption from these beverages was 46,627 kcal greater for children in the sugar-sweetened group than in the sucralose-sweetened group (5.8 × 77.3 × 104). In spite of this highly significant difference in calories consumed from the beverages, the total weight gain over this 18-mo study was only 1 kg greater for children in the sugar-sweetened group compared to sucralose group. No explanation was provided to account for the small difference in weight gain given the large difference in caloric consumption from the beverages." (Schiffman. 2013)

Despite the fact that Schiffman & Rother acknowledge that the scientists would not have been able to detect, if the children who consumed the sugar-sweetened beverages compensated by reducing their food intake, the reviewers fail to point out that neither this, nor the second "evidence" they cite, a 2-year study by Ebbeling et al. (2012), where Schiffman & Rother simply ignore the fact that the mere provision of diet sodas to the families of the adolescent subjects did reduce the weight gain in the active intervention period (1st year, see Figure 1, below), would confirm a negative real-world effect on body weight.

Figure 1: Change in body fat percentage (vs. basleline) of adolescents during the intervention & follow up period in the Ebbeling study (2012), of which the reviewers only cite the results of the follow up.

Let's be honest: If you actually take a look at the results from the Ebbeling study (Figure 1), you will have to concede that this study refutes the claim that artificial sweeteners make you fat. During the active treatment period, in the course of which the adolescent participants were...

• 

  "What Really Happens, When Nutrition Science Meets Real Life" | more

  ... supplied with noncaloric beverages (e.g., bottled water and “diet” beverages for the whole family) every 2 weeks, getting monthly motivational telephone calls with parents (30 minutes per call), 
• ... having three check-in visits with participants (20 minutes per visit), and 
• ... receiving written intervention messages with instructions to drink the delivered beverages and not to buy or drink sugar-sweetened beverages, were mailed to participants

...they do exactly what we originally expected them to do: They ameliorate the body fat gain in the adolescent subjects. In other words: As long as respective products are available, and dietary adherence is encourages, replacing regular sugar sweetened with artificial sweetened or unsweetened beverages can have a significant ameliorative effect on the body fat gains of adolescents - irrespective of the fact that they were obviously free to compensate with chocolate, cookies, etc..

Contemporary evidence from RCTs suggest either no, or beneficial effects

If you follow Schiffman's and Rother's lead and discard potential differences between sucrose and other sweeteners, acknowledge the fact that the results from previous rodent experiments have repeatedly failed to translate to human beings and take into account that this data is "inconsistent and conflicting" (Schiffman. 2013), anyways, you will be hard pressed to find arguments to support the claim that artificial sweeteners could hinder weight loss.

"No-Carb Foods, Artificial Sweeteners & The Cravings" | more

Potential mechanisms for the obesogenic effects: In a very detailed review Mattes & Popkin list a whole host of hypothesis ranging from the disproven stimulation of insulin and differences in the GLP-1 response, over osmotic effects and increase food palatability, up to the "Zero sugar, great, I'll have 10 instead of one of those cookies!" effect and the development of an extremely sweet tooth. What's important, though, is that none of this mechanisms is "supported by the available evidence, although some warrant further consideration" (Mattes. 2009).

In fact, the vast majority of RCTs clearly supports the assumption that non-nutritive sweeteners (NNS), artificial or not, promote weight loss and blunt weight (re-)gain (De la Hunty. 2006; Bellisle. 2007). The argument that these effects do satisfy the calories in vs. calories out hypothesis is pathetic, to say the least. Even a 100% controlled diet won't comply to an equation that is about as accurate as "1+2=343". We can thus register that:

1. There is ample evidence to support the beneficial effects of artificial sweeteners (including sucralose) as a tool during controlled dietary interventions.
2. There is insufficient evidence to support the claim that their regular consumption has a negative effect on body weight.

With respect to (2) we would even have to say that the limited amount of useful* evidence we have would rather suggest beneficial than detrimental effects (*a 'useful' study is not a study that tells me that obese individuals are more likely to consume artificially sweetened products than lean ones like the often cited epidemiological data). This is particularly true, for controlled interventions where sugar-sweetened beverages were replaced by their artificially sweetened counterparts.

The great unknown: Hunger, appetite and food reward

If data on the real-world effects of sucralose consumption on body weight gain is "scarce", consistent, experimentally verified hypotheses that would explain the potential underlying mechanism are quasi non-existent... or, I should clarify: They are still in their infancy. Against that background it's quite astonishing that more and more people appear to take it for granted that the consumption of artificially sweetened foods will mess with both, (a) your ability to control your energy intake and (b) the hedonistic response you derive from foods.

Table 1: Sweetness, dose to stimulate the sweet taste receptor (EC50; based on Matsuda. 2011) and correlation of sweetness and EC-50 value.

It goes without saying that there is no sucralose-specifc data out there, but the decrease in hypothalamic sweet taste receptor density I mentioned in the first installment of this series is something I'd expect to see in response to all artificial sweeteners that make it across the blood brain barrier (Note: Even Schiffman & Rother acknowledge that we do not know if they even do that!) - probably "sweetness" dependent,  by the way.  This would imply that sucralose would be the worst, cyclamate the least offender among the common artificial sweeteners in Table 1. With a sweetness that's 300x higher than that of sucrose, stevia would end up being the "(un?)happy medium".

Despite the fact that Schiffman & Rother don't really address this issue in their paper, I still want want to address the practical and thus relevant aspect of the various proposed theories for potential sweetener-induced increases in energy consumption.

Figure 2: Mean effective change in energy intake (%) in RCTs investigating the degree of energy compensation in response to the provision of artificial sweetened products (De la Hunty. 2006)

As the data from De La Hunty's 2006 meta-analysis of 32 study outcomes in Figure 2 clearly demonstrates, there is a statistically highly significant (p < 0.001) trend towards reduced energy consumption in the RCT [randomized controlled trial]. In that, the degree of compensation for the sudden energy reduction due to ingestion of calorically less dense, since artificially sweetened product ranged from statistically non-significant 18% to statistically highly significant 86% in trials such as Porikos et al. (1982), where 6 men lost and gained 0.8kg of body weight within 2x12 days in a metabolic ward on artificially sweetened and sucrose sweetened ad-libitum diets, respectively.

Non-nutritive sweetener (NNS) intake 1965-2004 (Mattes. 2009)

So, sweeteners can't ever make you hungry? I would not necessary subscribe to this idea. While the consumption of artificial sweetened foods as part of your regular diet, e.g. diet coke with your dinner, does not seem to be a problem, Mattes & Popkin (2009) rightly point out that "non-energy-yielding products may heighten appetite", when they are not "ingested in conjunction with other energy sources". So, if you are guzzling diet coke all day, this may very well trigger binge eating. With an ever increasing consumption of sweeteners from partially / totally artificially sweetened beverages (see table to the left), this could thus well be part of our obesity problem.

Just like the previously discussed (relatively short term) effects on insulin, GLP-1 and co, the #2 on the list of most frequently heard objections against the use of artificial sweeteners, i.e. dietary overcompensation, does thus appear to have little basis in fact. What we do not know, though, is whether the results will be identical for all types of sweeteners, or whether sucralose may be the toxic (this aspect will be covered in the next installment) or gut microbiome disrupting exception to the rule.

Sucralose induces changes in the gut microbiome

The last issue I want to address in this second installment of the "Sucralose, Hazardous or Innocent Trilogy" will thus revolve around the question, whether a modulatory effect of sucralose on the microbial composition of your gut could induce potential negative long-term effects that would not show up in the hitherto discussed RCTs.

Under the headline "Effect of Sucralose on the Number and Relative Proportions of Different Intestinal Bacterial Types", Schiffman & Rother argue that it has long been known that bacteria from the oral cavity and soil cannot use sucralose as a growth substrate. If the same was true for the bacteria in our guts the replacement of regular sugar with sucralose would thus starve our (beneficial) subtenants.

Table 2: Differences (%) in bacterial counts in feces of rodents on diets containing what in human terms would be ~14mg, 43mg, 71mg and 156mg of sucralose per day after 12 weeks treatment and 12 weeks into "recovery" (Abou-Donia. 2008)

Based on the fecal bacterial count of rodents on diets that would be equivalent to 14mg, 43mg, 71mg and 156mg of sucralose per day in human beings (see Table 2), Schiffman & Rother argue that chronic (12-week) ingestion of relatively low amounts of sucralose (a single can of Diet Crush Cream Soda, for example, has 42mg of sucralose) lead to highly significant reductions in the numbers of total anaerobes, bifidobacteria, lactobacilli, Bacteroides, clostridia, and total aerobic bacteria.

In view of the fact that Abou-Donia et al. (2008) observed the most significant losses in bifido- and lactobacillus strains, i.e. those strains that have repeatedly been implicated as the driving forces of the beneficial health effects of probiotic supplementation, this and not the previously discussed pro-diabesity effects should be the point where people start to freak out.

Table 4: Other sweeteners are preferred food for certain bacteria and may also alter the gut microbiome (Payne. 2012).

This is particularly true if you take into account that at least part of the beneficial effects of lactobacilli may be related to their ability to keep the number of enterobacteria, a large family of Gram-negative bacteria that includes both harmless symbionts, as well as a whole host of familiar pathogens, such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella and Shigella, Proteus, Enterobacter, Serratia, and Citrobacter in check (Liévin-Le Moal. 2006) - exactly those bacteria, which produce the nasty lipo polysaccharides (LPS) that have been associated with inflammation and its downstream metabolic effects, such as obesity, diabetes, heart disease, gastrointestinal cancer etc. and, as the data in Table 2 tells you. Now, unfortunately, the these villains are all part only type of bacteria that was not significantly decimated by the sucralose challenge.

As Schiffman et al. point out these reductions are not, as Brusick et al. (2009) suggest simply a result of "normal variation". In fact, the probability to see a similar random reduction in bifidobacterial count occur "naturally"within 12 weeks would be 1/5000. It is thus more than just unlikely that the71.9%, 76%, and 77.7% reductions in bifidobacteria counts Abou-Donia et al. observed at dosages of 3.3, 5.5, and 11 mg/kg/d were coincidental.

Prebiotics, anyone? In view of the alleged neg. effects on your gut microbiome, you may feel inclined to increase your prebiotic intake. If that's the case, this top 10 list of food items with prebiotic fiber contents of up to 65% of total weight may help:

1. Chicory root - 65%
2. Jerusalem artichoke - 32%
3. Dandelion greens - 24%
4. Garlic - 18%
5. Leek - 12%
6. Onion - 9% 
7. Cooked Onion - 5% 
8. Asparagus - 5% 
9. Wheat bran - 5% 
10. Banana - 1% 

Remember: These are the "richest" not necessary the "best" sources ;-)

If there is reason to be concerned it's about your gut health and its downstream metabolic effects: In view of the important role of bacteroides for the health of the intestinal eco-system (Lee. 2013) and their persistent reduction even after the 12-week recovery period, the selective antibiotic activity of sucralose is as of now the by far most disconcerting negative health effect discussed in this series.

If the changes Abou-Donia et al. observed in their rodent studies were to be confirmed in human studies, where the subjects consumed a balanced whole foods diet with a high prebiotic content. The profound changes the researchers from the Duke University Medical Center report in their paper from September 2008 would be reason enough to revise my previous conclusions about a potential contribution of sucrose to the diabesity (=obesity + diabetes) epidemic.

In fact, a revision of the potential long(er) term downstream effects of sucralose on your metabolic health could be all the more indicated, if it turns out that the alleged toxic and endocrine-disrupting effects I will discuss in the next installment of this series turn out to be substantiated, as well.

Reference:

• Abou-Donia, M. B., El-Masry, E. M., Abdel-Rahman, A. A., McLendon, R. E., & Schiffman, S. S. (2008). Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. Journal of Toxicology and Environmental Health, Part A, 71(21), 1415-1429.
• Bellisle, F., & Drewnowski, A. (2007). Intense sweeteners, energy intake and the control of body weight. European Journal of Clinical Nutrition, 61(6), 691-700.
• De la Hunty, A., Gibson, S., & Ashwell, M. (2006). A review of the effectiveness of aspartame in helping with weight control. Nutrition Bulletin, 31(2), 115-128.
• de Ruyter, J. C., Olthof, M. R., Seidell, J. C., & Katan, M. B. (2012). A trial of sugar-free or sugar-sweetened beverages and body weight in children. New England Journal of Medicine, 367(15), 1397-1406.
• Ebbeling, C. B., Feldman, H. A., Chomitz, V. R., Antonelli, T. A., Gortmaker, S. L., Osganian, S. K., & Ludwig, D. S. (2012). A randomized trial of sugar-sweetened beverages and adolescent body weight. New England Journal of Medicine, 367(15), 1407-1416.
• Liévin-Le Moal, V., & Servin, A. L. (2006). The front line of enteric host defense against unwelcome intrusion of harmful microorganisms: mucins, antimicrobial peptides, and microbiota. Clinical Microbiology Reviews, 19(2), 315-337.
• Mattes, R. D. (1996). Dietary compensation by humans for supplemental energy provided as ethanol or carbohydrate in fluids. Physiology & Behavior, 59(1), 179-187.
• Mattes, R. D., & Popkin, B. M. (2009). Nonnutritive sweetener consumption in humans: effects on appetite and food intake and their putative mechanisms. The American journal of clinical nutrition, 89(1), 1-14.
• Payne, A. N., Chassard, C., & Lacroix, C. (2012). Gut microbial adaptation to dietary consumption of fructose, artificial sweeteners and sugar alcohols: implications for host–microbe interactions contributing to obesity. Obesity Reviews, 13(9), 799-809.
• Porikos, K. P., Hesser, M. F., & Van Itallie, T. B. (1982). Caloric regulation in normal-weight men maintained on a palatable diet of concentional foods. Physiology & behavior, 29(2), 293-300.
• Schiffman, S. S., & Rother, K. I. (2013). Sucralose, A Synthetic Organochlorine Sweetener: Overview Of Biological Issues. Journal of Toxicology and Environmental Health, Part B, 16(7), 399-451. 

Inulin & Beta Glucan Reduce Body Fat Gain By -50% & -33%! Both Have Similar Effects on the Gut Microbiome, But Only Inulin Appears to Be More Than An Appetite Suppressant

What do these Jerusalem artichokes, agave, bananas, burdock, camas, chicory, coneflower, costus, dandelion, elecampane, garlic,jicama, Leopard's-bane, mugwort, onion, wild yams, yacon and a whole host of other foods have in common? Right! They contain inulin. Whether you will be able to get a whopping amount of 10% inulin in your diet w/out the use of supplements or "enriched" foods, is yet as questionable as how beneficial this actually is for friends of physical culture.

The gut microbiome is not just one of the hottest topics in the (health-)blogosphere, it is also a subject of ongoing research. Research, however, that is, if we are honest, still very much in its infancy. As impressive as the results from the latest studies into the metabolic downstream effects of the administration of fermentable fiber to rodents may be and as obvious as their relation to certain changes in the gut microbiome of the animals may appear - in the end, our understanding of the underlying mechanisms does not allow any reliable prognoses like "double the amount of lactobacilli and you will eventually be able to lose that pouch of body fat you've been carrying around for years now". And yet, if the results from the latest rodent experiments at the Imperial College in London, could be reproduced in humans, I can already foresee that both, the consumption and use of the foods I listed in the caption of the image to the right, as well as related products, extracts and supplements, which contain more or less significant amounts of the naturally occurring polysaccharides, we usually refer to as inulin, will increase in the months and years to come.

Fermentable fiber and the gut-brain-axes: The key to lifelong leanness?

If this is not your first visit to the SuppVersity, you will certainly be aware that the idea of a magic pill (or fiber) that will allow you to eat whatever, whenever and in whichever amounts without having to cope with the metabolic consequences is illusive. When the addition of 10% inulin (or beta glucan) to the diets of 36 male C57BL/6 mice had an "anti-obesogenic" effect, this does not mean that the poor critters who were kept on a hypercaloric high fat (41.8%) diet for 8 weeks did not get obese. What it does mean, though, is that the addition of 10% fermentable (=being food for certain gut bacteria) fiber in the form of

*the producers of these products did not fund or support the study (at least the scientists don't mention that in the respective disclosure ;-)

• inulin from Synergy(TM)*, a fructan based preparation containing both long and short chain
  fructooligosaccharides, or
• beta-glucan from Glucagel(TM)* a highly rich (,80%) barley derived b-glucan preparation

to their otherwise iso-caloric diet (the HFD control contained cellulose) was not without helped to mitigate the negative effects of this diet - a fact the majority of you, of whom I would expect that they are not on a fast-food diet should keep in mind, before they head over to their favorite online supplement vendor and type "Synergy inulin" into the search box.

Figure 1: Effect of addition of 10% fermentable fiber as inulin or beta glucan to the high fat diet of male mice on cumulative weight gain (left), body composition and fatness (middle) and food intake (right) over the course of 8 weeks (data adapted from Arora. 2012)

In spite of that, the results are simply too impressive not to think about their implications in otherwise healthy and even more so previously obese individuals. This is particularly true, because the same microbial changes about which the authors write in a previously published paper from May 2012 that the ...

"[...] increases in both Bifidobacteria and Lactobacillius and a significant increase in short chain fatty acids (SCFA) [went hand in hand with] increase in neuronal activation within the arcuate nucleus (ARC) of animals that received In [inulin] supplementation" (Anastasovska. 2012)

do not (and this is a result of the researchers very latest experiments) simply blunt the rodents appetite. If that was the case, the rodents that received the beta glucan supplemented chow and consumed 12% less energy should have had the most favorable body composition. A cursory glance at figure 1 will yet tell you that this was not the case, though.

Inulin beats beta glucan when it comes to body fat reduction / repression

If we take a closer look a the differential effects of inulin and beta glucan, there yet only one figure that really sticks out and that's the accumulation of fat within the musculature of the animals. The "beautiful marbling" people are looking for in their steaks, however, usually is a harbinger of impeding or even existing skeletal muscle insulin resistance. A muscle fat content above the high fat control (it's certainly a weakness that we don't have a "real" control group on standard rodent chow, here) as Arora et al. observed it in the tissue samples of the beta glucan group, does thus tell you something about its potential usefulness, or rather uselessness of this specific type of fermentable fiber.

Figure 2: Effects of the different types of fermentable fiber on cecal microflora groups (figures are in scientific notation, this means "1E+6" equals 1mio, "1E+9" would be 1 billion etc.; data based on Arora. 2012)

In conjunction with the information about the corresponding changes in the gut microbiome (see figure 2), which appear virtually identical in both groups (specifically the extreme increasesin in both Bifidobacteria (BIF) and Lactobacillius (LAB) really stick out), this does however suggest that the modulatory effect on the composition of the gut flora, or at least the part of it the scientists evaluated in the study at hand, cannot be the only driving force behind the beneficial metabolic effects of inulin.

Inulin or beta glucan? This is not a question... 

While the latter, i.e. inulin, which has by the way been found to directly suppress lipogenesis in a 2011 study by Belgian scientists in a similar HFD rodent model (Dewulf. 2011), appears to be promising for everyone, regardless of whether he or she is poisoning him- or herself with the standard American diet (which is, with its high fat and high carbohydrate content de facto an identical twin of the so-called "high fat diet" in rodent studies), the ingestion of larger amounts of the former, i.e. beta glucan, does at least appear questionable.

If you want to use inulin to your metabolic advantage, you better make sure you get your self a more comfortable place to answer the call of nature - it could call thrice as often! Moreover, large amounts of inulin and other fermentable fiber can induce gastrointestinal distress-

The question is therefore not so much whether it's worth supplementing (it's certainly worth to incorporate some of the initially mentioned foods into your diet, as most of them contain a whole list of other advantageous micronutrients) with inulin or beta glucan - the answer would obviously be inulin - but rather whether it's worth adding larger amounts of inulin to an already healthy diet. And while we cannot answer this question based on the results of the previously cited rodent studies, we could argue that Marwa Zenhom and her colleagues from the Christian Albrecht University in Kiel have already supplied relevant evidence that this would be the case (Zenhom. 2011). After all, the German researchers have been able to show that the PPAR-gamma related anti-inflammatory effects (significant reductions IL-12 secretion in Caco-2 cells and gene expression of IL-12p35, IL-8, and TNFa as well as NF-kB) of oligosaccharides are not (exclusively) brought about by their effects on the gut microbiome, because bacteria simply were not present in their in-vitro study with human Caco-2 cells (cells from the gut lining). Bassaganya-Riera et al. even argue that this effect could be beneficial for IBS patients (Bassaganya-Riera. 2011).

Whether having 10% of your diet in form of inulin, or to make this more conceivable, having 1 tablespoon of plain inulin for every 9 tablespoons of whatever else you eat is either feasible or reasonable, is a whole different story (to put that into perspective: The average inulin intake of Westerners is 1-10g per day (van Loo. 1995). Even 10g would yet only be enough if you ate only 100g of food within 24h!)... and I must forewarn you, if you go by the fecal volume of the mice in the Arora study, it is possible that you will spend >3x more time on the toilette than usual ;-)

References:

• Arora T, Loo RL, Anastasovska J, Gibson GR, Tuohy KM, Sharma RK, Swann JR, Deaville ER, Sleeth ML, Thomas EL, Holmes E, Bell JD, Frost G. Differential effects of two fermentable carbohydrates on central appetite regulation and body composition. PLoS One. 2012;7(8):e43263.
• Anastasovska J, Arora T, Sanchez Canon GJ, Parkinson JR, Touhy K, Gibson GR, Nadkarni NA, So PW, Goldstone AP, Thomas EL, Hankir MK, Van Loo J, Modi N, Bell JD, Frost G. Fermentable carbohydrate alters hypothalamic neuronal activity and protects against the obesogenic environment. Obesity (Silver Spring). 2012 May;20(5):1016-23.
• Astegiano M, Pellicano R, Terzi E, Simondi D, Rizzetto M. Treatment of irritable bowel syndrome. A case control experience. Minerva Gastroenterol Dietol. 2006 Dec;52(4):359-63.
• Bassaganya-Riera J, DiGuardo M, Viladomiu M, de Horna A, Sanchez S, Einerhand AW, Sanders L, Hontecillas R. Soluble fibers and resistant starch ameliorate disease activity in interleukin-10-deficient mice with inflammatory bowel disease. J Nutr. 2011 Jul;141(7):1318-25.
• Dewulf EM, Cani PD, Neyrinck AM, Possemiers S, Van Holle A, Muccioli GG, Deldicque L, Bindels LB, Pachikian BD, Sohet FM, Mignolet E, Francaux M, Larondelle Y, Delzenne NM. Inulin-type fructans with prebiotic properties counteract GPR43 overexpression and PPARγ-related adipogenesis in the white adipose tissue of high-fat diet-fed mice. J Nutr Biochem. 2011 Aug;22(8):712-22.  
• van Loo J, Coussement P, de Leenheer L, Hoebregs H, Smits G. On the presence of inulin and oligofructose as natural ingredients in the western diet. Crit Rev Food Sci Nutr. 1995 Nov;35(6):525-52.
• Zenhom M, Hyder A, de Vrese M, Heller KJ, Roeder T, Schrezenmeir J. Prebiotic oligosaccharides reduce proinflammatory cytokines in intestinal Caco-2 cells via activation of PPARγ and peptidoglycan recognition protein 3. J Nutr. 2011 May;141(5):971-7.