Put the "A" to the "D": Very High Dietary Vitamin A (Retinol, not Beta Carotene!) Content Ameliorates Visceral Adiposity and Improves Insulin Sensitivity in Obesity Prone Rats

What's the first letter in the alphabet? "D"? Well if you look at current research on vitamins, you would think so. Vitamin D is everywhere, vitamin A - if anything - its toxic antagonist. You, as a faithful student of the SuppVersity know better anyway: balance is where the magic lies; and thus you probably won't be surprised that not vitamin D, but vitamin A supplementation improves insulin sensitivity and ameliorates weight gain in a group of obesity prone rats on their favorite fattening stock-diet (Jeyakumar. 2011).

Image 1: Molecular structure of all-trans retinol

In the Journal of Diabetes, Obesity and Metabolism, Jeyakumar et al. published the results of an early 3-months intervention with a vitamin A-enriched diet (129mg vitamin A/kg diet) on visceral obesity and insulin sensitivity in 50days old obesity prone (WNIN/ob strain) rats:

Compared to stock diet-fed obese rats, vitamin A-enriched diet fed-obese rats had reduced body weight gain, visceral adiposity and improved insulin sensitivity as evidenced by decreased fasting plasma insulin and unaltered glucose levels.

Image 2: WNIN obese (A) and normal rat (B)
aged 12 months (image from Reddy. 2009)

The scientists explain their observations by another observation they made. Compared to rats fed the standard stock-diet, the vitamin A group exhibited an increased phosphorylation of the insulin receptor on the soleus muscle (this was the one the scientists used to access muscular insulin sensitivity via measuring gene transcription). By decreasing protein tyrosine phosphatase1B (PTP1B), consequently increasing insulin receptor phosphorylation and thus locally increasing insulin sensitivity, vitamin A had a glucose repartitioning effect, shuttling blood sugar into the muscle instead of having it converted to triglycerides that would consecutively be stored in the form of unhealthy visceral fat depots.

Although news like this usually go unrecognized, this is by far not the first study showing beneficial effect in obesity prevention and even treatment. In a 2005 study published in the Journal of Molecular Endocrinology,  Jeyakumar et al. had already published similar findings, indicating that an increase in dietary Vitamin A intake resulted "in a significant reduction in the adiposity index and retroperitoneal white adipose tissue (RPWAT) weight in obese rats" (Jeyakumar. 2005).

Jeyakumar et al.'s results stand in line with previous largely unrecognized studies on the effects of low vitamin A levels on adipose tissue development about which Ribot et al. (Ribot. 2001) write in the research journal Obesity:

Vitamin A-deficient diet feeding led to a marked increase of adiposity and to a small increase of body weight. Hypertrophy of white adipose tissue depots correlated with enhanced PPAR-gamma-2 expression. Hypertrophy of BAT, in contrast, correlated with a decrease of PPAR-gamma-2 expression that may contribute to the known reduced thermogenic potential of BAT under conditions of vitamin A restriction. Treatment with tRA [trans retinoic acid =vitamin A] triggered a reduction of adiposity and body weight that correlated with a down-regulation of PPAR-gamma-2 expression in all adipose tissues.

And in July 2003 Felipe et al. (Felipe. 2004) submitted a paper to the American Diabetes Association describing how

RA [retinoic acid] administration to normal mice resulted in reduced resistin mRNA levels in brown and white adipose tissues, reduced circulating resistin levels, reduced body weight, and improved glucose tolerance

in mice. While there appear so be a difference in the localization of resistine expression in rodents and humans (in rodents it is mainly released by fat cells, in humans and primates primarily by immune and epithelial cells), the negative effects of high serum levels of resistin on insulin sensitivity appears to be same in both species.

After all, that seems not so bad for a "vitamin", the reputation of which is almost as bad as that of the most fundamental building block of all your hormones: cholesterol. And guess what, foods such as eggs, liver and other organ meats are high in both: Vitamin A (as retinol not beta carotene, which many people have a hard time to convert) and cholesterol! Wouldn't this be a good reason to (re-)introduce these traditional, once highly appreciated foods back into your diet? One or two eggs a day (of course including the yolk), some liver once a week and a lot of sun and outdoor activity to bolster up both your vitamin A and D levels - what more could you ask for?

Exercise OR Calorie Restriction? Is This a Valid Question? Differential Epigenetics of Exercise and Calorie Restriction Suggest Otherwise.

It is beyond me, why the war between proponents of exercise based and calorie reduction based approaches to weight loss are still raging. As a faithful "student" of the SuppVersity, you know that I have always been recommending a combination of both for improved body composition, well-being and general health and was pretty angry, when Gary Taubes claimed in the course of Dr. Oz's ridiculous dissertation on the dangers of low carb diets, that exercise would only stimulate hunger and would thus fail to produce a beneficial effect on weight loss and related health problems (cf. video 1, below). A group of researchers (Karrie. 2011) from the Department of Nutritional Sciences at the University of Texas have now conducted a research study that may well shed some light onto what exactly (in this case this means on a epigenetic level) happens in the course of calorie restriction and/or exercise induced weight loss...

Video 1: Gary Taubes on Dr. Oz' show talking about the futility of exercise.
(Dr. Oz, official homepage)

Karrie, et al. had analyzed adipose gene expression in 48 female diet-induced obesity (DIO) mice in response to 8 weeks of either and ad-libitum fed CONTROL diet, a 30% calorically reduced regimen (CR), a treadmill exercise regimen (EX, with ad-libitum control diet), or  a continuation of the hypercaloric high fat diet (DIO) which made the mice fat in the first place (before the start of the experiment). What the scientists found is quite interesting and - at first sight - appear to rectify Taubes' skepticism with regards to exercise:

Relative to the DIO controls, both CR and EX reduced adiposity by 35–40% and serum leptin levels by 80%, but only CR increased adiponectin and insulin sensitivity.

Meaning visible improvements in terms of body fat were almost identical (cf. fig. 1), while favorable metabolic changes in the areas of  the hunger / satiety, insulin and leptin regulating peptide, as well as insulin sensitivity on the receptor level, occurred only in consequence to a reduction in caloric intake beyond maintenance.

Figure 1: Body weight and composition changes after 6 weeks on different diet / exercise protocols.
(data adapted from Karrie. 2011)

Only a few days ago I reported similar results, i.e. no effects of exercise alone on insulin sensitivity in the Layne study.  Other than Layne et al., whose primary focus was on m-TOR and AMPK responses in muscle tissue, the study at hand provides additional data on the differences in the epigenetic responses to calorie restriction, on the one, and exercise, on the other hand, which may well explain the (disappointing) observations:

Gene expression microarray analysis of visceral white adipose tissue revealed 209 genes responsive to both CR and EX, relative to the DIO group.  However, CR uniquely altered expression of an additional 496 genes, whereas only 20 were uniquely affected by EX.  Of the genes distinctly responsive to CR, 17 related to carbohydrate metabolism and glucose transport, including glucose transporter (GLUT) 4.

What this means is that both exercise, as well as calorie reduction, have 209 gene responses in common (probably responsible for the similar effects on weight loss); yet, additional 496 genes are modulated exclusively by calorie restriction and among these are 17, of which we already know that they are related to carbohydrate metabolism and glucose transport. It is thus suggesting itself to speculate that these genes are the ones, responsible for the beneficial effects on insulin sensitivity, which could not be observed in the exercise only group.

So, was Gary Taubes right, afterall? No. While it may be that exercise alone is not capable to upregulate insulin sensitivity its benefits on overall health, weight loss and above all weight maintenance have been so well established that it would be outrageous to question the advice any sensible nutritional counselor will provide his overweight clients with: Eat healthy (high protein, low / moderate carb, enough fat, whole foods, etc.), and moderately reduce your calorie intake, and begin an exercise regimen that is demanding, but not overcharging. Eventually, when this program has become a habit and the habit becomes a lifestyle, you can be certain that you are never going to be "the biggest loser" again.

There Are Two Sides to Each Coin: Vitamin D Increases Insulin Sensitivity in Obese, Yet Decreases it in Lean Mice

I am probably repeating myself, but I cannot emphasize enough that a common fallacy of medical research is the focus on pathologies. A recent example with respect to the "omnipotency" (that's what the Internet news could make you believe) of vitamin D comes from researchers at George Town University (GU. Press Release).

The scientists were able to replicate the results of previous studies, where high dose vitamin D supplementation had "significantly reduced development of estrogen receptor-positive (ER+) breast cancer", but for estrogen receptor-negative (ER-) breast cancer they found either no effect (lean mice) or even an increased rate of cancerous growth in the group of obese mice.

What's yet even more interesting that a similar contradiction was evident with respect to vitamin D's widely perpetuated beneficial effects on insulin resistance. In the pathologic model of the obese mice, vitamin D @ 15-25k IU per day was in fact able to ameliorate insulin resistance, in the lean, naturally insulin sensitive mice, however, insulin sensitivity was reduced by supplemental vitamin D.

As I've discussed it in the context of the most recent fish oil study (and will probably repeat for other "super nutrients"), in 99.9% of the cases the effect of - especially high dose - supplementation with ostensibly harmless "vitamins" or "nutrients" vary enormously depending on the subjects current nutritional and health status. To derive one-size-fits-it-all recommendations from individual studies and to transfer results obtained from a pathological model without further scientific investigations to a healthy one is careless and may turn out to be very dangerous.

Ironclad Liver Hampers Insulin Sensitivity: Association Between Hepatic Iron Load and Insulin Resistance Discovered

"Insulin resistance", "insulin sensitivity", etc. Type in these key words and find 4.000.000 +1 results on Google. I want to focus on the +1 here and briefly report the results of a study (Haap. 2011) coming from the University of Thübingen, Germany.

Via magnetic resonance gradient echo imaging technique Michael Haap and his colleges assessed the iron load in the livers of of 113 healthy nondiabetic subjects [69 females, 44 males; age 47 ± 1 yr; body mass index (BMI) = 28.9 ± 0.5 kg/m2], who were "at increased risk for type 2 diabetes". Various statistical analysis of their data revealed that:

[Hepatic iron levels] adjusted for age negatively associated with serum ferritin levels (P < 0.0001) and positively associated with IS [insulin resistance] (P = 0.009). In addition, T2* values [indicator of hepatic iron load] associated with LF [liver fat] (P = 0.008) but not with BMI (P = 0.6). In a multivariate model, IS adjusted for gender, age, and BMI was associated with T2* values (P = 0.015). IS adjusted for gender and age was independently associated with LF (P = 0.033) and T2* values (P = 0.004). In a stepwise regression analysis, LF explained 13.5% (P < 0.01) of the variation in IS, and HIL [hepatic iron load] explained an additional 4.1% (P = 0.03).

With 4.1% the contribution of iron to the development of type II diabetes is certainly only one out of a multitude of factors. I would yet still be interested in further information on the interplay of iron, insulin and blood glucose, also because low ferritin levels, which, according to the study, go hand in hand with high hepatic iron loads, have also been implicated in other metabolic disorders such as hypothyroidism, which in and out of itself would further aggravate existing blood sugar and weight issues within the pre-diabetic study population.

Acquittal: Anti-Oxidants do not Blunt the Beneficial Effect of Endurance Training on Insulin Sensitivity!

Regular visitors of the SuppVersity will remember that there has been and still is a controversy about whether or not athletes and average gymrats benefit from antioxidants or whether this may even blunt training induced adaptation effects. Other than a 2009 study by Ristow et al. (Ristow. 2009), a more recent investigation into the effects of antioxidant supplementation (Yfanti. 2011), coming from my northern neighbors from Denmark, did not find any negative effects of antioxidants on the exercise induced rise in insulin sensitivity.

In the study 21 young, healthy men, who received 500 mg vitamin C and 400 IU vitamin E (α-tocopherol) daily, completed a 5-days-a-week supervised intense endurance-training (interval training on Tuesday & Thursday; steady-state cardio on Wednesday & Friday). Insulin response, maximal oxygen consumption (VO_2max), maximal power output (P_max) and body composition (fat mass, fat-free mass) were measured and "muscle biopsies were obtained for determination of the concentration and activity of proteins regulating glucose metabolism". The scientists summarize their results as follows:

Although plasma levels of vitamin C (P < 0.05) and α-tocopherol (P < 0.05) increased markedly in the AO group, insulin-stimulated glucose uptake increased similarly in both the AO (17.2%, P < 0.05) and the PL (18.9%, P < 0.05) group in response to training. VO_2max and P_max also increased similarly in both groups (time effect: P < 0.0001 for both) as well as protein content of GLUT4, hexokinase 2 and total Akt (time effect: P ≤ 0.05 for all).

I don't know if you consider this "good" or "bad" news, but in any case, I suspect you will want to know what happened to the participants body composition (at least I would want). Well, the scientists say, there were no significant pre-post changes and from a statistic point of view, this is unquestionably right. I find it interesting, nevertheless that the average decline in fat mass was somewhat larger in the placebo (-21%)  vs. the anti-oxidant group (-8%); the intra-group differences are however so large that, with the given count of subjects, this is hardly meaningful.

Want to Stay Lean on a High-Fat Diet? Consume Whey Protein Everyday.

Listeners of Carl Lenore's Super Human Radio already know: Dr. Paul Arciero of Skidmore College is going to publish a study the results of which confirm that obese individuals can lose weight and improve markers of metabolic health by just adding a 20g shake of whey protein 3x a day.

While you still have to wait for the detailed results of this study to be published, another group of scientists (Shertzer. 2011) derived similar results from a study on mice. Despite being on a high fat diet, mice who received 100mg of whey protein isolate (WPI) per liter of their drinking water (WPI group) ...

had lower rates of body weight gain and percent body fat and greater lean body mass, although energy consumption was unchanged. These results were consistent with WPI mice having higher basal metabolic rates, respiratory quotients, and hepatic mitochondrial respiration. [...] Livers from WPI mice had significantly fewer hepatic lipid droplet numbers and less deposition of nonpolar lipids. Furthermore, WPI improved glucose tolerance and insulin sensitivity.

While you are waiting for the human study to be published (the SuppVersity will have it first ;-), get yourself some tasty whey protein and listen to Dr Arciero on Super Human Radio!

L-Arginine Biscuits Exhibit Ameliorated Insulin Response. A Viable Alternative for People with Metabolic Syndrome!?

"L-Arginine ameliorates insulin resistance and has beneficial effects on blood pressure", "Fat people love cookies and tend to develop insulin resistance!" - if these two thoughts get together in the head of an Italian scientists, a new product is born: the L-Arginine Biscuit!

In a recent study Emanuela Setola (Setola. 2011) investigated the effect of a biscuit with 6.6g arginine on selected metabolic parameters of 7 healthy subjects. The results are encouraging:

A significant increase of nitric oxide (NOx) and cGMP levels were significantly increased with Biscuit +L-ARG 6.6 g and Powdered L-ARG as compared to Biscuit. AUC NOx and cGMP were significantly increased (p<0.04vs Biscuit). Percentage incremental increase of post-ischemic blood flow significantly increased with Biscuit +L-ARG 6.6 g and Powdered L-ARG, suggesting a functional effect of L-ARG added to the food preparation. Further, at 240 minute mean arterial blood pressure and peripheral vascular resistances slightly declined with Biscuit +L-ARG 6.6 g without reaching a statistical significance. At metabolic levels, the addition of L-ARG to a biscuit decreased insulin levels in the presence of similar glycemic levels, in particular a significant decrease of AUCinsulin during the test with Biscuit +L-ARG 6.6 g in comparison to Biscuit alone was found (p<0.05).

The last result, i.e. the decreased insulin release is probably the most interesting finding of this study and was further investigated by the researcher:

From the results of glucose and insulin, two indices were derived: a Modified Matsuda, (index of whole-body insulin sensitivity) and the Disposition Index (index of the product of insulin sensitivity and first phase insulin secretion). We were able to define that both indices were significantly increased with 6 Biscuits having 6.6 g of L-Arginine while intermediate values were found when 3 Biscuits (3.3 g) were eaten as compared to Biscuits without L-Arginine addition.

After all, I think it would be better to avoid cookies and biscuits completely, but if you just cannot resist, you may well add some arginine to the dough for this years Christmas baking.