Artificial Sweetener Saccharin Increases Weight Gain in Rodent Study Without Increasing Food Intake | Plus: Meta-Analysis of Human Studies Says: "No Reason to Worry!"

Artificial Sweetener Saccharin Increases Weight Gain in Rodent Study Without Increasing Food Intake | Plus: Meta-Analysis of Human Studies Says: "No Reason to Worry!"

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Should you freak out about a small increase in body weight in a small-scale rodent study that is attributed to the consumption of saccharin in yogurt?

While epidemiological studies show that the consumption of products containing non-nutritive sweeteners (NNS) is associated with increased adiposity (Colditz. 1990; Fowler. 2008), type 2 diabetes mellitus (T2DM), metabolic syndrome and cardiovascular disease (Dhingra. 2007; Lutsey, Steffen. 2008). A mechanistic link between aspartame, sucralose, stevia & co and weight gain as well as its ill metabolic and cardiovascular consequences in humans is non-existent (learn more).

Rather than weight increases controlled human studies show that the consumption of artificially sweetened foods promote, not hinder the loss of body fat (Sørensen. 2014).

You can learn more about sweeteners at the SuppVersity

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In animal models, though, the results have been more conflicting. While many studies show no effect of artificial sweetener consumption, the latest stud by Kelly Carraro Foletto and colleagues is not the first rodent study to suggest that non-nutritive sweeteners may also interfere in the regulation of compensatory appetite promoting weight gain (Davidson. 2011; Polyák. 2010; Rogers. 1988). This does yet not refute the findings of one of the latest meta-analysis of the effects of low-energy sweetener consumption on energy intake and body weight in man - a meta-analysis published in Nature's prestigious International Journal of Obesity that says...

Figure 1: The forest plots of the practically most relevant data of individual and combined effect sizes for sustained intervention studies comparing the effects on body weight of sweeteners versus sugar (upper panel) and versus water (lower panel) shows that not a single long(er) term study found negative effects - the exact opposite is the case. Even compared to water the use of low-energy sweeteners (artificial or not) lead to measurable, yet not always significant decreases in body weight in human trials (Rogers. 2015).

"that the balance of evidence indicates that use of LES [low or no energy sweeteners] in place of sugar, in children and adults, leads to reduced EI and BW, and possibly also when compared with water" (Rogers. 2015 | my emphasis).

And with respect to the often-cited "evidence" from animal and observational studies, the autors of the meta-analysis submit that...

"[...] the present review of a large and systematically identified body of evidence from human intervention studies, with varying designs, settings and populations (including children and adults, males and females, and lean, overweight and obese groups), provide no support for that view. The question then is whether those hypotheses should be rejected or whether, as seems unlikely, the relevant human intervention studies are consistently flawed in a way that leads, in most cases, to exactly the opposite outcome" (Rogers. 2015)

I do thus want to warn you: Do not overrate the already relatively small amount of extra-weight the rodents in saccharin group of Foletto's recent study gained (see Figure 2, left).

Figure 2: Cumulative weight gain and total cumulative energy intake of (only) 16 male Wistar reds fed diets that were supplemented with either saccharin-sweetened or non-sweetened yogurt added (Foletto. 2015)

In a previous study, Folleto et al. had already observed that saccharin can induce weight gain when compared with sucrose in Wistar rats despite similar total caloric intake. In their latest study they did not try to prove that this effect is independent of the rodents' energy intake and mediated by insulin-resistance and / or modified levels of leptin and PYY in the fasting state.

Was it fat they gained or lean tissue mass? Well, I would like to answer these important questions, but Foletto did not disclose (or not even measure?) this important parameter. The practical relevance and reliability of their results is further reduced due to the small cages (44x34x16 cm individual cages) into which the rodents were confined to reduce their voluntary physical activity during the 14 weeks of the experiment, as well as the exclusion of rats who didn't consume the aspired 70% of the planned 75 kcal in form of yogurt per week (the number of rats who fell into this category is also not disclosed).

To this ends, the researchers randomly assigned 16 male Wistar rats to receive ~78kcal per week from either saccharin-sweetened (0.3% saccharin) yogurt or non- sweetened yogurt (0.5 kcal/g) in addition to chow (2.93 kcal/g) and water ad lib. For 14 weeks, Foletto, et al. measured the total food intake (from yogurt and chow) daily and the weight gain on a weekly basis (the results are plotted in Figure 2). Fasting leptin, glucose, insulin, PYY and HOMA-IR levels were measured only at the end of the 14-week study period, though.

Table 1: In view of the fact that any existing negative effects of dietary sweeteners may well be compound-specific. It is certainly worth noting that saccharin is no longer used in modern sweetener formulations of sodas (Wikipedia. 2015)

In spite of the already reported ~5% increase in cumulative weight gain over 14 weeks (p=0.027), the researchers found no differences in HOMA-IR (=insulin resistance), fasting leptin or PYY levels between groups that could mechanistically explain why the rodents who received saccharin sweetened yogurt gained more weight than their peers who received non-sweetened yogurts.

Measurable weight increases are a common pattern in rodent studies particularly for the (today rarely used) artificial sweetener saccharin. It is thus well possible that any existing negative effects are compound-specific. For aspartame, for example, similar evidence is rare to non-existent.

Bottom line: In the absence of a proven theory about the mechanism that may trigger the increased weight gain and in view of the lack of health-relevant data (no information about the body composition of the rodents) and health-relevant side-effects you would usually see in response to pathologic weight gain (changes in insulin resistance, leptin or PYY), I can only refer you back to the quote from the latest meta-analysis of the effects of low- to no-energy-sweetener intake on food intake and weight gain in humans, which say that "the balance of evidence indicates that use of LES [low or no energy sweeteners] in place of sugar, in children and adults, leads to reduced EI and BW, and possibly also when compared with water" (Rogers. 2015).

Furthermore, more relevant evidence from human clinical trials supports the use of artificially sweetened foods as dieting aids (Sørensen. 2014 | learn more).

Whether that's enough to convince you that the unproven negative effects of saccharin on caloric expenditure or increases in the glucose transport mediated by gut sweet-receptors, of which Foletto et al. speculate that they may explain the results of their study, are relevant enough to avoid non-nutritive sweeteners altogether is now up to you. For me it's not enough... | Comment on Facebook!

References:

• Foletto, Kelly Carraro, et al. "Sweet taste of saccharin induces weight gain without increasing caloric intake, not related to insulin-resistance in Wistar rats." Appetite (2015).
• Rogers, P. J., et al. "Does low-energy sweetener consumption affect energy intake and body weight? A systematic review, including meta-analyses, of the evidence from human and animal studies." International Journal of Obesity (2015).
• Sørensen, Lone B., et al. "Sucrose compared with artificial sweeteners: a clinical intervention study of effects on energy intake, appetite, and energy expenditure after 10 wk of supplementation in overweight subjects." The American journal of clinical nutrition (2014): ajcn-081554.

Is »BAIBA« the Next Big Thing in Fat Loss Supplements? 24% Reduction in Fat Gain is an Impressive Number, But...

Is »BAIBA« the Next Big Thing in Fat Loss Supplements? 24% Reduction in Fat Gain is an Impressive Number, But...

BAIBA beta-aminoisobutyric acid fat burner fat burning leptin leptin deficiency lose fat weight loss pill

Could BIBA be the active ingredient in a pill that solves your weight problems once and for all? Or is that too good be true?

Beta-aminoisobutyric acid, aka BAIBA, is a natural catabolite of thymine. As with many other purported "next big things in fat loss supplements", early rodent studies suggest that it can significantly reduce body fatness through a mechanism that appears to involve increases in fatty acid oxidation (FAO) and reductions in de novo lipogenesis - in particular in the liver (Maisonneuve. 2003 & 2004; Begriche. 2008).

As Karima Begrich et al. point out in a more recent review of the literature, "experimental evidence [... also] suggested that BAIBA could reduce body adiposity through increased leptin expression and secretion" (Begriche. 2010).

Some people say that caffeine is the last real "fat burner" left on the market

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Against that background, it is only logical to ask whether we have overlooked a potent natural fat burner with a mechanism of cation that may be beneficial for both losing fat (increase in fat oxidation and decrease in fat storage) and keeping it off (modulation of leptin expression and secretion).

Unfortunately, it does not take long to find the first evidence that blows a hole into the neat "BAIBA could solve the diabesity epidemic"-theory. It comes right from one of the previously cited studies.
In their 2008 study, Begriche et al. were able to confirm that the provision of 100mg/kg per day (for humans that would be ~8mg/kg per day) of Beta-aminoisobutyric acid triggers significant reductions in body fat gain in lean mice (Figure 1, left).

Figure 1: 100mg/kg/day BAIBA may be an anti-weight gain supplement The data from obese rodents (rights) does yet suggest that it is not a weight loss supplement (Maisonneuve. 2004) | Anti-obesity, but not weight loss effects were also observed in obesity prone rodents in a 2008 study by Begrich et al. at the same dosage of BAIBA.

What the same amount of BAIBA did not do, though, was to prevent the weight gain in already obese mice (Figure 1, right). In view of the fact that the same discrepancies were observed for liver fat and total body weight (not shown in Figure 1), the currently available evidence clearly doesn't support the use of BAIBA as a classic "fat burner".

In obesity prone mice, BAIBA (100mg/kg) did not just ameliorate the body fat gain, it also reduced (c,d) the number of fibrotic leasons (a,b) of the liver that occured when the ob +/+ mice got fat (Begrich. 2008).

Is BAIBA even safe? In the absence of human studies that's difficult to say, but in rodents it had no ill effects on mtDNA replication (Mainonneuve. 2004) and displays a generally low toxicity. As Begrich et al. point out, their "further investigations are [still] requested to determine whether BAIBA could induce deleterious effects," even though, "it seems that this endogenous derivative could have a favourable safety profile that might be attractive for pharmacological usage" (Begrich. 2010). Deteriorations of the lipid or glucose metabolism, were not observed in any of the currently published studies and at a dosage of 100mg/kg BAIBA reduced the fibrotic leasons in the livers of obesity prone mice and improved the level of lactate dehydrogenase, a potential marker of liver problems (Begrich. 2008).

Overall, it does thus appear as if Begrich's own conclusion that BAIBA supplements "may be indeed an attractive pharmacological strategy in order to prevent (and/or treat) obesity" (Begrich. 2010) is only partly warranted:

• While BAIBA may be useful to ameliorate the body fat gain in lean individuals and would thus in fact be an "attractive pharmacological strategy in order to prevent [...] obesity" (ibid.) in an obesogenic environment,
• it appears to be more than just 'a little too early' to assume that BAIBA supplements could also be used to "treat" (ibid.) obesity in individuals who are already carrying >50% more body fat on their frame than the average lean person.

It is however more than the fact that many of you are probably (still) lean that keeps BAIBA in the game: If you look at the data in Figure 2, it becomes obvious that BAIBA may do more than to prevent the body fat gain in people who have always been lean: its effect on leptin, in particular, could be of even greater use for people who have lost a significant amount of body fat and are now struggling with the nasty yoyo effect.

Figure 2: The increase in adipocyte (=fat cell) leptin and adiponectin production that was observed in the petri dish is particularly interesting for people who have already lost a significant amount of body fat (Begrich. 2010). If it translates into in vivo human studies, it may help those people to stay lean and reverse "metabolic damage".

As you can see in Figure 2, in vitro data shows that the direct exposure of fat cells (adipocytes) of mice, which are at a particularly high risk of becoming obese, will trigger a significant increase in leptin and adiponectin production. Why's that important? Well, of these...

• 

  Metabolic Damage, Energy Intake & the Human "Energy Thermostat" - An Update Based on Recent Studies | read it!

  the increase in adiponectin that is produced by one's fat cells has been linked to important health markers, like increased insulin sensitivity and improved markers of lipid management.
• the increase in leptin production, however, may be of greater importance, because the diet- or rather fat-loss induced remodelling of the adipose tissue (many small empty fat cells) will reduce the production of the "you're fat enough" signal leptin and thus increase the risk of formerly obese individuals to regain every pound (or even more) of body fat they have painfully lost over months of hard dieting.

With that being said, the possibility that BAIBA may be able to reverse a potential cause of something that is often referred to as "metabolic damage" of which it appears as if it was at least partly triggered by a reduction in relative leptin production (i.e. the amount of leptin that is produced at a certain level of body fat) brings BAIBA back into the game. 

Bottom line: Whether an increase in leptin production is, as Figure 3 from Begrich's previously cited review suggests, the only (or at least the most important) mechanism of the beta-aminoisobutyric acid induced anti-obesity effect will yet have to be confirmed in future studies.

Figure 3: If Begrich et al. (2010) are right, the beneficial effects of BAIBA are mediated mostly, if not exclusively by leptin. Due to a lack of human data, BAIBA must - as of now - still be classified as "promising, but unproven" anti-obesity supplement.

Of even greater importance than investigations into what I would like to call the "leptin hypothesis of BAIBA's anti-obesity effects", though, is the simple confirmation of its effects in independent human studies. I mean, rodents are (often) a good model of human metabolism, but there are instances where slight metabolic differences between man and mouse can have a huge impact on several practically relevant research outcomes. It is thus well possible that unexpected human-specific "side effects" like an extreme increase in appetite and energy intake could reduce or blunt the purported anti-obesity prowess of BAIBA. Before the aforementioned human studies have not been conducted, peer-reviewed and published, I recommend to stay skeptical about BAIBA being the "next big thing in fat loss supplements." | Comment on Facebook!

References:

• Begriche, Karima, et al. "β‐Aminoisobutyric Acid Prevents Diet‐induced Obesity in Mice With Partial Leptin Deficiency." Obesity 16.9 (2008): 2053-2067.
• Begriche, Karima, Julie Massart, and Bernard Fromenty. "Effects of β‐aminoisobutyric acid on leptin production and lipid homeostasis: mechanisms and possible relevance for the prevention of obesity." Fundamental & clinical pharmacology 24.3 (2010): 269-282.
• Maisonneuve, Caroline, et al. "Mitochondrial and metabolic effects of nucleoside reverse transcriptase inhibitors (NRTIs) in mice receiving one of five single-and three dual-NRTI treatments." Antimicrobial agents and chemotherapy 47.11 (2003): 3384-3392.
• Maisonneuve, Caroline, et al. "Effects of zidovudine, stavudine and beta-aminoisobutyric acid on lipid homeostasis in mice: possible role in human fat wasting." Antiviral therapy 9.5 (2004): 801-810.

Cardio After Weights! Doing Resistance Before Endurance Training Has More Beneficial Effects on Leptin, Cortisol, Testosterone and Body Composition in Young Men

Cardio After Weights! Doing Resistance Before Endurance Training Has More Beneficial Effects on Leptin, Cortisol, Testosterone and Body Composition in Young Men

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I can almost guarantee that the results of this study are not sex-specific. Ladies, pick up the weights fater you hit the treadmill, stairmaster, elliptical or other torture instrument you like to use!

It has been a while since the last study on exercise order (cardio or weights first) has been published. Now, scientists from the University of Kurdistan have conducted another study to investigate the effects of intrasession sequencing of concurrent resistance and endurance training on the serum leptin, testosterone, cortisol responses and body composition in obese men.

And don't worry, we are not talking about useless acute-phase data that shows no correlation with either strength or muscle gains, or fat loss (West. 2012). Sheikholeslami-Vatani and colleagues conducted an eight-week study on thirty obese young male students without continuous exercise history (age: 23.2±1.4 year, BMI: 31.8±1.6 kg/m²).

You can learn more about the optimal exercise order at the SuppVersity

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The subjects were randomly divided into three groups: concurrent resistance-endurance (CRE, n = 10) group, concurrent endurance-resistance (CER, n = 10) group and control (C, n = 10) group (no training program). The concurrent training groups (CER and CRE) trained three times a week on alternate days for 8 weeks. The training itself consisted of which consisted of ...

"running with 70—75% of maximal heart rate (HRmax) for 10 minutes which gradually increased to 80% HRmax for 21.5 minutes [plus] resistance training consisted of 3 sets of 8 repetitions at 80% of 1 repetition maximum (1RM) in 5 resistance exercises (leg extensions, lying leg curl, triceps pushdown, bench press and lateral pull down)" (Sheikholeslami-Vatani. 2015). 

In-between the endurance and resistance (or vice versa) training parts of the workouts, the subjects rested for 5 minutes. Blood sampling and skin-fold measurements to asses the body composition was conducted 48 hours before the start of the course and again 48 hours after the last training session (learn why waiting longer for the body comp test may have been better, but no study does that).

Figure 1: Relative changes in hormone levels (left) and absolute and relative changes in body fat fat free mass and body fat % (right) after 8 weeks of doing nothing (C) or doing cardio (CER) or weights (CRE) first (Sheikholeslami-Vatani. 2015).

I've plotted the most important results in Figure 1a & b. So, let's take a look: The first thing that everyone should see is that both workout regimen had relevant health and physique effects:

• 

  Similar gains w/ weights vs. cardio first in trained men | more.

  normalization of leptin levels (health)
• slight increases in testosterone (health)
• increases in cortisol (which are benign | learn why)
• significant reductions in body fat (health + physique)
• increases in fat free mass (health and physique)

In that, the resistance training first (CER) group came off slightly better in all tested study outcomes. Statistical significant inter-group differences, however, were observed only in comparison to the control group. In view of the fact that the body fat (total and %) improvement reached statistical significance compared to control only in the endurance first, group, yet not in the strength first group, one may still argue that the difference between cardio first (CER) and weights first (CRE) was "almost significant" ;-)

Weights or Cardio? What's the Best Visceral Fat Burner + How Often, Long and Intense Do You Have to Train | Learn more!

So, weights first is the way to go? Well, I assume I should write that doing both on separate days and thus doing having 5-6 workout days per week may have even more pronounced effects on the body composition of obese young men. In the end, though, I have no evidence to prove that doing the same amount of cardio on a separate day would actually have yielded greater improvements in body composition. Against that background and in view of the fact that three workouts per week is everything that fits into the busy schedules of the average trainee, we are left with the confirmation that (a) doing (intense) cardio and weights in one session feasible and effective when the goal are health and physique improvements and that (b) if you or your clients combine both, you better start with the weights, not the cardio part | Comment!

References:

• Sheikholeslami-Vatani, D., et al. "The effect of concurrent training order on hormonal responses and body composition in obese men." Science & Sports (2015).
• West, Daniel WD, and Stuart M. Phillips. "Associations of exercise-induced hormone profiles and gains in strength and hypertrophy in a large cohort after weight training." European journal of applied physiology 112.7 (2012): 2693-2702.