Seabuckthorn Leaves Increase PPAR-Alpha & PPAR-Gamma Expression, Keep the Liver Fat Free and Fatty Oxidation Up. Plus: PPARs - High or Low? How Are They Supposed to Be?

This time, the magic is in the leaves, not the fruits or kernels. And it's dose dependent. With an almost linear increase from 500-1,000mg/kg

Honestly, I don't think that it is coincidence that many of the most promising medical plants are shrubs that live on barren soil, like sand dunes and cliffs and are full of thorns as well as innate polyphenolic defense mechanisms. Whatever the "evolutionary" basis may be, if we go by the beneficial metabolic effects, researchers from the Department of Food Science and Human Nutrition at the Chonbuk National University in the Republic of Korea, it appears worth going through all the traditional used folk medicine across the world and identify which of them work, how they work and whether they may already have what it takes to get rid of one or the other of the typical Western diseases.

In the case of the ethanolic extract of seabuckthorn (Hippophae rhamnoides L) Pichiah et al. used in their most recent experiment, this would be ameliorative effects on weight gain through down-regulation of adipogenic and lipogenic gene expression.

Less weight gain more fatty acid turnover, better glucose management and leptin sensitivity

The ameliorative effects on the detoriation of glucose metabolism, the reduced but still significant weight gain of the 60% fat diet (additional fat 100% from lard) and the profound overexpression of leptin, which is indicative of the fact that the mice developed full-blown leptin resistance within the 13-weeks of HFD administration, were all ameliorated to a greater degree in the high dose seabuckthorn leaf extract group (human equivalent  ~6.5g/day).

Figure 1: Effect of the different diets on weight gain, visceral fat weight, feed intake and energy intake (left; data expressed relative to control diet); effects on blood sugar (AUC in glucose tolerance test) and leptin (Pichiah. 2012)

The differences between high and low dose supplementation of the extract which had been prepared by

"[...] by soaking the dried, powdered leaves in 70% ethanol for 7 days at room temperature. Then the extract was concentrated by evaporating ethanol using a rotary vacuum evaporator (N-N Series, EYELA, Tokyo, JAPAN) set at 60°C and 100 hPa" (Pichiah. 2012)

were even more pronounced, when we compare the effects on fatty acid oxidation (CPT-1), the PPAR-alpha and -gamma values.

Figure 2: Carnitine palmitoyltransferase I (CPT1), PPAR-alpha & -gamma activity and triglyceride & cholesterol content in the liver (left; expressed relative to rodents on normal chow). Histology of liver sections at 200x magnification for the different diets (Pichiah. 2012)

What's yet most striking is however that the liver - the organ that's so heavily involved in the etiology of insulin resistance - was virtually "fat-free" in the rodents who received the 1,000mg/day dose. The total triglyceride and cholesterol content was even lower than in the mice on the normal diet and the overall darker staining in the slices on the right of figure 2 is only further evidence of the beneficial effects the seabuckthorn extract had on the liver histology.

The effects of a 5% conjugated linoleic acid diet do actually resemble that of lipodystrophy, i.e. pathological fat loss and inability to store body fat. Strange, no? Well that's PPAR-gamma (read more).

PPAR-gamma? Wasn't that what you actually wanted to avoid? In a way this is right, since PPAR-gamma and even alpha are somewhat Janus-faced molecules (overview for PPAR-alpha). As beneficial as their expression in the liver may be, both inhibit the oxidation of glucose. PPAR-gamma is also involved in the maturation process from pre-adipocytes to mature adipocytes, increases lipogenesis in white adipose tissues, decreases the cell surface fatty acid transporter on muscle cells and increases glucose uptake in adipocytes (exclusively). All that is healthier than fat clogging your liver, but it's not exactly something that will make you leaner if you are work out and consume a junk-free diet.

In fact, the PPAR-gamma suppressing effects of the trans-10, cis-12 isomer of conjugated linoleic acid (CLA; cf. Kennedy. 2008) are actually what what produces such profound effects, as they were observed in the study I discussed on July 22, 2012 (see link beneath the image of the mice).

TTA and fish oil are potent antagonists of liver PPAR expression. With the uncoupling and anti-inflammatory effects of TTA being the key to unleash & maintain fat-burning (read more).

Bottom line: It appears as if the liver is - once again - emerging as a central player in "sick obesity", meaning being fat and sick and not just fat. Which reminds me of yesterday's post on Gluten and the development of metabolic disease, where fatness is no criteria, at all. The expression of the "liver cleansing" PPAR-gamma enzymes on the other hand was.

This in turn reminds me of the effects of fish oil and TTA (a pan PPAR-activator), which - despite their questionable use as a long-term intervention can in fact stimulate intra-hepatic fatty acid oxidation to levels which are so high that oxidation rates in and out of itself could bring about some problems.

Other nutritional factors you should take into account are choline (a deficiency will actually cause fatty liver disease; read more about choline) or taurine. And on the endocrine side of things you want to keep an eye on optimal DHEA levels (read more about its effects on PPAR-gamma), thyroid hormones, testosterone and estrogen (Nemoto. 2000).

References

• Kennedy A, Chung S, LaPoint K, Fabiyi O, McIntosh MK. Trans-10, cis-12 conjugated linoleic acid antagonizes ligand-dependent PPARgamma activity in primary cultures of human adipocytes. J Nutr. 2008 Mar;138(3):455-61.
• Nemoto Y, Toda K, Ono M, Fujikawa-Adachi K, Saibara T, Onishi S, Enzan H, Okada T, Shizuta Y. Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice. J Clin Invest. 2000 Jun;105(12):1819-25.
• Pichiah PB, Moon HJ, Park JE, Moon YJ, Cha YS. Ethanolic extract of seabuckthorn (Hippophae rhamnoides L) prevents high-fat diet-induced obesity in mice through down-regulation of adipogenic and lipogenic gene expression. Nutr Res. 2012 Nov;32(11):856-64.

Docosahexaenoic Acid (DHA) Blunts Negative Side Effects of Conjugated Linoleic Acid (CLA) W/out Hampering Its Effects on Body Fat Loss & the Expression of Obesity Genes

She already knew what scientists have recently discovered and now confirmed: You better stack CLA and DHA if you want lean and health offspring ;-)

Conjugated linoleic acid (CLA) is not only an omega-6 fatty acid, it's also a trans-fat (though a natural one) and still even scientists believe that it could contribute to the solution of the diabesity epidemic, if it (a) finally yielded the same extreme fat loss (yep, just the blubber, nothing else) results in human beings as in rodents (cf. "CLA Annihilates Body Fat and Increases Endurance") and (b) anywhere near appropriate doses would not hold he risk of inducing fatty liver disease and insulin resistance (Clément. 2002). At least with respect to (b) a "bodybuilding approach" to CLA supplementation which is based on the "if hammering your head against the wall hurts, you better make sure you wear a helmet" principle of stacking CLA and PUFAs, esp. the long-chain omega-3 fatty acid DHA, has already yielded some promising results in a study that has been published earlier this year (Fedor. 2012a).

Since, the deposition of fat in the liver in response to CLA supplementation is in the end only the logical consequence of CLA's lipolytic (=fat releasing) and anti-lipogenic (=inhibition of fat storage) effects in the adipose tissue, the absence of adequate data on the amount of fat in adipose tissue and muscle or the fatty acid composition of liver, adipose tissue, and muscle, nor did we monitor the changes in the expression of genes involved in fatty acid metabolism in adipose tissue and muscle in the respective study did not allow for the conclusion that the co-supplementation of DHA would not blunt the beneficial fat loss effects of CLA, as well.

Is it possible that high dose DHA blunts the negative and the positive effects of CLA?

In a paper that's going to be published in the next issue of Metabolic Syndrome And Related Disorders Dawn M. Fedor et al. describe the results of a follow up study, which dealt with this very question and I guess I am not giving away more than what you will already inferred from the headline of this post, when I tell you that the answer to the question in the subheading is "No, DHA does not blunt the beneficial effects of conjugated linoleic acid on adipose tissue!"

Figure 1: Relative body weight, liver weight, periuterine fat mass, muscle weigh, liver total lipid weight, adipose total lipid weight, and muscle total lipid content of the mice after 4 weeks on a 0.5% CLA, 0.5% CLA + 1.5% DHA or 1.5% DHA diets expressed relative to respective data from mice on the standard chow (Fedor. 2012b)

If you take a closer look at the data in figure 1 you will realize that the provision of a diet that contained 0.5% CLA (only the "active", but potentially hazardous t10, c12 isomer was used in the study) and 1.5% DHA did not blunt the beneficial effects on total and periuterine body fat mass in eight-week-old, pathogen-free female C57BL/6N mice. On the other hand, it did mitigate the negative effects on liver weight and (and this is actually quite remarkable) had identical beneficial effects on liver fat as the DHA only diet.

DHA + CLA = perfect synergists

Although the "equation" above may sound as if I had taken it right from one of those shiny adds in a muscle mags, it does in fact look, as if the combination of CLA + DHA was the silver bullet for healthy body fat (and I repeat only body fat not lean mass!) reductions in the absence of any dietary and/or exercise interventions.

Figure 2: Expression of selected genes involved in the synthesis, storage and release of fatty acids from the adipose tissue; the respective values (in a.u.) of the control group were all 100, so you can thing of these as percentages, as well (Fedor. 2012)

Moreover, the analyses of the expression of pro- and anti-obesity genes in the adipose tissue does actually support this claim:

"CLA significantly decreased the expression of LXRb, PGC1a, PPARg, SREBP1C, ACOX1, and CD36 adipose mRNA when compared to the control group. We also observed a trend for CLA to decrease the expression of HSL (P=0.08). DHA was not able to prevent any of these decreases in gene expression. CLA significantly increased UCP2 mRNA expression when compared to control group; DHA again had no effect." (Fedor. 2012b)

If we translate all these acronyms the scientists use to describe the data I've plotted for you in figure 2 into plain cause and effect relations, we could simply state: CLA induced changes in the expression of genes in the adipose tissue of the rodents that would prevent the maturation of adipocytes and the synthesis and accumulation of fatty acids, while increasing their release into circulation,  and DHA did not effect these changes.

DHA takes care of the energy that's released / not stored in fat cells

What the co-administration of DHA did, however, was to prevent the deposition of the energy that was released, respectively not even stored in the adipocytes in the liver -- and it did that so effectively that the overall weight of the liver of the mice in the CLA + DHA group was not greater than the the liver weight of the rodents in the control group.

Figure 3: Liver fatty acid composition (µmol/g) and omega-3 : omega-6 ratio after 4 weeks on regular (control), 0.5% CLA, 0.5% CLA + 1.5% DHA and 1.5% DHA diets (Fedor. 2012b)

In fact, the co-administration of conjugated linoleic acid and DHA did even reduce the total fatty acid content of the liver (not to a statistically significant degree, though) and brought about profound changes in its fatty acid content - most prominently, a whopping +975% increase in the omega-3 : omega-6 ratio (see small graph in figure 3) that were even slightly more pronounced in the CLA + DHA group than in the DHA only group (you do remember that CLA is an omega-6 trans-fat, right?).

Finally a stack that works -- but will it work in humans, as well? 

I don't know if it dawned on you, already, but dairy and butter from grass cows already has both CLA and DHA in it - what a lucky coincidence, isn't it? Still, there is one downside: You simply cannot eat enough of it to get anywhere close to the human equivalents of the amounts that are used in rodent studies.

Now, although both the changes in body fat levels in the CLA + DHA group were consistent with those observed in the CLA only group and the effects of the combination treatment on the changes in hepatic fatty acid composition were consistent with those observed in the DHA only group, there is still one question we have to answer: Are we going to see similar esults in humans?

To be honest, I still cannot answer this question, but if you take into consideration that no previous human trial used dosages in the 20-30g range simply because that would be unethical given the associated side effects, we may soon get an answer to this question - as soon as scientists dare to slowly escalate the dosage, trusting on the ability of supplemental DHA to blunt the negative, while conserving the beneficial effects of CLA.


References:

• Clément L, Poirier H, Niot I, Bocher V, Guerre-Millo M, Krief S, Staels B, Besnard P. Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse. J Lipid Res. 2002 Sep;43(9):1400-9.
• Fedor DM, Adkins Y, Mackey BE, et al. Docosahexaenoic Acid prevents trans-10, cis-12-conjugated linoleic Acid-induced nonalcoholic Fatty liver disease in mice by altering expression of hepatic genes regulating fatty acid synthesis and oxidation.Metab Syndr Relat Disord. 2012a;10:175–180
• Fedor DM, Adkins Y, Newman JW, Mackey BE, Kelley DS. The Effect of Docosahexaenoic Acid on t10, c12-Conjugated Linoleic Acid-Induced Changes in Fatty Acid Composition of Mouse Liver, Adipose, and Muscle. Metab Syndr Relat Disord. 2012b Nov 21.

Vibration Training Shakes Away Your Liver Fat - 9% Liver Fat, 7% Visceral Fat & 26.4% Intra-Muscular Fat Loss + Reduced Inflammation Without Extra Dietary Intervention

If you actually work out on the vibration plate (instead of just standing there) it may in fact be an effective adjunct to regular exercise for must of us.

I have to admit that I am regularly laughing about the women on the vibration plates in my fitness studio. Now that I have read the latest paper from the Department of Medical Sciences at the University of Tsukuba, however, I will probably see them standing on the "wacker plates" with different eyes. In said study which was conducted by Sechang Oh et al. (2014) the scientists tried to elucidate the effects of what they call "acceleration training" (this is in fact what we know as vibration training) on the physical function, body composition, hepatic and metabolic function, fat contents in the liver and skeletal muscles of overweight subjects (BMI = 28 kg/m²) with non-alcoholic fatty liver disease (NAFLD).

For the lean NAFLD sufferers I'd suggest HIIT instead of a vibrator ;-)

Never Train To Burn Calories!

Tabata = 14.2kcal /min ≠ Fat Loss

30s Intervals + 2:1 Work/Rec.

Making HIIT a Hit Part I/II

Making HIIT a Hit Part II/II

No Time? 1 Min is Enough

The 18 participants (4 men and 14 women) took part in the vibration program twice a week for 12 weeks. Participants performed upper and lower body exercises on a vertical vibration machine (Power Plate Pro6, Badhoevendorp, the Netherlands). The protocol itself consisted of three sessions (movement preparation, strength and power, and massage) and had a total duration of 40 minutes - including a rest interval of 30 seconds after each movement.

A movement preparation session included hamstring stretch, calf stretch, side stretch, and hip joint stretch (frequency, 30 Hz; amplitude, low; time, 30 seconds; set, 2). A strength and power session included deep squat, wide stance squat, lunge, push up, triceps dips, crunch, front plank, and pelvic bridge (frequency, 30–35 Hz; amplitude, low; time, 30 seconds; set, 2). A fial session consisted of massage of the calf, hamstring, lower back, shoulder, and face (frequency, 40 Hz; amplitude, high; time, 60 seconds; set, 2). Trained staff supervised all training sessions to ensure correct execution (Figure S1 provides details on the AT program used in this study)."

What is important to point out is the fact that the subjects did not receive any lifestyle counseling, and did not decrease their habitual energy intake or increase their regular physical activity.

In practice, the energy intake of the subjects actually increased (by 246kcal/day, i.e. 13%) and the physical activity - probably to "compensate" for the "exhausting" vibration training *irony* - was reduced so that their total daily energy expenditure on non-exercise days ended up being 320kcal lower (-14%). Since there were large inter-individual differences, these changes didn't reach statistical significance, though.

The surprisingly pronounced effects you can see in Figure 1 have thus been triggered by the often laughed at "exercise" regimen.

Figure 1: Changes in body composition in response to 12x2 vibration training sessions in the absence of lifestyle interventions, diet or additional exercise (Oh. 2014)

I see you are impressed. 6% lower body fat, increased muscle mass, 7% reduced visceral fat... that's impressive, right? Well, I was similarly flabbergast, when I saw the results of this peer-reviewed study. One thing we should keep in mind, though, is the fact that the subjects were not fit, but fat.

When it's propely designed, add. vibration training can increase athletic performance in fem. athletes (Fagnani. 2006).

So this can't be useful for athletes, right? Wrong. Totally wrong. While vibration training will probably never replace athletic training, it "is a suitable training method to improve knee extension maximal strength, counter-movement jump, and flexibility" at least in young female athletes, but only "if it is properly designed" (Fagnani. 2006). Only if a subject-specific, previously determined and professionally monitored optimal frequency, amplitude, and g-force is used (something a regular gym probably doesn't offer) and the muscle activation measured the beneficial effects will show (Fagnani. 2006).

The same type of exercise that will be hardly challenging for someone who is working out regularly will thus be pretty intense for them - and (!) the higher body weight makes the exercises on the vibration plates extra intense.

Figure 2: Pre- vs. post-changes in selected markers of metabolic health (Oh. 2014)

As Figure 2 reveals, these changes in body composition went hand in hand with a plethora of improvements in several markers of metabolic health of which yet only the decrease in gamma-GT, AST, free fatty acids (FFA) and total cholesterol reached statistical significance. The marginal decrease in insulin sensitivity, on the other hand, was not statistically significant.

Figure 3: Quadriceps strength and circumference, as well as intramyocellular lipids (IMCL) before and after the intervention (Oh. 2014)

What was statistically significant were the size and strength gains in the quadricreps and the reduction of intramyocellular (in the muscle) fat, which has previously been associated with muscular insulin resistance in obese individuals (depletion of the intramuscular fat can in fact restore muscular insulin sensitivity | Greco. 2002).

Your liver will thank you for working out on a full-body vibrator ;-) Even if you are not willing to give up the rest of your obesogenic lifestyle - which is obviously not suggested.

Bottom line: If we also take into consideration that all these beneficial changes went hand in hand with reductions in leptin, TNF-alpha, IL-6 and significant reductions in hepatic steatosis, i.e. the amount of fat that clogged up the liver of the subjects and liver stiffness, the results of the study at hand clearly indicate that "passive" exercise is much better than none exercise, when it comes to the treatment of non-alcoholic fatty liver disease.

What's most impressive, though, is that this works without dietary intervention and / or significant weight loss, solely by changes in body composition and site-specific fat loss | Comment on this article on Facebook!

References:

• Fagnani, Federica, et al. "The effects of a whole-body vibration program on muscle performance and flexibility in female athletes." American journal of physical medicine & rehabilitation 85.12 (2006): 956-962.
• Greco, Aldo V., et al. "Insulin resistance in morbid obesity reversal with intramyocellular fat depletion." Diabetes 51.1 (2002): 144-151.
• Oh, Sechang, et al. "Acceleration training for managing nonalcoholic fatty liver disease: a pilot study." Therapeutics and clinical risk management 10 (2014): 925.

Pigs Would Pick MSG - Glutamate Seals the Gut, Decreases Liver & Muscle Fat & Increases Plasma Amino Acids in Swine

Piglets would buy MSG food ;-)

Mono-sodium glutamate (MSG) and the "Chinese restaurant syndrome", obesity and overeating are often thrown together into a single psedo-scientific crock pot with the result being a brew that's 50% hear-say, 40% fear and 10% science. The study we are going to look at today is unquestionably part of the latter ingredient and its results do stand in line with my previously stated concern "that MSG is one of those substances that is usually found in foods with a whole host of other nutrient-poor ingredients, anti-nutrients and proven obesogenic, pro-inflammatory and otherwise unhealthy substances and food additives" ("MSG, NFALD, Leaky Gut & Brain ...") and could thus rather be corollary to, than causative of the toll the fast, convenient and nutrient deficient foods in the Western diet are taking on our health.

Published ahead of print in the online version of the journal Amino Acids you will find a study by a group of researchers from the Texas A&M University. The study was, according to the authors intended to "fill [the] important gap of knowledge about glutamate nutrition and metabolism in animals" (Rezaei. 2012). Luckily their study subjects were pigs, allegedly young pigs, but still omnivores like us and one of the best models of the human digestive tract we have:

"Both humans and pigs are highly dependent on dietary quality since symbiotic microorganisms within the gut play a relatively minor role in modifying the nutrients that are ingested. Intestinal  transit times and digestive efficiencies are comparable. Postabsorptive metabolism is also similar in many respects, although the wide differences in length of gestation and the numbers of young born introduce a potentially significant divergence in nutrient needs for reproduction. [...] Nevertheless, when minimum nutrient requirements of swine and established recommended daily allow­ ances of humans are expressed per kilogram of dietary dry matter (assuming an intake of 500 to 800 g of dry matter per day by teenagers and adults), these values are highly related. It is only reasonable that one not draw unsupport­able inferences from one species to another, but with the possible exception of nonhuman primates, it is apparent that the omnivorous pig is one of the best models for study of nutrition issues in the omnivorous human." (Miller. 1987)

Against that background it is quite intriguing that Rezaei. et al. did not find any of the suspected negative side effects of MSG up to a dosage of 4% in the diet of their piglets.

Figure 1: Weight development and feed intake and effciacy in pigs on diet containing different amounts of supplemental MSG (data based on Rezaei. 2012)

In fact, instead of eating more, the pigs that received the MSG-supplemented diets consumed slightly, but significantly less food than their peers. Despite these appetite suppressing effects of the diet, the piglets in the high MSG arm of the study still gained the most body weight and thusly had the 'optimal' (for lovers of Chines restaurant probably rather 'most detrimental') gain:feed ratio.

The amino acid modifying effects of MSG

When we are seaching for the underlying reasons of these changes, it may be worth taking a look at the amino acid composition of the plasma of the piglets after 21 days on diets supplemented with different amounts of MSG at 1 and 4 h after feeding. During this prostprandial phase, the scientists observed

• 

  More about MSG in human health

  significant increases  in aspartate, glutamate, glutamine, histidine, citrulline, arginine, taurine, alanine, methionine, valine, phenylalanine, isoleucine, leucine, proline, cysteine, ornithine, and lysine in plasma at both time points, i.e. one and four hours after feedin,
• highly significant increases in asparagine, serine, threonine, tryptophan, and tyrosine 1h after feeding and
• significant increases in alanine, citrulline, glutamate, methionine, ornithine, phenylalanine, proline, and tryptophan in the first hour of the postprandial window

If we also take into account previous rodent studies which have shown that MSG reduces the deposition of fatty acids in white adipose tissue (Kondoh. 2008), it cannot be ruled out though that these increases in weight gain were related to increases in lean- not fat tissue (remember: muscle is heavier than fat); after all we are dealing with growing young pigs, in which you would expect an increase in essential and non essential amino acid availability to help with skeletal muscle metabolism (Mahan. 1998).

Figure 2: Total lipid content in percent of control in response to MSG feeding at different doses (left) and the modulatory effects of sodium intake (NaCl) on the effects of MSG (right; data based on Rezaei. 2012)

As the data in figure 2 goes to show this hypothesis appears to stand in line with the decreased fatty acid deposition in liver and skeletal muscle, which will at the same time prevent negative side effects of intra-hepatic and -skeletal lipid accumulation on liver and muscle glucose uptake.

Does salt modify the effects of MSG? And what's the role of the gut in all this?

Against that background it is actually a pitty that we don't have data on the fatty acid content of liver and muscle tissue in response to the different levels of dietary salt in the diets (figure 2, right). I mean, at first sight it appears that more salt could 'ameliorate' the detrimental effects of MSG feeding on the body weight of the rodents, but if the latter was not detrimental, but beneficial, this would certainly entail the question if it's not MSG per se, but rather it's co-appearance with too much, or due to it's ability to boost all taste perception to little sodium in the previously mentioned fast, convenient and nutrient deficient foods, way too many people have gotten addicted to.

You see, just as so many times before things are way more complex than they may seem at first sight and if the interactions of body weight, lean mass, intrahepatic and intramuscular lipids and dietary salt with MSG was not already enough, the data in figure 3 brings another (side?) effect into play the importance of which must not be underestimated - the effect of MSG on the intestinal morphology of the pigs:

Figure 3: Jejunal morphology and jejunal concentrations of DNA, RNA, protein, ATP, and glutathione in 28-day-old pigs weaned at 21 days of age (Rezaei. 2012)

I don't know if you remember the side effect of the chronic ingestion of zinc on the intestinal structure of rodents that caused quite a stir in the zinc-loving bodybuilding community back in June!? In essence, the effects of mono-sodium glutamate on the microvilli, which are responsible for the absorption of nutrients look very similar to the ones that were observed by Taneja et al.in response to Zinc supplementation (SuppVersity: June 13, 2012). As previously mentioned this is per se not a bad thing and could in fact come very hand to people with chronic inflammatory conditions suffering from a "leaky gut" or people who want to protect their gut from the side effects of the chronic use of NSAIDs, where MSG has only recently been implicated as a viable tool to prevent and heal mucosal damage (Amagas. 2012).

Figure 4: Postprandial glucose levels (left) and intestinal morphology (right) of mice on diets with different concentrations of mono-sodium glutamate (Rezaei. 2012)

As figure 4 goes to show this could actually work with MSG without the zinc-induced increases in insulin and blood glucose (see figure 2 in previous article). Whether these effects are directly related to the ingestion of MSG or its glutamin-sparing effects n the gut cannot be said for sure, though:

"Grant alert" Despite the fact that I am pretty sure that the actuall data in this study is accurately reported, I still want to point out that the scientists received "a grant from the International Glutamate Technical Committee". It's explicitly listed in the "acknowledgments" and probably not much of an issue outside of the discussion in which you will obviously miss references to potential negative side effects (which have not been observed in the study, though).

"Thus, dietary supplementation with glutamate may enhance the availability of dietary glutamine in plasma. As a versatile amino acid, glutamate participates in both synthetic and oxidative pathways in the small intestine, resulting in the production of proteins, ornithine, citrulline, proline, arginine, alanine, aspartate, glutathione, CO2, and ATP. Therefore, dietary supplementation with glutamate increased the plasma concentrations of these amino acids  and jejunal concentrations of glutathione in weaned pigs. Compelling evidence shows that dietary glutamate is a major energy substrate for the small intestine, which is an organ with a particularly high met- abolic rate. In support of this notion, we found that dietary MSG supplementation increased jejunal concentrations of ATP in weaned pigs. Additionally, glutamate is an excitatory neurotransmitter, thereby regulating the motility of the gastrointestinal tract. Thus, when a weaning diet is deficient in glutamate, gut atrophy occurs and the efficiency of utilization of dietary protein for growth and other physiological functions is greatly decreased." (Rezaei. 2012)

As evidence from previous studies by Kondoh et al. suggests, the effects of glutamate do not end at the intestinal brush border. Its centrally mediated downstream effects after interacting with l-Glutamate receptors in the intestines are however still not fully understood and could either be beneficial (as the work by Kondoh et al. would suggest; Kondoh. 2008 & 2009), be without physiological consequences or - as the mainstream myth suggests - "be the devil"; with the latter being much more likely in people with genetic or already established metabolic problems which result in a deficiency of glutamate dehydrogenase (Stanley. 2009).

Bottom line: The last mentioned problems certain individuals who have inherited or acquired problems with the enzymatic conversion of glutamate are yet not the only reason why I strongly caution against taking the results of the study at hand as a free ticket for limitless MSG consumption. If it's not the MSG that's going to make you fat, I can assure you that those 'foods' in which it is used will be getting the job done pretty quickly and will thus compensate for any possibly existent improvements in intestinal and whole body amino acid metabolism.

Parmigiano Reggiano aside from seaweed the #1 "real food" offender in terms of MSG and still good for your bones (Pampaloni. 2011) - one of many examples of the fallacy of black-and-white thinking. To heal your gut, glutamine would yet still be your better choice, I suppose ;-)

That said, there are still unresolved issues related to the negative effects of MSG on the immune system and the thymus. The dosages that are required to observe toxic effects may be hilarious if you take into account how much of it you find in an individual food item, and even if you started supplementing with MSG, or lived on fast- and convenient food, only, you will probably be hard pressed to get up to the 50g+ human equivalent of mono-sodium glutamate which was sufficient to significantly decrease thymus cell viability in rats (Pavlovic. 2009). In case you feel you are endangered and belong to the people who rather wear a helmet than stop hammering their head against a wall, you could try to counter that with an additional 6-7g of vitamin C (for the rodents that worked)... but let's be honest, wouldn't your life be much easier, if you simply stuck to whole foods and don't worry about the occasional piece of aged Parmesan cheese with 1680 mg glutamate per 100g. It could not just be good for your gut, but has been shown to be good for your bones (Pampaloni. 2011), probably not because, but at least despite the high MSG content.

References:

• Amagase K, Ochi A, Kojo A, Mizunoe A, Taue M, Kinoshita N, Nakamura E, Takeuchi K. New therapeutic strategy for amino acid medicine: prophylactic and healing promoting effect of monosodium glutamate against NSAID-induced enteropathy. J Pharmacol Sci. 2012;118(2):131-7.
• Kondoh T, Torii K (2008) MSG intake suppresses weight gain, fat deposition, and plasma leptin levels in male Sprague-Dawley rats. Physiol Behav 95:135–144.
• Kondoh T, Mallick HN, Torii K. Activation of the gut-brain axis by dietary glutamate and physiologic significance in energy homeostasis. Am J Clin Nutr. 2009 Sep;90(3):832S-837S.
• Mahan DC, Shields RG Jr. Essential and nonessential amino acid composition of pigs from birth to 145 kilograms of body weight, and comparison to other studies. J Anim Sci. 1998 Feb;76(2):513-21.
• Miller ER, Ullrey DE. The pig as a model for human nutrition. Annu Rev Nutr. 1987;7:361-82. 
• Pampaloni B, Bartolini E, Brandi ML. Parmigiano Reggiano cheese and bone health. Clin Cases Miner Bone Metab. 2011 Sep;8(3):33-6.
• Pavlovic V, Pavlovic D, Kocic G, Sokolovic D, Sarac M, Jovic Z. Ascorbic acid modulates monosodium glutamate induced cytotoxicity in rat thymus. Bratisl Lek Listy. 2009;110(4):205-9.
• Stanley CA. Regulation of glutamate metabolism and insulin secretion by glutamate dehydrogenase in hypoglycemic children. Am J Clin Nutr. 2009 Sep;90(3):862S-866S.
• Rezaei R, Knabe DA, Tekwe CD, Dahanayaka S, Ficken MD, Fielder SE, Eide SJ, Lovering SL, Wu G. Dietary supplementation with monosodium glutamate is safe and improves growth performance in postweaning pigs. Amino Acids. 2012 Nov 2.

Get Lean & Stay Lean with Emedin, Galangin & Antibiotics. Plus: Breakfast & Morning Glucose Metabolism. Diet Once, Never Eat to Satiety Again? Adipocyte Size & NAFLD

Instead of making excuses for posting yet another "short news" collection instead of the next installment of the Athlete's Triad series, I will honestly tell you that I simply wasn't in the mood. Moreover, I have the feeling that I have already outlined what is going to work, i.e. train less, eat more and don't get all psyched up about being lean and looking good. Live your life! Against that background my gut tells me that any further details would just get you off track and back into the viscous cycle of overtraining, overdieting and overthinking why things don't work out for you by evoking the impression that as long as you take supplement X you could get away with doing a little bit 'less less' and eat a little bit 'less more'.

This would be about as counter-productive as the eternal quest for the ultimate body fat blocker or fat burner of which today's Get lean and Stay Lean Quickie does actually feature three. While the temporary use of all of them as a crutch or 'afterburner' to a reasonably planned diet and workout regimen certainly makes sense, it's not like anyone of us got fat, because he or she was "fat burner deficient". A fat burner is not an essential nutrient and only an adjunct to diet and exercise! Keep that in mind not just when you read the following short news items, but also whenever you enter a supplement store (real or on the Internet) and find a new "revolutionary fat burner" on sale -- regardless of whether it has Dr. Oz or Mr. O on the packaging it won't actively, i.e. on its own and in the absence of a dialed in nutritional regimen, make you lose body fat.

• Cassia tora (Leguminosae) seed, yet another "next big thing" to get rid of the blubber?  (Tzeng. 2012 --) The results the scientists from the Department of Internal Medicine, at the Pao Chien Hospital in  Ping Tung City will be publishing in the January 2013 issue of Food Chemistry do at at least look intriguing.  Although - and this goes to show you that SuppVersity readers always (well "almost always" ;-) are the first know first - at least one of the active ingredients in Cassia tora, which is also known as Senna tora and is, besides its use in Ayurveda medicine, also used in Sri Lankan cousin, is an old friend: Emodin! The stuff that gives rhubarb the fat burning prowess you read about in not  too long ago, here at the Suppversity.
  
  

  

  CSEE  had dose dependent ameliorative effects on body weight gain and visceral body fat levels that were - ad the highest dose - identical to those of the thiazolidinedione (TZD) drug pioglitazone (Tzeng. 2012)

  After fattening them for 2 weeks with the notorious high fat diet, the Koreans assigned their now obese lab rats to groups who received either
  
  • Cassia seed ethanol extract (CSEE) by oral gavage, once per day for 8 week with CSEE doses of 100, 200, and 300 mg/kg in a volume of 2 ml/kg distilled water,
  • the diabetes drug pioglitazone dosed at 20mg/kg/day, or
  • a placebo, containing just the distilled water.
  Without any effects on the amount of food the animals consumed, the Cassia seed ethanol extract totally blunted the HFD induced weight gain (weight gain was identical to control group on normal chow, see figure to the right).
  
  In that. the highest dosage had the greatest effect on both body weight gain, as well as plasma lipid levels and epididymal WAT sizes in HFD-fed rats. These effects were probably mediated by CSEE's beneficial effect on the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase. In addition, the researchers found that the cassia seed extract directly increased genes that are responsible for fatty acid oxidation and down-regulated their fat synthesizing counterparts in the visceral white adipose tissue of the animals.
  
  Whether CSEE is going to be a go-to supplement of the future cannot be said, now. What is certain, however, is that it constitutes yet another example of a potentially highly effective natural alternative to the established pharmacological 'treatment' (or rather management) of the diabesity epidemic.
  
• Obese, once and forever, unless you diet for the rest of your life? (Kirchner. 2012) -- A paper that's been published in the latest issue of the Journal of the American Diabetes Association, clearly suggests that the ravenous appetite of "reduced-obese" individuals, i.e. people who have been dieting for weeks and months to shed they weight they have accumulated over years is not (solely) psychologically induced gluttony.
  
  

  

  Suggested read: "Longterm 5% Calorie Restriction & Longterm Dieting Make You Fat and Insulin Resistant." (read full article)

  When Kirchner et al. put their diet-induced obese mice were on a  food restricted for 5 weeks, they did in fact reach the same body fat levels as age-matched rodents who had never received anything but the standard chow. Their  blood glucose levels normalized and their insulin sensitivity increased, but the "reduced-obese" mice also showed markedly increased fasting-induced hyperphagia. In fact, when they given ad libitum access to their beloved high fat diet, they ate like there was no tomorrow and ended up gaining weight at a much faster pace than their never-obese peers, who were likewise allowed free access to the HFD.
  
  And it gets even worse, as the conclusion the scientists draw based on their results says that despite the fact that "caloric restriction on a HFD provides metabolic benefits", it may actually require a previously obese dieter to continue on the path of caloric restriction (i.e. never eat to 'satiety') for the rest of his/her life!
  
• Morning to evening decline in insulin response to carbs suggests breakfast is the time where your body reacts most sensitive to carbs (Saad. 2012) -- Likewise published in the latest issue of Diabetes is a study by Ahmed Saad and colleagues from the Mayo College of Medicine in Rochester and the the University of Padova in Italy, which does at first not really sound like it was revolutionary new. Two definitive advantages of the study at hand were yet that the scientists used healthy individuals as subject and gave them regular mixed meals instead of a glucose solution in order to confirm the existence and identify the characteristic features of the diurnal pattern of glucose tolerance most people take for granted.
  
  

  

  The implications of this study for intermittent fasting are not as clear as you may think and certainly don't imply that you must break your fast in the morning (read more about breaking the fast, here)

  Overall 20 healthy volunteers with normal fasting glucose (4.8 ± 0.1 mmol/L) and HbA_1c (5.2 ± 0.0%) participated in the study. They were provided with identical mixed meals during breakfast, lunch, or dinner at 0700, 1300, and 1900 h in a random order on 3 consecutive days. Physical activity was held constant so that e.g. muscle glycogen depletion and subsequent increases in AMPK induced GLUT-4 expression  would not skew the results.
  
  What Saad et al. fonud was that the postprandial glucose excursion was significantly lower (P < 0.01) at breakfast than lunch and dinner. At the same time the β-Cell responsivity to glucose was higher. This means there was more insulin released per unit of glucose, than during lunch or dinner.
  
  The time the hepatic insulin extraction was also lower at breakfast; although the difference reached statistical significance only in comparison to the dinner condition. Since the overall meal glucose appearance did not differ between meals and that the suppression of endogenous glucose production "tended to be lower (P < 0.01) and insulin sensitivity tended to be higher (P < 0.01) at breakfast than at lunch or dinner" (Saad. 2012), it is no wonder that the spike in blood glucose was largely augmented, when the subjects consumed the standardized meal for breakfast.
  
• Adipocyte size is a determinant of non-alcoholic fatty liver disease (NAFLD) risk (Petäjä. 2012) -- One thing scientists still have not really understood is how some obese people seem to be way better off than others, although their BMIs, fat and lean mass appears to be identical. In view of the latest paper by a group of researchers from Finland and Sweden on the association between the average fat cell size and the occurrence of NAFLD, it could well be that ratio of the total adipose volume to the total fat cell number, which obviously is the adipocyte size, may be providing at least another piece to the puzzle that holds the answer to this question.
  
  

  

  In a previos post on the yoyo effect, I already discussed some aspects of adipocyte morphology - read more

  The scientists have studied 119 non-diabetic subjects in a cross-sectional study. The participants had a median age of 39 (26-53) years, and a mean BMI of 30.0±5.7kg/m². Subcutaneous abdominal fat cell size, as well as the total amount of liver fat were measured by proton magnetic resonance spectroscopy, intra-abdominal (IA) and abdominal subcutaneous adipose tissue (SC) volumes by magnetic resonance imaging (MRI) and an additional gene analysis yielded information about the genotype (susceptible or not susceptble to metabolic syndrome) of the individuals.
  
  Simply based on a multiple linear regression analysis, age, gender, BMI, the intra-abdominal to subcutaneous fat ratio and the subject's PNPLA3 genotype, the results were only able to explain 42% of the variation of the liver fat. The inclusion of the adipocyte sizes increased the predictive value by 11%, so that "21% of the known variation in liver fat could be explained by adipocyte size alone" (Petäjä. 2012) This does yet also mean that once we are up to a 90% explanation  (which is unrealistic, by the way) the adipocyte size will only be able to explain "of the known variations".
  
• Antibiotic that's commonly used in animal fattening kills body fat (Szkudlarek-Mikho, 2012) -- Reserachers from the College of Medicine at the University of Toledo in Ohio have found that polyether ionophoric antibiotics including monensin, salinomycin, and narasin, which are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming have toxic effects on adipose cells.
  
  

  

  Whether eating the chicken that ate antibiotics is going to make  you lean does still have to be established. Based on the results of the study at hand, it does however appear likely that eating antibiotics could - I do however doubt that they will achieve that without potentially serious side effects.

  Although previous studies suggest that salinomycin has anti-carcinogenic effects (Huczyński. 2012), the sharp increase in poultry consumption over the last decade(s) and the increased use of these "growth promoting" antibiotics by veterinaries and poultry farmers has often been suspected to be involved in the increase in metabolic and autoimmune diseases.
  
  At least in view of the former, i.e. metabolic diseases in general and obesity, in particular, it may therefore be surprising that the scientists from the University of Toledo discovered that the tested ionophoric antibiotics did not just inhibit the differentiation of cancer, but also that of preadipocytes into adipocytes:
  

  "The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor γ." (Szkudlarek-Mikho. 2012)

  Now, I would fully subscribe to the scientists suggestion that these "ionophoric antibiotics can be exploited as novel anti-obesity therapeutics", but until that has been done and we know which other cells' differentiation they may inhibit, as well, I'd strongly discourage anyone from 'supplementing' with the antibiotics from his or her poultry farmer next door. After all, you may well end up not just with less body fat, but with less brain tissue, as well... what? You don't care? Oh I see. The doctor must have inserted the cannula into your ears instead of your belly on your last liposuction, right?
  
• Alpinia officinarum, a plant in the ginger family, stops fat gains in its tracks (Jung. 2012) -- Jung, Jang, Ahn and the rest of the researchers from the Korea Food Research Institute in Seongnam, report in their latest paper that an ethanol extract from Alpinia officinarum, a plant in the ginger family that's cultivated in Southeast Asia and is also known as lesser galangal, is yet another mainstay of traditional medicine with significant anti-obesity effects.
  
  

  

  It looks almost like ginger and works almost like ginger, but A. officinarum contains galangin, not gingerol and works via the PPAR-gamma pathway, as well. That's something gingerol doesn't do (Huang. 2012)

  Originally used throughout Asia in curries and perfumes, A. officinarum contains a dietary flavenol called galangin, which has already been shown to exert profound anti-cancer effects (Kapoor. 2012), whether it is solely responsible for the in vitro and in vivo inhibitory effects on lipid accumulation during the differentation of 3T3-L1 adipocytes is not certain, but appears to be likely.
  
  Via its effects on the fat synthesis and breakdown and PPAR-gamma activity the A. officinarum extract (AOE) lead to dose-dependent decreases in body weight gains of mice who were fed a high fat diet. It also reduced the visceral and liver fat deposition and partially restored the abnormally elevated insulin and leptin levels of the rodents.
  

  "Collectively, these results suggest that AOE prevents obesity by suppressing adipogenic and lipogenic genes. AOE has potential for use as an antiobesity therapeutic agent that can function by regulating lipid metabolism." (Jung. 2012)

  Certainly another nice find, but let's be honest, what's the real value of all this herbs? I mean yeah they work almost as effectively (in some cases even better) than pharmacological drugs, but both share a detrimental downside, that's not mentioned under "side effects" on the package insert or supplement bottle: They will only manage a problem the root course of which is the net result of a totally messed up diet.

That's it and since you've gotten the bottom line in advance and another time, just to make sure nobody can over-read it, in the last paragraph of the last news item, I just want to remind everyone that there are a couple of other interesting science news and links, for example about ...

• the pro-carcinogenic effects of shift work and to a lesser degree constantly working at night (read),
• the connection between high GI carbs and prostate cancer (read), or
• the idiocy of battling the high GI carb induced decline in cognitive performance with even more sugar (read)

waiting for you on Facebook. Have a nice day and get lean and stay lean ;-)

References

• Huang TH, Teoh AW, Lin BL, Lin DS, Roufogalis B. The role of herbal PPAR modulators in the treatment of cardiometabolic syndrome. Pharmacol Res. 2009 Sep;60(3):195-206. Epub 2009 Apr 7.
• Huczyński A, Janczak J, Antoszczak M, Wietrzyk J, Maj E, Brzezinski B. Antiproliferative activity of salinomycin and its derivatives. Bioorg Med Chem Lett. 2012 Dec 1;22(23):7146-50.
• Jung CH, Jang SJ, Ahn J, Gwon SY, Jeon TI, Kim TW, Ha TY. Alpinia officinarum Inhibits Adipocyte Differentiation and High-Fat Diet-Induced Obesity in Mice Through Regulation of Adipogenesis and Lipogenesis. J Med Food. 2012 Nov;15(11):959-67.
• Kapoor S. Galangin and its emerging anti-neoplastic effects. Cytotechnology. 2012 Oct 25.
• Kirchner H, Hofmann SM, Fischer-Rosinsky A, Hembree J, Abplanalp W, Ottaway N, Donelan E, Krishna R, Woods SC, Müller TD, Spranger J, Perez-Tilve D, Pfluger PT, Tschöp MH, Habegger KM. Caloric restriction chronically impairs metabolic programming in mice. Diabetes. 2012 Nov;61(11):2734-42. doi: 10.2337/db11-1621.
• Petäjä EM, Sevastianova K, Hakkarainen A, Orho-Melander M, Lundbom N, Yki-Järvinen H. Adipocyte size is associated with NAFLD independent of obesity, fat distribution and PNPLA3 genotype. Obesity. 2012. Ahead of Print.
• Saad A, Dalla Man C, Nandy DK, Levine JA, Bharucha AE, Rizza RA, Basu R, Carter RE, Cobelli C, Kudva YC, Basu A. Diurnal pattern to insulin secretion and insulin action in healthy individuals. Diabetes. 2012 Nov;61(11):2691-700.
• Szkudlarek-Mikho M, Saunders RA, Yap SF, Ngeow YF, Chin KV. Salinomycin, A Polyether Ionophoric Antibiotic, Inhibits Adipogenesis. Biochem Biophys Res Commun. 2012 Oct 31.
• Tzeng TF, Lu HJ, Liou SS, Chang CJ, Liu IM. Reduction of lipid accumulation in white adipose tissues by Cassia tora (Leguminosae) seed extract is associated with AMPK activation. Food Chem. 2013 Jan 15;136(2):1086-94. doi: 10.1016/j.foodchem.2012.09.017.

Sweet, But Not Innocent!? The Fattening Effects of the Non - Nutritive Sweeteners Erythritol & Aspartame Are On Par With Equally Sweet Sugar Water

I just hope that today's SuppVersity article is not going to cause scenes like this, because when it all said and done it may be less likely, but not impossible that it is (for whatever vexed reason) still aspartame that caused the negative effects observed in the study at hand.

It is one of the recurring motifs here at the SuppVersisty and at the same time one of the most popular issues of dispute in the health and fitness community: The Obesogenic Effects of Artificial Sweeteners. Or, in plain English, the question  

"Can I use Sucralose, Aspartame and Acesulfam-K without taking the risk of getting fatter - not leaner, as I actually intended?"

For all three of the explicitly mentioned agents human studies clearly suggest that the answer is "Yes, you can!" And I will now dare saying that the of the most recent study from the Oita University in Japan are not going to change that - as long as you use them instead of carbs in your diet the said zero-calorie sweetener are going to help not block weight loss.

So why did the mice in the Mitsutomi study get obese then?

By anticipating the most important conclusion, I have made things easy for us, after all the only questions we still have to answer are:

• Why did the mice in the Mitsutomi study get obese?

• Is it possible that this is an erythritol-specific effect?

It would appear as it it could not be all too difficult to answer the first question. It was after all part of the research interests of the Japanese scientists, so that you would expect it to be answered in the discussion of their result. Well, let's see then, ...

Exactly what the energy drinks promise, the sugar water got the rats "on sucrose" going: They were >40% more active than their peers - without caffeine as you may notice (Mitsotomi. 2013)

"Compared with sucrose supplementation, NNS supplementation decreased the serum glucose level. Interestingly, compared with the control treatment, NNS supplementation increased the serum insulin level in mice with DIO. In addition, NNS administration influenced glucose tolerance compared to controls.

These observations suggest that NNS supplementation induced insulin resistance by increase of tissue triglyceride, although some NNSs are used to control hyperglycemia.

NNS supplementation increased the WAT leptin level in DIO mice in the present study.

It is possible that the high leptin level was related to body adiposity. Indeed, NNS administration increased the weight of epididymal fat. Thus, it is possible that the high leptin level was related to the influence on body adiposity." (Mitsotomi. 2013)

No, I don't see an explanation, rather a concise summary of the results, that tells us that the addition of plain sugar (33%)  to the drinking water did - as the scientists already expected - lead to a decrease in food intake and an increase in obesity and its nasty unhealthy side effects.

Figure 1: Differences in food intake & body composition of mice with 33% sucrose and 4% erythritol + aspartame in the drinking water (left) expressed relative to control w/ plain water, histology of lover (top) and white adipose tissue (WAT, bottom) of mice with regular (control) and sucrose respectively NNS drinking water (Mitsotomi. 2013)

Much to their own surprise, Mitsotomi et al. did also observe that the group that received the "non-nutritive sweeteners" as a 4% solution (99% of which were erythritol and 1% was aspartame) in their drinking water got exactly as fat (see Figure 1), had a slightly less pronounced increase in adipocyte size, and experienced a similar fatty acid deposition in the liver (NAFLD). And as if that had not been bad enough, there were also pathological changes in the "fat burning brown adipose tissue" (BAT) of the rodents in the NNS group - a physiological deterioration, Mitsotomi et al. observed exclusively in the erythritol + aspartame goup.

Figure 2: Leptin resistance (in WAT) and the major downregulation in UCP-1 (in BAT; both left) are candidates of which the researchers believe that they were responsible for the visible defect (right) in the BAT architecture (Mitsotomi. 2013)

Let's be honest, if you take another look at the BAT histology in Figure 2 (right) even you as a non-expert will see that there is a major difference between the meshed BAT in the rodents on the control diet and the messy BAT of the NNS group, compared to which the brown fat cells of the sugar guzzlers still look very healthy.

Remember: All this mess happened in the absence of an increase in calorie intake

Just to make this clear: This is not the first study to show that artificial sweeteners can have obesogenic effects in rodent models. In contrast to Naismith et al. (1995) and Blundell & Hill (1986) who observed a "pradoxical effects" of  artificial sweeteners on the appetite of their lab rodents, the rats in the study at hand did not overeat, though! They also moved about as much as their peers in the control group and still got fat and sick.

Want to change your "Fat-o-type"? Work out! | read more

In other words, the weight gain the Japanese researchers recorded was neither a result of a mismatch between energy intake and expenditure nor the consequence of a promotional effect of artificial sweeteners on the "sweet tooth" of the rodents. Rather than that it was either brought about or accompanied and promoted by the impairment of the thermogenic capacity of the brown adipose tissue, of which you can argue, based on histologies in Figure 2 that the brown adipose tissue of the furry "subjects" of this study was not just functionally, but also structurally compromised by the ingestion of the non-nutritive sweeteners.

The defective brown adipose tissue (BAT) and the correspondingly reduced UCP 1 expression (UCP increases mitochondrial uncoupling in BAT and burns off energy to increase the body temperature), led to a significant reduction in oxygen consumption. With the latter being a direct marker of fatty acid oxidation the it is difficult to say which came first, the defect in BAT or the onset of obesity. What we can say for sure, though, is that the defective BAT had its share in the rapid weight gain and the corresponding metabolic deterioration.

This could be an erythritol specific effect

Despite the fact that Mitsotomi et al. did not address the potential influence the type of artificial sweetener they used, it is not unlikely that the use of erythritol, of which I have seen dozens of toxicity studies, but no long(er) term feeding studies in a potentially obesogenic diet scenario, could explain the unexpected study outcome. So: "Is this an erythritol specific effect?"

An advantage of erythritol is that it has almost the same sweetness profile as sugar (sucrose), but is 30-40% less sweet (de Cock. 2012)

Without further studies, it is obviously not possible to answer this question, it does however not appear to be unlikely that it were the 99% of erythritol in the commercial erythritol + aspartam mixture the researchers used in their study that's to blame for the obesogenic effects. If this was a general NNS effect, a similar impairment of the brown adipose tissue and corresponding increases in body, muscle and liver fat should after all have been observed in previous studies, already. To my knowledge these studies do not exist - specifically not for aspartame. Without speculating about unpredictable interactions within the two we are thus left with erythritol as out only culprit.

While erythritol has only 60% to 70% of the sweetness of sucrose (comparing 10% solutions in water; this means you need much more of it to achieve a similar sweetness) it has an almost identical sweetness profile (no "off" tastes; cf. de Cock. 2012). This is not the only reason both scientists and the food industry are fond of the low-calorie sweetener. It's rather the combination of its gut- and tooth-friendliness that makes it such a valuable addition to everything sweet. So, despite the fact that it does share the the anti-caries effects with sugar alcohols like xylitol, it is so easy on the gut that its use is not restricted to chewing gums and other "food" items that need only marginal amounts of sweeteners to achieve the desired degree of sweetness. If you want to sweeten larger amounts of foods / beverages, erythritol is thus the sugar alcohol of choice

There is evidence that suggests aspartame reduces insulin - at least during workouts | learn more

Why don't you suspect aspartame? The reason that I am scrutinizing erythritol and not aspartame is simple. Despite or rather because of all the hoopla around potential toxic effects of aspartame it is one of the best researched artificial sweeteners and evidence for obesogenic effects in the absence of increases in food intake are simply non-existent. It may thus make this article more popular among the high number of aspartame haters out there, but it would not help us understand the experimental results,if I started lamenting about how Coke and Pepsi are trying to kill us.

If you take a peak at the Wikipedia article and many scientific papers, you will learn that erythritol has been shown to be mostly (90%) absorbed before the chyme enters the colon (Bernt. 1996). The non-negligible rest of the erythritol  (10%), on the other hand, is said to pass through the short and long intestine, where it is generally believed not to fermented by the gut bacteria (Arrigoni. 2005).

The cholesterol increase scientists observed in response to a high sucralose diet is another of the many yet not fully understood side effects of artifical sweeteners | learn more

In view of a more recent study by Beards et al. (2010) it is however more than questionable that this assumption for which researchers usually cite the in vitro results Arrigoni et al. presented in a 2005 paper is accurate.

Beards and her colleagues from the University of Reading in the UK were after all able to show that erythritol is not simply excreted undigested. Rather than that it is fermented and leads to changes in the bacterial composition and a 6.25x increase in acetate production.

In view of the beneficial effects of SFCA (acetate, propionate and butyrate) on the production of satiety hormones this certainly appears to be a good thing. From studies by Patil et al. we do however know that chronically high SCFA levels and decreased relative bacteroides levels are characteristic of features of human obesity (Patil. 2012; see Angelakis. 2012, as well).

If we include the comparatively short timespan (24h) in the course of which the said changes in the bacterial composition and acetate production in the Beards study occured and assume that this may, after days of constant erythritol exposure have destabilized the previous "ecosystem" in the gut, it does not appear too far fetched to assume that the rodents may have suffered from weight gain and all sorts of metabolic deterioration as a consequence of the potential lactobacilli + Atopobium overgrowth in response to the erythritol in their drinking water.

By now it should no longer appear totally odd to assume that neither artificial sweeteners per se, nor the "bad bad" aspartame are to blame for the "fat effects" the researchers observed in the study at hand, right? I mean, of all the three short chain fatty acids, butyrate, acetate and propionate, acetate is the one with the weakest antiobesogenic effects (Lin. 2012) and in view of the fact that it is preferentially used as a substrate for de novo lipogenesis (=deposition of fat) in colonocytes, hepatocytes and adipocytes (Samuel. 2008), both the fatty liver and the 172% increase in body fat could be explained by the constant influx of acetate from a dysbiotic gut - right?

Suggested Read + Podcast: "he Pro-Insulinogenic Effect of Artificial Sweeteners + Mechanisms & Consequences" | read more

Reason to be afraid - yes or no?"It could be possible...", these are the four little words that would have to go before each and every of the sentences in this conclusion. It could be possible that the interaction of erythritol with the gut microbiome of the rodents drove the accumulation of lipids in the liver, which would in turn have lead to the development of insulin and leptin resistance and could have compromised the function of the "fat burning brown adipose tissue" of our furry friends. The latter could have sped up the weight gain and may eventually explain why the mice in the "non-nutritive sweetener" group were by no means better off than their similarly obese peers in the sucrose group.

Despite the fact that it could also be possible that similar negative effects on the accumulation of liver and whole body fat would be observed in humans, the failure of the brown adipose tissue wouldn't be much of a problem for us, a species that has long lost most of its brown fat stores (learn more). Against that background and in view of the fact that I'd hope that no one of you follows a 60% fat, 20% carbohydrate diet and tries to sooth his / her sweet tooth with 2-3l of erythritol + aspartame sweetened water per day, I'd suggest you refrain from freaking out until we do have more compelling evidence that the stress hormones you will be producing are not more harmful than the few mg of sugar alcohols in your protein bars.

References:

• Angelakis E, Armougom F, Million M, Raoult D. The relationship between gut microbiota and weight gain in humans. Future Microbiol. 2012 Jan;7(1):91-109.
• Arrigoni E, Brouns F, Amadò R. Human gut microbiota does not ferment erythritol. Br J Nutr. 2005 Nov;94(5):643-6. 
• Beards E, Tuohy K, Gibson G. Bacterial, SCFA and gas profiles of a range of food ingredients following in vitro fermentation by human colonic microbiota. Anaerobe. 2010 Aug;16(4):420-5.
• Bernt WO, Borzelleca JF, Flamm G, Munro IC. Erythritol: a review of biological and toxicological studies. Regul Toxicol Pharmacol. 1996 Oct;24(2 Pt 2):S191-7. Review.
• Blundell JE, Hill AJ. Paradoxical effects of an intense sweetener (aspartame) on appetite. Lancet 1986;1(8489):1092–3.
• de Cock P. Erythritol. In "Sweeteners and Sugar Alternatives in Food Technology". 2nd edition. Ed. O'Donnell & Kearsley. Wiley. 2012.
• Lin HV, Frassetto A, Kowalik EJ Jr, Nawrocki AR, Lu MM, Kosinski JR, Hubert JA, Szeto D, Yao X, Forrest G, Marsh DJ. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One. 2012;7(4):e35240. 
• Mitsutomi K et al. Effects of a nonnutritive sweetener on body adiposity and energy metabolism in mice with diet-induced obesity. Metabolism. Oct. 2013 [ahead of print]
• Naismith DJ, Rhodes C. Adjustment in energy intake following the covert removal of sugar from the diet. J Hum Nutr Diet 1995;8:167–75.  
• Patil DP, Dhotre DP, Chavan SG, Sultan A, Jain DS, Lanjekar VB, Gangawani J, Shah PS, Todkar JS, Shah S, Ranade DR, Patole MS, Shouche YS. Molecular analysis of gut microbiota in obesity among Indian individuals. J Biosci. 2012 Sep;37(4):647-57.
• Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, Hammer RE, Williams SC, Crowley J, Yanagisawa M, Gordon JI. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16767-72.
• Sell H, Deshaies Y, Richard D. The brown adipocyte: update on its metabolic role. Int J Biochem Cell Biol 2004;36: 2098–104.