Alan Aragons Research Review October 2013 [Back to Contents] Page 1

Copyright October 1st, 2013 by Alan Aragon

Home: www.alanaragon.com/researchreview

Correspondence: aarrsupport@gmail.com

2 The neurophysiology of human appetite.

By Andrew Abbate

6 Interval training in the fed or fasted state improves body composition and muscle oxidative capacity in overweight women. Gillen JB, Percival1 ME, Ludzki1 A, Tarnopolsky MA,

Gibala MJ. Obesity. 2013 Nov;21(11): 2249-55. [Wiley

Online]

7 Metabolic effects of milk protein intake strongly depend on pre-existing metabolic and exercise status. Melnik BC, Schmitz G, John SM, Carrera-Bastos P,

Lindeberg S, CordainL. Nutr Metab (Lond). 2013

Oct;10(1)60: doi:10.1186/1743-7075-10-60 [N&M]

9 Undenatured type II collagen (UC-II(R)) for joint

support: a randomized, double-blind, placebo-controlled study in healthy volunteers. Lugo JP, Saiyed ZM, Lau FC, Molina JP, Pakdaman MN,

Shamie AN, Udani JK. J Int Soc Sports Nutr. 2013 Oct

24;10(1):48. [JISSN]

10 Resistance training reduces fasted- and fed-state

leucine turnover and increases dietary nitrogen retention in previously untrained young men. Moore DR, Del Bel NC, Nizi KI, Hartman JW, Tang JE,

Armstrong D, Phillips SM. J Nutr. 2007 Apr;137(4):985-91.

[PubMed]

12 Vemma a fairy tale of hope, a reality of nope. By Alan Aragon

14 Interview with Eric Helms about his latest peer-

reviewed publication on protein needs of lean, trained athletes in an energy deficit. By Alan Aragon

Alan Aragons Research Review October 2013 [Back to Contents] Page 2

The neurophysiology of human appetite.

By Andrew Abbate

____________________________________________________

We have reached an age where weight control has been turned upside down from an instinctual, highly regulated system, to a

process requiring considerable cognitive effort. - Peters et al., 2002

Embracing the prevailing intersection between anthropology and

physiology that the Paleo Diet/Movement debate continually

inspires, Id like to start from the beginning of human consciousness to introduce this topic. However, since thats a textbook-length undertaking, well substitute breadth for depth and focus on the key component that facilitates human hunger

urges, dopamine. When we come out on the other side well hopefully have at least partially demystified the conscious

barrier between instinct and will, the dueling cerebral forces that

dictate our diet decisions. On an unconscious physiological

level, driving food intake upstream (before) dopamine

fluctuations, we are dealing with the command center of brain activity, where the primary signals originate: The hypothalamus (via regulatory neuropeptides such as leptin, cholecystokinin,

ghrelin, orexin, insulin, neuropeptide Y, and through the sensing

of nutrients, such as glucose, amino acids and fatty acids) is

recognized as the main brain region regulating food intake as it

relates to caloric and nutrition requirements, as Volkow (a remarkable lady whose research is consistently compelling) and

colleagues summarize concisely.1 Note: bolded above are the

two neuropeptides are delve into later on.

Again, my questions here are big, and only half-answered in the

lab because animals dont express cognitive control comparable to that observed in humans. However, the unconscious

physiological similarities mentioned above are still operative, so

this raises questions relevant to our dopaminergic examination:

at what point does eating more become not worth it? How is that

impetus to eat consciously manipulatable? And at what point

does this internal monologue become obsessive, pathological,

disorderly? Now, as much as Id like to explore eating disorders, I am not a mental health professional, so well leave that topic on the shelf. However, as a fitness enthusiast and scientist I can

certainly divulge the fundamental neurological inputs to the

hunger equation, behavioral and biochemical, specifically with

respect to dopamine, so well compress the scope: How does dopamine control the human appetite, how can conscious control

affect hunger, and how do other hormones cooperate with

dopaminergic appetite modulation?

The prefrontal cortex (PFC), behavior and food

The cerebral evolution that guided the course of our primitive

human family tree, the expansion of our brains neocortex, is really that change that made us us. The neocortex is the place

where our conscious thoughts originate and go on to propagate

actions its the processing center that hosts all the extraordinary phenomena of conscious human cognition. If you

look at human brains relative to other species what youll really

see in lower species is analogous to whats underneath all those folded lobes (also known as convolutions) of the neocortex,

down to the bare essentials for life-maintenance in many species

for which there is no substantial cortex. A monkey brain image

is an adequate visual aid to inform an understanding of why

some monkey behaviors are easily anthropomorphized, theres a little neocortex in there.

Image source: http://www.nibb.ac.jp/brish/Gallery/cortexE.html Unrelated: The mouse brain kind of looks like a mouse, which is funny.

Within the neocortex is a still massive subsection called the

prefrontal cortex (PFC), and this is the part that we consult

before reaching for a bite of chocolate cake, and then another,

and then maybe just one more. For a relatively long period in

scientific history we had evidence that the PFC was primarily

responsible for causing impulsive decisions, not preventing

them. But in 1992 Duvauchelle and colleagues, expanding on

some of their previous work, solidified a young hypothesis that

the PFC plays some role in modulating dopamine release in the

reward center of the brain.2 Then in 2008 Del Arco and Mora

expanded on this further by demonstrating that the PFC

modulates reward-seeking behavior charged by dopamine and

environment can play a significant role on how these two brain

regions, PFC and reward center, interact.3 That is, translated to

human practicality, our environment affects our reward-seeking

behavior, and that necessarily includes hunger.

It wasnt until early 2010 that human brain imaging revealed a dynamic interconnectivity between the PFC and other parts of

the brain, showing that, yes, the PFC is responsible for charging

those immediate reward desires, those consecutive bites of cake;

but we now know that it also innervates temperance, that, I want more but its not really worth it internal monologue. Diekhof and Gruber dub this paradigm the desire-reason

dilemma.4 And knowing this, that the same part of the brain that

encourages reward-seeking also suppresses it, will be important

in understanding how this all relates to appetite. When instinct

and will collide, the PFC becomes a battleground, and sudden

food-seeking urges are not always the end result when satiety

and dopamine collide.

Alan Aragons Research Review October 2013 [Back to Contents] Page 3

Dopamine and appetite

A basic understanding of dopamine is necessary to take all of

this in its proper context, and chances are you all already know

that in normal people, elevated brain dopamine enhances mood,

reinforces incentive (i.e. its a motivating hormone: doing something you enjoy causes its release, and dopamine itself

motivates you to keep going), and it facilitates just about every

facet of human behavior from involuntary muscle control to

belief in the supernatural.5 However, when examining

dopamines behavioral effects with respect to appetite, there is a crucial distinction that many scientists have failed to consider

until recently, affect versus motivation, or liking versus

wanting.6

In a laboratory setting, liking and wanting are best separated by

examining palatability, or how the brain responds to different

tastes, because sensory taste input is entirely dissociated from

desire to eat.7 It is therefore possible to measure wanting

independently, isolating the instances when desire is causative.

Wanting food, hunger, is an active pursuit of a known reward, or

as Finlayson et al. reports, Wanting implies a direction, not just a force. Therefore, obtaining a measure of wanting [a specific

food] can be dissociated from a non-specific drive to eat.8 This foundation is important if we want to decouple dopamine and

desire from inter-individual preferences, and it helps us elucidate

specific neurochemical impulses linking dopamine and hunger.

Although I alluded to its role a few paragraphs ago, we still

havent fully addressed the mechanism dopamine exercises in human appetite, the big question: does dopamine increase

hunger or suppress it? The answer lies in the complex,

inextricable overlap between two distinct neurocircuits: the

hypothalamic, unconscious system (as mentioned in the first

paragraph) and the reward system (as also mentioned in the first

paragraph the one largely inhibited by that reason-desire dilemma processed in the PFC).

1,4 What happens when these

circuits malfunction or miscommunicate is presumably what

happens when we compulsively overeat, the dopamine procured

from eating is not enough, so we crave more. When it happens

chronically, a pathological mechanism comes into play, and

thats one reason we can now define obesity as a disease state.

Examining obesity through a pathological lens, this overlap

suggests conditional, repeatedly compromised dopamine

responses in the reward center. Volkow and others elaborate on

this paradigm, describing it as the point at which the expected reward (processed by memory circuits) over-activates the reward

and motivation circuits while inhibiting the cognitive control

circuit.9 To better understand how the cognitive control circuit in the PFC is overpowered, lets restructure that model by first going back to a well-defined role for dopamine, then look at an

image that clears things up a bit better: If dopaminergic function

is normal, dopamine response to food consumption decreases

appetite. That foundation is very well established and,

considering neurosciences nuanced nature, its quite convenient that we can accept it; however, keep in mind that we are hinging

this assumption not on dopamine levels themselves, but rather

dopamine sensitivity, which involves receptor function and

interaction with hormones.

The other side predicts, expectedly, that if dopamine sensitivity

function is compromised, perhaps if dopamine receptors are

fewer in a persons reward center, that person is more susceptible to compulsive eating and obesity.

1,10,11 Now, back

the neurocircuit discrepancy When we talk about a mismatch in the expected reward vis-a-vis the actual reward, we are only focussing on the conscious part of the reward center activity

when reason trumps desire, and this is where the PFC comes

back into play. The expected reward response can only win out

if we are reflecting on a memory; in this case memory of the

reward is received by a different brain region called the

amygdala. The PFC then relays impulses to the reward center in

response to cues initiated by presenting an image, a reminder,

any kind of cue of a desirable object, including food and addictive drugs.

12,13 If the conscious inhibitory response is strong

enough, we resist. What Volkow and her colleagues are saying

when they reference the expected reward overpowering our

conscious control is that the cue (desire) overpowers control

(reason), and this is because of a compromised response to

dopamine in the reward center.1,14,15

If its still unclear, take a look at this image, keeping in mind some of the keywords

mentioned above and acknowledging that the (-) sign connecting

the PFC and the reward center is what happens when reason

takes control and we decide not to eat:

Larger/complete diagram here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124340/figure/F1/

Palatability, that taste preference we established in the first

paragraph, also comes back into the picture when we examine

cued responses processed initially in the amygdala, should we be

afforded the luxury of only remembering and craving the foods

we enjoy.9,16

Stress eating is also a common response in dopamine-compromised people, likely because what were craving in these compulsory instances is more-so dopamine than

nutrition.9 Apparently, dopamine sensitivity plays the critical

role in modulating appetite, which opens the door to

interdisciplinary research perspectives that connect dopamine

insensitivity, the other ways it manifests itself, and obesity risk,

but for the analysis at hand we should acknowledge that

behavioral conditioning is not always effective, and will-power

may not be enough for people predisposed to dopamine

insensitivity to resist hedonic urges. However, for many of us,

Alan Aragons Research Review October 2013 [Back to Contents] Page 4

behavioral conditioning can be the antidote to memory input

from craving cues, preventing that overpowering effect its observable in practice and statistically verifiable in science, but

heres a very important detail that I touched upon in the first paragraph: palatability is not a necessary factor in addictive

eating patterns, because even nonpalatable foods can come to be desired and potentially over-consumed.23

To recap and simplify, food consumption elevates dopamine,

and if the response to that increase in dopamine is not adequate,

appetite can go on uninhibited.9 The type of food, palatability of

food, and macronutrient content of food cannot be isolated

because in pathological over-consumption, palatability is not

necessary, and different cravings for different macronutrient

compositions depends on too many independent variables e.g.

gender, age, hunger state, time of day, and phase of the

menstrual cycle.23,24

You can create animals that do not produce dopamine, said Volkow. They die of starvation. They dont eat. Its as dramatic

as that.26

So, knowing (a) a normal dopamine response to food

consumption will innervate normal satiety and (b) modulating

dopamine systems can affect hunger, we can move on to two of

the upstream players in appetite control, which expectedly work

through dopamine, and now that the arduous information is laid

out, the picture becomes clearer (at least for ghrelin).

Ghrelin, the hunger hormone produced in the stomach, is

released in response to low energy status.25

In 2012, Kern and

colleagues examined the interaction between ghrelin and

dopamine agonism in mice with chemically induced anorexia in short, they discovered that ghrelin increases appetite when its

receptor couples with a specific type of dopamine receptor,

inactivating it.17

Followup research in 2013 further elucidated

ghrelins dopaminergic role in appetite by reporting that direct stimulation of dopamine receptors decreases ghrelins appetite stimulating effects, and removing the ghrelin receptor attenuates

proper dopamine-induced satiety.18

These insights unite Volkow

et al.s research and Avena et al.s research, which take somewhat opposing stances on how dopamine modulates

appetite.9,11,19

All research considered, the key observation we

can extract from ghrelins interaction with dopamine receptors is that dopamine levels themselves do not necessarily reflect

normal dopamine sensitivity, as stressed earlier.

Next, lets take leptin, which would presumably have an opposite effect on dopaminergic appetite stimulus, since we

know that leptin suppresses appetite in healthy adults.1 Notably,

leptin is far more dynamic and difficult to disambiguate than

ghrelin for self-explanatory reasons; its just a more dynamic hormone. For example, we know that leptin decreases reward

response to food intake and cue-induced appetite induction by

decreasing dopaminergic firing rate in the reward center.20

Thats a mouthful, so lets back up. Thinking about food makes us crave food, and leptin makes that craving less intense. This

may seem contradictory, since weve seemingly established that decreased dopamine signaling would lead to increased appetite,

but to clear up the contradiction we need to rehash dopamines quintessential role in motivating reward-seeking behavior.

Dopamine itself motivates reward-seeking, sometimes in the

form of food. Its dopamine sensitivity that were examining when trying to figure out when things go awry, and leptin keeps

that dopamine sensitivity sustained in the reward center while

simultaneously increasing conscious inhibition of food intake by

increasing conscious control in the PFC.21

Leptin also increases

dopamine synthesis in the reward center, possibly to reinforce

normal dopamine sensitivity and therein normal appetite

regulation.21

All-in-all, we can say that leptin closes the

perceived gap between between predicted reward and actual

reward, which is a roundabout way of saying, again, that leptin

reinforces normal dopamine signaling, and compromised leptin

sensitivity can reinforce compulsive eating behavior, an

unfortunate positive feedback loop.1,22

An open-ended question: Are Oreos really more addictive

than cocaine?

At first glance this hypothesis, recently propagated through

mainstream media, seems outrageous, and it is a duplicitous

situation in which science antagonizes logic. Food and drugs, as

we can surmise from understanding how dopamine motivates

reward, are inextricably related in addiction research, and this

paradigm presents a treacherous pattern, comparing exogenous,

pharmacological responses with endogenous, homeostatic

responses clearly there is much more to the story. Gently intertwining logic and science, lets first return to the brain comparison image presented in the introduction to this article,

mouse brain versus human brain. The PFC can inhibit our

reward-seeking urges with food and drugs. Mice cant do this. Mice do not have conscious control over their decisions. So

when we examine compulsive behavior in the reward center,

which mice and humans both have, and take conscious control

completely out of the equation, we lose explanatory power

comparing the two models. For a human model, lets turn back to Dr. Volkow in a lecture summary published in April of 2012:

Many experts dismiss food as an addictive substance because it doesnt lead to most people behaving like addicts compulsively seeking food despite negative consequences. So, the reasoning goes, food cant be as addictive as a drug like crack cocaine. What that fails to recognize, however, is that crack cocaine itself isnt as addictive as is commonly believed. If you look at people who take drugs, the majority are not addicted, Volkow said. Indeed, even for drugs like crack and

heroin, fewer than 20% of users become addicted.26

In contrast, if you look at the proportion of people who are currently obese some 34% of adults over 20 its a significantly larger group. Add in those who are overweight, and fully two-thirds of Americans clearly have significant difficulties controlling their food intake. So, measured by the proportion of those who behave in health-risking ways with each substance, food could actually be considered several times more

addictive than crack.27

This is where I want to leave you to formulate your own

hypotheses about food and addiction. Its a complex, polarized topic in neuroscience and a relevant, emotionally charged topic

in cultural discussions about obesity. From here, I think logic

Alan Aragons Research Review October 2013 [Back to Contents] Page 5

and science can find common ground given what we know about

dopamine and appetite, informing a behavioral approach best

centered on habitual moderation, avoiding overeating itself

rather than avoiding certain foods. A generalization rarely best

suits practical application, but in this case I think its the best we can do: instead of saying, some foods are addictive, we might be better off saying, some behaviors are addictive, where overconsumption is a conditioned, but breakable habit in

otherwise healthy people. ________________________________________________________________________________________________________

Andy Abbate graduated pre-medical from Boston College in 2013 with a BA in Economics, extensive undergraduate coursework in biochemistry and graduate-level coursework in analytical and organic chemistry. He is currently pursuing an MS in Biomedical Science at Drexel University and hopes to continue graduate-level study in biological neuroscience. ________________________________________________________________________________________________________

References

1. Volkow ND, Wang GJ, Baler RD. Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn Sci. 2011 Jan;15(1):37-46. [PubMed]

2. Duvauchelle CL, Levitin M, MacConell LA, Lee LK, Ettenberg A. Opposite effects of prefrontal cortex and nucleus accumbens infusions of flupenthixol on stimulant-induced locomotion and brain stimulation reward. Brain Res. 1992 Mar 27;576(1):104-10. [PubMed]

3. Del Arco A, Mora F. Prefrontal cortex-nucleus accumbens interaction: in vivo modulation by dopamine and glutamate in the prefrontal cortex. Pharmacol Biochem Behav. 2008 Aug;90(2):226-35. [PubMed]

4. Diekhof EK, Gruber O. When desire collides with reason: functional interactions between anteroventral prefrontal cortex and nucleus accumbens underlie the human ability to resist impulsive desires. J Neurosci. 2010 Jan 27;30(4):1488-93. [PubMed]

5. Beninger RJ. The role of dopamine in locomotor activity and learning. Brain Res. 1983 Oct;287(2):173-96. [PubMed]

6. Finlayson G, King N, Blundell JE. Liking vs. wanting food: importance for human appetite control and weight regulation. Neurosci Biobehav Rev. 2007;31(7):987-1002. [PubMed]

7. Berridge KC. Measuring hedonic impact in animals and infants: microstructure of affective taste reactivity patterns. Neurosci Biobehav Rev. 2000 Mar;24(2):173-98. [PubMed]

8. Finlayson G, King N, Blundell JE. Is it possible to dissociate 'liking' and 'wanting' for foods in humans? A novel experimental procedure. Physiol Behav. 2007 Jan 30;90(1):36-42. [PubMed]

9. Volkow ND, Wang GJ, Fowler JS, Telang F. Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology. Philos Trans R Soc Lond B Biol Sci. 2008 Oct 12;363(1507):3191-200. [PubMed]

10. Volkow ND, Wang GJ, Maynard L, Jayne M, Fowler JS, Zhu W, Logan J, Gatley SJ, Ding YS, Wong C, Pappas N. Brain dopamine is associated with eating behaviors in humans. Int J Eat Disord. 2003 Mar;33(2):136-42. [PubMed]

11. Avena NM, Rada P, Hoebel BG. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev. 2008;32(1):20-39. [PubMed]

12. Roesch MR, Olson CR. Impact of expected reward on neuronal activity in prefrontal cortex, frontal and supplementary eye fields and premotor cortex. J Neurophysiol. 2003 Sep;90(3):1766-89. [PubMed]

13. Wilson SJ, Sayette MA, Fiez JA. Prefrontal responses to drug cues: a neurocognitive analysis. Nat Neurosci. 2004 Mar;7(3):211-4. [PubMed]

14. Petrovich GD, Ross CA, Holland PC, Gallagher M. edial prefrontal cortex is necessary for an appetitive contextual conditioned stimulus to promote eating in sated rats. J Neurosci. 2007 Jun 13;27(24):6436-41. [PubMed]

15. Volkow ND, Fowler JS, Wang GJ, Goldstein RZ. Role of dopamine, the frontal cortex and memory circuits in drug addiction: insight from imaging studies. Neurobiol Learn Mem. 2002 Nov;78(3):610-24. [PubMed]

16. Mark GP, Smith SE, Rada PV, Hoebel BG. An appetitively conditioned taste elicits a preferential increase in mesolimbic dopamine release. Pharmacol Biochem Behav. 1994 Jul;48(3):651-60. [PubMed]

17. Kern A, Albarran-Zeckler R, Walsh HE, Smith RG. Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron. 2012 Jan 26;73(2):317-32. [PubMed]

18. Romero-Pic A, Novelle MG, Folgueira C, Lpez M, Nogueiras R, Diguez C. Central manipulation of dopamine receptors attenuates the orexigenic action of ghrelin. Psychopharmacology (Berl). 2013 Sep;229(2):275-83. [PubMed]

19. Abizaid A. Ghrelin and dopamine: new insights on the peripheral regulation of appetite. J Neuroendocrinol. 2009 Sep;21(9):787-93. [PubMed]

20. Scarpace PJ, Zhang Y. Leptin resistance: a prediposing factor for diet-induced obesity. Am J Physiol Regul Integr Comp Physiol. 2009 Mar;296(3):R493-500. [PubMed]

21. Fulton S, Pissios P, Manchon RP, Stiles L, Frank L, Pothos EN, Maratos-Flier E, Flier JS. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron. 2006 Sep 21;51(6):811-22. [PubMed]

22. Farooqi IS, Bullmore E, Keogh J, Gillard J, O'Rahilly S, Fletcher PC. Leptin regulates striatal regions and human eating behavior. Science. 2007 Sep 7;317(5843):1355. [PubMed]

23. White MA, Whisenhunt BL, Williamson DA, Greenway FL, Netemeyer RG. Development and validation of the food-craving inventory. Obes Res. 2002 Feb;10(2):107-14. [PubMed]

24. Haddock CK, Dill PL. The Effects of Food on Mood and Behavior: Implications for the Addictions Model of Obesity and Eating Disorders. Drugs & Society 01/1999; 15:17-47. DOI:10.1300/J023v15n01_02 [T & F Online]

25. Maier C, Schaller G, Buranyi B, Nowotny P, Geyer G, Wolzt M, Luger A. The cholinergic system controls ghrelin release and ghrelin-induced growth hormone release in humans. J Clin Endocrinol Metab. 2004 Sep;89(9):4729-33. [PubMed]

26. National Survey on Drug Use and Health. Substance Use and Dependence Following Initiation of Alcohol or Illicit Drug Use. March 27, 2008. [NSDUH]

27. Szalavitz M. The Cholinergic System Controls Ghrelin Release and Ghrelin-Induced Growth Hormone Release in Humans. April 05, 2012 [TIME Health & Family]

Alan Aragons Research Review October 2013 [Back to Contents] Page 6

Interval training in the fed or fasted state improves body composition and muscle oxidative capacity in overweight women.

Gillen JB, Percival1 ME, Ludzki1 A, Tarnopolsky MA, Gibala

MJ. Obesity. 2013 Nov;21(11): 2249-55. [Wiley Online]

OBJECTIVE: To investigate the effects of low-volume high-

intensity interval training (HIT) performed in thefasted (FAST)

versus fed (FED) state on body composition, muscle oxidative

capacity, and glycemiccontrol in overweight/obese women.

METHODS: Sixteen women (27 8 years, BMI: 29 6 kg/m2,

VO2peak: 28 3 ml/kg/min) were assigned to either FAST or

FED (n = 8 each) and performed 18 sessions of HIT (10 60-s

cycling efforts at 90% maximal heart rate, 60-s recovery) over 6 weeks. RESULTS: There was no significant difference

between FAST and FED for any measured variable. Body mass

was unchanged following training; however, dual energy X-ray

absorptiometry revealed lower percent fat in abdominal and leg

regions as well as the whole body level (main effects for time, P

0.05). Fat-free mass increased in leg and gynoid regions (P 0.05). Resting muscle biopsies revealed a training-induced

increase in mitochondrial capacity as evidenced by increased

maximal activities of citrate synthase and -hydroxyacyl-CoA dehydrogenase (P 0.05). There was no change in insulin sensitivity, although change in insulin area under the curve was

correlated with change in abdominal percent fat (r = 0.54, P 0.05). CONCLUSIONS: Short-term low-volume HIT is a time-

efficient strategy to improve body composition and muscle

oxidative capacity in overweight/obese women, but fed- versus

fasted-state training does not alter this response.

SPONSORSHIP: Natural Science and Engineering Research

Council (NSERC) operating grant and McMaster University

internally sponsored research grant to MJG.

Study strengths

This study is conceptually strong since it investigates a question

thats been hotly debated for what seems to be over a decade now. The interesting twist is the use of high-intensity interval

training (HIIT) instead of low-intensity steady-state (LISS),

which is a welcome variation on the theme since HIIT better

economizes training duration. This is the first study to ever

examine the effect of fed versus fasted HIIT on glucose control,

muscle metabolic capacity measured via citrate synthase (CS)

and -hydroxyacyl-CoA (-HAD) activity, and body composition. Training sessions were supervised. Pre-training breakfasts were

standardized & duplicated on testing day. Maintenance of

normal diet habits was confirmed with 3-day diet records at the 3

& 6-week points via nutritional software. Body composition was

assessed via DXA.

Study limitations

The authors acknowledged two limitations the absence of a control group doing conventional endurance-type training, and

the inability to assess sex-based differences (the sample was all

women). I would add to this that the results are not necessarily

applicable to lean/athletic subjects looking to push the limits

since the subjects used were untrained/obese. Another limitation

was the absence of resistance training. Cardio-only programs are

not optimal, but this limitation is somewhat of a necessarily evil

given the nature of this investigation, which is focused on

comparing feeding effects on a single training mode. It also

would have been useful if the authors reported the macronutrient

intakes of the subjects in each group, since after all, they went

through the trouble of software-analyzing diet records, and this

information would have been useful. A final limitation is that the

results might be limited to the training protocol used, which was

three sessions per week consisting of 10 cycles of 60 seconds at

90% of maximal heart rate alternated with 60 seconds of

recovery at 50 W.

Comment/application

The main finding was a lack of significant difference between

conditions in any of the parameters assessed, regardless of

differences in nutritional intake around training sessions. As

seen above, this included a lack of significant difference in body

composition change (in addition to a lack of differences in

glucose control & mitochondrial capacity). Interestingly, this

was the first study to ever observe a gain in fat-free mass as a

result of low-volume HIIT in women.

Something that might be easy to overlook (but that the authors

diligently acknowledged), was the trend toward a greater lean

mass increase in the fed group (P = 0.07, as shown above).

Although this greater increase in lean mass did not reach

statistical significance, it conjures the question of whether a

significant difference would become apparent in a trial lasting

longer than 6 weeks. It would also be interesting to see how

changes in lean mass would be influenced by a concurrent

progressive resistance training program. With perhaps a single

exception,1 the research that actually assess body composition

shows that HIIT is effective for reducing fat mass.2 However, the

present study additionally indicates the lean mass-increasing

potential of HIIT especially in the fed state (though not seen here to a statistically significant degree). Its important to note that the recomp effect (decrease in fat mass and increase in lean mass) seen in the present study is not too surprising since

the subjects were overweight/obese and untrained.

Alan Aragons Research Review October 2013 [Back to Contents] Page 7

Metabolic effects of milk protein intake strongly depend on pre-existing metabolic and exercise status.

Melnik BC, Schmitz G, John SM, Carrera-Bastos P, Lindeberg

S, CordainL. Nutr Metab (Lond). 2013 Oct;10(1)60:

doi:10.1186/1743-7075-10-60 [N&M]

ABSTRACT: Milk protein intake has recently been suggested

to improve metabolic health. This Perspective provides evidence

that metabolic effects of milk protein intake have to be regarded

in the context of the individuals pre-existing metabolic and exercise status. Milk proteins provide abundant branched-chain

amino acids (BCAAs) and glutamine. Plasma BCAAs and

glutamine are increased in obesity and insulin resistance, but

decrease after gastric bypass surgery resulting in weight loss and

improved insulin sensitivity. Milk protein consumption results in

postprandial hyperinsulinemia in obese subjects, increases body

weight of overweight adolescents and may thus deteriorate pre-

existing metabolic disturbances of obese, insulin resistant

individuals. SPONSORSHIP: None listed.

Commentary

Since this paper is a narrative review instead of a controlled

experiment, its simply not conducive for critique based on methodological strengths and limitations. Instead, Ill do some general commentary, focusing on the assertions of the paper that

are not adequately supported by scientific evidence. Before I get

into that, heres some background on the present review. Melnik et al wrote this paper in response to a recent paper by McGregor

and Poppitt, who reviewed a substantive body of literature on

milk protein showing a diversity of favorable effects on

metabolic health and body composition.3 Melnik et al felt it was

warranted to challenge these views and throw in some

cautionary notes that were purportedly overlooked. What

follows are boxed excerpts alternated with my commentary.

The above excerpt appears in the introductory paragraph of the

paper, and it encompasses several dubious presumptions. First of

all, its painting a guilt-by-association picture. Clearly, its fallacious to assume a causal relationship between the presence

of dairy in the diet and the so-called diseases of civilization. In

addition, they make a false distinction between structural

proteins and signaling proteins since the examples they use both

contain each type. Fish and meat are both rich sources of

BCAAs, which the authors rail against throughout their paper.

They call milk an abundant provider of fast dietary proteins. However, its relatively elementary knowledge that 80% of milk protein is the slowly digested/absorbed casein, with the faster

protein (whey) rounding out the minority. Nevertheless, recent

research directly refutes the fear of fast milk proteins being agents of glucose control impairment/insulin resistance. Ellis

and Dhaliwal compared the 12-week effects of either whey,

casein, or glucose supplementation in overweight and obese

subjects and found whey to actually improve fasting lipids and

insulin levels.4 Finally, the papers they reference in support of

the claim that Palaeolithic dairy-free diets exhibit lower insulin levels with improved insulin sensitivity were all speculative pieces rooted in nothing more than hypothesis. It would be

impossible to support such a claim with objective, controlled

data yet the authors boldly point the finger at dairy consumption as a key factor in the diseases of civilization. This

is quite a bodacious leap of logic.

The concern surrounding prolonged postprandial

hyperinsulinemia without significant changes in in blood glucose

levels is immaterial considering that this was the result of

ingesting isolated leucine (or in one of the studies, leucine plus

glucose). Ironically, one of the studies Melnik et al cited simply

did not support their disdain for BCAA. To quote Hoppe et al,5

In the milk-group, fasting s-insulin concentrations doubled, which caused the insulin resistance to increase similarly. In the meat-group, there was no increase in insulin and insulin resistance. As the BCAAs increased similarly in both groups, stimulation of insulin secretion through BCAAs is not supported.

Note that the latter results were seen in a 7-day study on 8 year-

old children, so they should be viewed in a highly preliminary

light.

Reference #37 in Melnik et als paper is cited twice in attempt to support the claim that milk protein consumption is a special

agent of increased fasting insulin levels and weight gain. What

they fail to mention is that this was a 12-week study involving

the addition of 1 liter (32 oz or 4 cups) of milk-based beverage

to the normal/habitual diet of overweight adolescent subjects.6

One of the treatments was a liter of skim milk, which contains

roughly 350 kcal. The other 2 treatments (whey & casein-based

beverages) had similar kcal content. This put the subjects in the

experimental groups under a sustained hypercaloric balance, so

weight gain should be an obvious outcome compared to the

control condition which was water.

Melnik et al close their paper by blaming milk protein for

prostate cancer via mTORC1 activation.7 They also cite

Palaeolithic, physically active hunter-gatherers consumed structural proteins like fish and meat. In contrast, modern Neolithic humans have mutated into physically inactive individuals, who particularly consume signalling proteins from milk providing abundant fast dietary proteins leading to high plasma BCAA and glutamine levels [15]. Palaeolithic dairy-free diets exhibit lower insulin levels with improved insulin sensitivity protecting against the development of diseases of civilization [16-19].

In obese subjects, oral administration of leucine induces exaggerated and prolonged postprandial hyperinsulinemia without significant changes of blood glucose levels [34-36]. In children, daily intake of 53 g milk protein, but not of 53 g meat induced hyperinsulinemia and insulin resistance under fasting conditions [10].

In overweight adolescents daily intake of 35 g whey protein or casein significantly increased fasting plasma insulin levels [37]. Thus, there is substantial evidence that increased milk protein consumption in obese individuals persistently over-stimulates insulin secretion, which in the long term may promote early onset of -cell apoptosis. [...] Supplementation of milk protein (either 35 g whey protein, skim milk protein, or casein) to overweight adolescents further increased body weight [37].

Alan Aragons Research Review October 2013 [Back to Contents] Page 8

epidemiological data to support a link to prostate cancer and

high intakes of dairy.8,9

In support of this concern, Tseng et al

proposed that dairy consumption can potentially raise prostate

cancer risk through a calcium-mediated pathway.10

Newmark

and Heaney have countered that the phosphate content may be a

more likely source of prostate cancer risk from high dietary

intake of dairy products.11

However, keep in mind that these

data are observational, and thus speculative in nature.

In stark contrast to the hypotheses of Melnik et al, a role for milk

proteins in cancer prevention (yes, bold) has been proposed by

Parodi as follows:12

Various experiments showed that tumour prevention by dietary whey protein was accompanied by increased glutathione levels in serum and tissues as well as enhanced splenic lymphocyte proliferation, phagocytosis and natural killer, T helper and cytotoxic T cell activity. Whey protein components, beta-lactoglobulin, alpha-lactalbumin and serum albumin were studied infrequently, but results suggest they have anticancer potential.

In addition to the latter research, Huncharek et al pooled the data

from 45 observational studies using a meta-analytic method, and

found that observational studies do not support an association

between dairy product use and an increased risk of prostate

cancer.13

As the trusty clich goes, correlation does not automatically

equal causation. There is evidence of an inverse association

between dairy intake and certain cancers. In a recent review of

the evidence, Lampe states the following:14

For most cancers, associations between cancer risk and intake of milk and dairy products have been examined only in a small number of cohort studies, and data are inconsistent or lacking. Meta-analyses of cohort data available to date support an inverse association between milk intake and risk of colorectal and bladder cancer and a positive association between diets high in calcium and risk of prostate cancer.

By the same logic Melnik et al employ to blame milk protein for

prostate cancer, it can also be said that milk protein will also

save you from colorectal and bladder cancer. But obviously, this

claim cannot be made based on observational data. Nevertheless,

the possibility of a high dairy intake being a causal factor in the

pathogenesis of prostate cancer cannot be completely dismissed.

At the same time, it cannot be presumed true, due to the lack of

controlled data supporting this hypothesis.

Melnik et als claim that milk protein is the specific culprit behind prostate cancer must therefore be viewed with caution, as

should the very nature of epidemiological outcomes. An

example of what I consider to be a highly questionable

association thats been replicated in the literature is red meat consumption raising the risk for type 2 diabetes (T2D).

15,16 There

could be a slew of unaccounted variables at play that

erroneously indict red meat. Similar implausibility is evident in a

recent prospective cohort study by de Koning et al, who found

that red meat intake within a low-carbohydrate diet was

associated with increased risk for T2D.17

Another of my favorite

face-palm outcomes is the daily consumption of eggs increasing

the risk for T2D.18

These biologically implausible outcomes

illustrate how observational data must be viewed as merely

hypothesis-generating, rather than conclusive or confirmative.

Naturally, I was curious about the Dairy Councils stance on the prostate cancer issue, so I dug up what they had to say:

18

Results of epidemiological studies of dairy foods or dairy food nutrients such as calcium and prostate cancer are inconsistent, with studies showing either a positive (35-39) or no (40-44) association. [...] Also, an increased risk for prostate cancer is associated with calcium intakes (>1,500 mg/day) exceeding current dietary recommendations (45,47-49).

On the note of foods and cancer risk, a very amusing satirical

piece was recently run in the American Journal of Clinical

Nutrition. Schoenfeld and Ioannidis conducted a systematic

review of 50 common ingredients in cookbooks and found that

80% of them were associated with cancer risk or benefit in the

epidemiological literature.19

The authors take-home message is that epidemiology is a messy soup of variables that must be

viewed skeptically. This quote captures the essence of their

satire and undercurrent of truth:

Given that we examined the effects most specific to individual ingredients, we did not examine more complex analyses involving nutritional pathways, biochemical nutritional measurements, and metabolites or combinations of ingredients. However, we hypothesize that similar patterns of research conduct and reporting also apply to these other aspects of nutritional epidemiology.

Alan Aragons Research Review October 2013 [Back to Contents] Page 9

Undenatured type II collagen (UC-II(R)) for joint support: a randomized, double-blind, placebo-controlled study in healthy volunteers.

Lugo JP, Saiyed ZM, Lau FC, Molina JP, Pakdaman MN,

Shamie AN, Udani JK. J Int Soc Sports Nutr. 2013 Oct

24;10(1):48. [JISSN]

BACKGROUND: UC-II contains a patented form of

undenatured type II collagen derived from chicken sternum.

Previous preclinical and clinical studies support the safety and

efficacy of UC-II in modulating joint discomfort in osteoarthritis

and rheumatoid arthritis. The purpose of this study was to assess

the efficacy and tolerability of UC-II in moderating joint

function and joint pain due to strenuous exercise in healthy

subjects. METHODS: This randomized, double-blind, placebo-

controlled study was conducted in healthy subjects who had no

prior history of arthritic disease or joint pain at rest but

experienced joint discomfort with physical activity. Fifty-five

subjects, who reported knee pain after participating in a

standardized stepmill performance test, were randomized to the

placebo (n = 28) or the UC-II (40 mg daily, n = 27) cohort for

120 days. Joint function was assessed by measuring knee flexion

and knee extension as well as time to experiencing and

recovering from joint pain following strenuous stepmill exertion.

RESULTS: After 120 days of supplementation, subjects in the

UC-II group exhibited a statistically significant improvement in

average knee extension compared to placebo (81.0 +/- 1.3o vs

74.0 +/- 2.2o; p = 0.011) and to baseline (81.0 +/- 1.3o vs 73.2

+/- 1.9o; p = 0.002). The UC-II cohort also demonstrated a

statistically significant change in average knee extension at day

90 (78.8 +/- 1.9o vs 73.2 +/- 1.9o; p = 0.045) versus baseline. No

significant change in knee extension was observed in the placebo

group at any time. It was also noted that the UC-II group

exercised longer before experiencing any initial joint discomfort

at day 120 (2.8 +/- 0.5 min, p = 0.019), compared to baseline

(1.4 +/- 0.2 min). By contrast, no significant changes were seen

in the placebo group. No product related adverse events were

observed during the study. At study conclusion, five individuals

in the UC-II cohort reported no pain during or after the stepmill

protocol (p = 0.031, within visit) as compared to one subject in

the placebo group. CONCLUSIONS: Daily supplementation

with 40 mg of UC-II was well tolerated and led to improved

knee joint extension in healthy subjects. UC-II also

demonstrated the potential to lengthen the period of pain free

strenuous exertion and alleviate the joint pain that occasionally

arises from such activities. SPONSORSHIP: InterHealth

Nutraceuticals, Inc., Benicia, California.

Study strengths

This study presents novel findings since its the first to examine the effect of undenatured type 2 collagen (UC-II) in subjects

who experienced knee pain after strenuous physical exertion but

had no prior history of arthritic disease. Subjects, clinical staff,

and data analysis/management staff remained blinded as to who

received treatment or placebo. I would also add that non-

pharmacological (natural) therapies for managing pain related to osteoarthritis and rheumatoid arthritis are important, given the

prevalence of both diseases. If consistently demonstrated as

effective, its fair to speculate that UC-IIs availability & affordability would be reasonable since its not some exotic or scarce material (its derived from chicken sternum).

Study limitations

The authors diligently acknowledge two limitations. First, the

time to onset of initial pain was limited to a 10-minute interval,

which casts some doubt about the clinical importance of such a

short assessment period. Secondly, its possible that the subjects might have early signs of arthritis that do not meet formal

diagnostic criteria (thereby reducing the validity of the claim that

UC-II is effective for those with no prior history of arthritic

disease). This possibility also points to the potential limitation of

not directly assessing inflammatory biomarkers, which could

provide a more objective set of data on the effects of UC-II.

Comment/application

The main findings were that UC-II significantly improved knee

range of motion (extension), as well as increased time of

exercising before experiencing joint discomfort, as depicted

above. The authors thus concluded:

UC-II is a unique ingredient that supports healthy joints. Previous studies have focused on the efficacy of this ingredient in OA subjects. By including healthy subjects in this study, and using non-disease endpoints as a measure of efficacy, it is believed that the benefits that derive from UC-II usage now extends to include healthy individuals.

Regarding safety, three studies aside from the present one are

cited indicating the absence of adverse effects in humans and

animals in trials lasting up to 90 days.20-22

Particularly

impressive is a 24-week multicenter intervention by Wei et al

who found that sternally derived type 2 chicken collagen (likely

very similar to that used in the present study) significantly

improved symptoms of rheumatoid arthritis at a daily dose of 0.1

mg (the present study used 40 mg).23

Although it was not as

potent as the comparator (the drug methotrexate), it had a lower

incidence of adverse effects. The evidence overall suggests that

UC-II is a promising non-drug therapy option for those suffering

from rheumatoid arthritis or osteoarthritis and possibly for those with joint pain that does not fit standard diagnostics.

Alan Aragons Research Review October 2013 [Back to Contents] Page 10

Resistance training reduces fasted- and fed-state leucine turnover and increases dietary nitrogen retention in previously untrained young men.

Moore DR, Del Bel NC, Nizi KI, Hartman JW, Tang JE, Armstrong D, Phillips SM. J Nutr. 2007 Apr;137(4):985-91. [PubMed]

PURPOSE: We aimed to determine the impact of intense resistance training, designed to increase lean body mass (LBM), on both fasted and fed whole body protein kinetics in untrained young men. METHODS: Twelve healthy males (22 +/- 2 y of age; BMI, 24.3 +/- 2.4 kg/m(2)) participated in a 12-wk (5-d/wk) resistance training program. Before and after training, a primed constant infusion of [1-(13)C]leucine was used to measure whole body leucine turnover, protein breakdown, and nonoxidative leucine disposal in the fasted and fed states. Participants were studied during 5-d controlled diet periods that provided a moderate protein intake [1.4 g/(kg body wt/d)]. We estimated protein turnover and nitrogen balance. RESULTS: Training increased LBM (61.6 +/- 6.9 vs. 64.8 +/- 6.7 kg, P < 0.05). After training, whole body leucine turnover was reduced (P < 0.01) in both fasted (167 +/- 18 vs. 152 +/- 17) and fed (197 +/- 23 vs. 178 +/- 21) states [all values micromol/(kg LBM . h)]. Training-induced decreases (P < 0.01) in protein breakdown occurred in the fasted (165 +/- 18 vs. 144 +/- 17) and fed (111 +/- 23 vs. 93 +/- 20) states. Following training, nonoxidative leucine disposal was similarly reduced (P < 0.01) in the fasted (144 +/- 18 vs. 126 +/- 18) and fed (151 +/- 20 vs. 133 +/- 19) states. Nitrogen balance was more positive after training (13.7 +/- 8.1 vs. 33.4 +/- 12.5 g/(kg LBM/d), P < 0.01) indicating an increased retention of dietary nitrogen. CONCLUSIONS: The increase in nitrogen balance after training demonstrates a more efficient utilization of dietary nitrogen, suggesting that protein requirements for novice weightlifters are not elevated. SPONSORSHIP: Supported by a grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada (S.M.P.).

Study strengths

This study is innovative since it was the first to examine the

effect of resistance training on whole-body protein metabolism

(via leucine kinetics) in the fasted and fed state. By default, it

investigated whether protein intake at 1.4 g/kg is necessary or

beneficial under resistance training conditions, but the

interesting aspect was seeing whether the physiological demand

for this level of intake increases or decreases over time. DXA

was used to assess body composition. The progressive resistance

training sessions were supervised by research personnel. Three-

day diet records were software-analyzed at the start, midpoint,

and end of the study. Dietary control overall was tight.

Study limitations

The authors acknowledge that measuring leucine turnover

cannot assess tissue-specific changes (i.e., skeletal muscle

protein flux); it can only estimate changes at the whole-body

level. However, they also measured changes in LBM and muscle

fiber cross-sectional area, so this minimized the assessment gaps

that mere leucine kinetics might leave. I would add to this that

nitrogen balance (another whole-body index of protein turnover)

has limited accuracy in representing actual muscle protein status;

it typically over-estimates it. Furthermore, the results seen in this

study could be limited to hypercaloric conditions in untrained

subjects. A final limitation would be the lack of a comparison

group consuming protein at a higher-end dose that might

optimize the rate of muscular gains (~1.8 g/kg). It would have

been interesting to see whether this dose could have exceeded

the LBM gains seen with 1.4 g/kg, despite hypercaloric

conditions.

Comment/application

The main findings were three-fold. First the expected set of

outcomes: progressive resistance training caused a significant

increase in LBM, muscle fiber hypertrophy, and maximal

strength. Secondly, resistance training caused a reduction in both

postabsorptive (fasting) and postprandial (fed) protein turnover

after resistance training in young men and are the result of

decreases in whole-body protein breakdown and protein

synthesis, as indicated by leucine kinetics. Finally, as shown in

the table above, nitrogen balance was more positive after

training compared with before training.

The present study supports and extends the findings of a

previous study from the same lab. Hartman et al observed

similar outcomes (increase in strength, LBM, and net protein

balance, and nitrogen balance).24

The training-induced reduction

in protein turnover and higher net protein balance combined with

increased nitrogen balance led them to a similar conclusion as

the authors of the present study that dietary protein requirements decrease as a result of resistance training.

Its notable that not all previous work agrees with the present study. Others have observed increased leucine turnover as a

result of resistance training, particularly in older subjects.25

Its tempting to conclude that, based on the present studys results, resistance training decreases protein requirements. However, its important to consider that lean, trained athletes in hypocaloric

conditions have benefited from substantially higher intakes than

1.4 g/kg.26

Furthermore, its likely that rigorous, periodized training programs (especially ones that include over-reaching

phases) can to impose higher protein demands. Combining high-

volume, periodized, progressive training with hypocaloric

conditions is not likely to yield the increase in nitrogen retention

and reduction in leucine turnover seen in the present study.

Alan Aragons Research Review October 2013 [Back to Contents] Page 11

\

1. Macpherson RE, Hazell TJ, Olver TD, Paterson DH, Lemon PW. Run sprint interval training improves aerobic performance

but not maximal cardiac output. Med Sci Sports Exerc. 2011

Jan;43(1):115-22. [PubMed]

2. Boutcher SH. High-intensity intermittent exercise and fat loss. J Obes. 2011;2011:868305. [PubMed]

3. McGregor RA, Poppitt SD. Milk protein for improved metabolic health: a review of the evidence. Nutr Metab (Lond).

2013 Jul 3;10(1):46. [PubMed]

4. Pal S, Ellis V, Dhaliwal S. Effects of whey protein isolate on body composition, lipids, insulin and glucose in overweight

and obese individuals. Br J Nutr. 2010 Sep;104(5):716-23.

[PubMed]

5. Hoppe C, Mlgaard C, Vaag A, Barkholt V, Michaelsen KF. High intakes of milk, but not meat, increase s-insulin and

insulin resistance in 8-year-old boys. Eur J Clin Nutr. 2005

Mar;59(3):393-8. [PubMed]

6. Arnberg K, Mlgaard C, Michaelsen KF, Jensen SM, Trolle E, Larnkjr A. Skim milk, whey, and casein increase body weight

and whey and casein increase the plasma C-peptide

concentration in overweight adolescents. J Nutr. 2012

Dec;142(12):2083-90. [PubMed]

7. Melnik BC, John SM, Carrera-Bastos P, Cordain L. The impact of cow's milk-mediated mTORC1-signaling in the initiation

and progression of prostate cancer. Nutr Metab (Lond). 2012

Aug 14;9(1):74. [PubMed]

8. Allen NE, Key TJ, Appleby PN, Travis RC, Roddam AW, Tjnneland A, Johnsen NF, Overvad K, Linseisen J, Rohrmann

S, Boeing H, Pischon T, Bueno-de-Mesquita HB, Kiemeney L,

Tagliabue G, Palli D, Vineis P, Tumino R, Trichopoulou A,

Kassapa C, Trichopoulos D, Ardanaz E, Larraaga N, Tormo

MJ, Gonzlez CA, Quirs JR, Snchez MJ, Bingham S, Khaw

KT, Manjer J, Berglund G, Stattin P, Hallmans G, Slimani N,

Ferrari P, Rinaldi S, Riboli E. Animal foods, protein, calcium

and prostate cancer risk: the European Prospective

Investigation into Cancer and Nutrition. Br J Cancer. 2008 May

6;98(9):1574-81. [PubMed]

9. Song Y, Chavarro JE, Cao Y, Qiu W, Mucci L, Sesso HD, Stampfer MJ, Giovannucci E, Pollak M, Liu S, Ma J. Whole

milk intake is associated with prostate cancer-specific mortality

among U.S. male physicians. J Nutr. 2013 Feb;143(2):189-96.

[PubMed]

10. Tseng M, Breslow RA, Graubard BI, Ziegler RG. Dairy, calcium, and vitamin D intakes and prostate cancer risk in the

National Health and Nutrition Examination Epidemiologic

Follow-up Study cohort. Am J Clin Nutr. 2005

May;81(5):1147-54. [PubMed]

11. Newmark HL, Heaney RP. Dairy products and prostate cancer risk. Nutr Cancer. 2010;62(3):297-9. [PubMed]

12. Parodi PW. role for milk proteins and their peptides in cancer prevention. Curr Pharm Des. 2007;13(8):813-28. [PubMed]

13. Huncharek M, Muscat J, Kupelnick. Dairy products, dietary calcium and vitamin D intake as risk factors for prostate

cancer: a meta-analysis of 26,769 cases from 45 observational

studies. Nutr Cancer. 2008;60(4):421-41. [PubMed]

14. Lampe JW. Dairy products and cancer. J Am Coll Nutr. 2011 Oct;30(5 Suppl 1):464S-70S. [PubMed]

15. Pan A, Sun Q, Bernstein AM, Schulze MB, Manson JE, Willett WC, Hu FB. Red meat consumption and risk of type 2

diabetes: 3 cohorts of US adults and an updated meta-analysis.

Am J Clin Nutr. 2011 Oct;94(4):1088-96. [PubMed]

16. Pan A, Sun Q, Bernstein AM, Manson JE, Willett WC, Hu FB. Changes in red meat consumption and subsequent risk of type 2

diabetes mellitus: three cohorts of US men and women. JAMA

Intern Med. 2013 Jul 22;173(14):1328-35. [PubMed]

17. de Koning L, Fung TT, Liao X, Chiuve SE, Rimm EB, Willett WC, Spiegelman D, Hu FB. Low-carbohydrate diet scores and

risk of type 2 diabetes in men. Am J Clin Nutr. 2011

Apr;93(4):844-50. [PubMed]

18. Djouss L, Gaziano JM, Buring JE, Lee IM. Egg consumption and risk of type 2 diabetes in men and women. Diabetes Care.

2009 Feb;32(2):295-300. [PubMed]

19. Schoenfeld JD, Ioannidis JP. Is everything we eat associated with cancer? A systematic cookbook review. Am J Clin Nutr.

2013 Jan;97(1):127-34. [PubMed]

20. Bagchi D, Misner B, Bagchi M, Kothari SC, Downs BW, Fafard RD, Preuss HG. Effects of orally administered

undenatured type II collagen against arthritic inflammatory

diseases: a mechanistic exploration. Int J Clin Pharmacol Res.

2002;22(3-4):101-10. [PubMed]

21. Crowley DC, Lau FC, Sharma P, Evans M, Guthrie N, Bagchi M, Bagchi D, Dey DK, Raychaudhuri SP. Safety and efficacy

of undenatured type II collagen in the treatment of

osteoarthritis of the knee: a clinical trial. Int J Med Sci. 2009

Oct 9;6(6):312-21. [PubMed]

22. Marone PA, Lau FC, Gupta RC, Bagchi M, Bagchi D. Safety and toxicological evaluation of undenatured type II collagen.

Toxicol Mech Methods. 2010 May;20(4):175-89. [PubMed]

23. Wei W, Zhang LL, Xu JH, Xiao F, Bao CD, Ni LQ, Li XF, Wu YQ, Sun LY, Zhang RH, Sun BL, Xu SQ, Liu S, Zhang W,

Shen J, Liu HX, Wang RC. A multicenter, double-blind,

randomized, controlled phase III clinical trial of chicken type II

collagen in rheumatoid arthritis. Arthritis Res Ther.

2009;11(6):R180. [PubMed]

24. Hartman JW, Moore DR, Phillips SM. Resistance training reduces whole-body protein turnover and improves net protein

retention in untrained young males. Appl Physiol Nutr Metab.

2006 Oct;31(5):557-64. [PubMed]

25. Campbell WW, Crim MC, Young VR, Joseph LJ, Evans WJ. Effects of resistance training and dietary protein intake on

protein metabolism in older adults.Am J Physiol. 1995

Jun;268(6 Pt 1):E1143-53. [PubMed]

26. Helms ER, Zinn C, Rowlands DS, Brown SR. A systematic review of dietary protein during caloric restriction in

Resistance Trained Lean Athletes: A Case for Higher Intakes.

Int J Sport Nutr Exerc Metab. 2013 Oct 2. [Epub ahead of

print] [PubMed]

Alan Aragons Research Review October 2013 [Back to Contents] Page 12

Vemma a fairy tale of hope, a reality of nope.

By Alan Aragon

________________________________________________

Intro & background

Vemma (an acronym for vitamins, essential minerals,

mangosteen, aloe + green tea) is a privately held direct sales

company that uses multilevel marketing (MLM also called network marketing) to generate revenue. Vemma was founded in

2004 by Benson K. Boreyko, who has a long history of running

large MLM businesses prior to launching Vemma, whose 2012

revenue totaled $117 million. According to Vemma, their US

revenue saw a 46% increase over last year, followed by Canada

with 34%, and Europe with a 22% increase (full press release

here). Its safe to say that Vemma is no small business.

Like many modern MLMs, Vemmas product line is focused on nutritional products marketed to promote health and wellness.

Tied in with this is the promise of financial success through

recruitment into their sales force. Heres an example of Vemmas advertising copy:

The foundation of Vemma's success lies firmly in the results achieved from our clinically studied, single-formula product line. At the company's core is our mission to help others by enhancing their well-being, and offering an income stream to people who introduce others to a product line they believe in.

Targeting the youth

Vemma reported an 85% increase in sales recruits in the US in

2012. Its reasonable to speculate that a growing proportion of these recruits are high school and college-aged. The screen shot

directly above takes up almost all of the space on Vemmas home page. The picture of the guy next to his slick, black BMW

is 22 year-old Alex Morton, featured in a press release as one of

Vemmas success stories. Here is a video clip of his sales pitch, where he proudly claims hes earning $3500 per week (at 6:38 into the vid). Anyone whos sat through an MLM presentation knows that they play on the audiences fear of working a few decades for an ungrateful corporation and retiring broke, like the

majority. Either join the MLM, or accept a miserable life

doomed to financial hardship. Thats the absurdly false dilemma put forth by the recruiter. At these sales meetings, the value of a

college education is dismissed or downplayed, and the

conventional road of climbing the corporate ladder is

discouraged and mocked. New recruits are told that within 3-5

years after joining, they can create enough residual income to

become financially free. This is the age-old promise of MLMs in general, its not just a pitch exclusive to Vemma.

Although the idea of achieving financial independence in a few

short years of part-time effort sounds attractive to many, the

reality of the matter is much less exciting. Have a look at

Vemmas own 2012 income dislosure report:

While Vemma is hyped as a cash machine ready to dish out

riches to all who join in, the hard numbers tell a different story.

Notice how 85.73% of the sales force makes between $667.78

and $3260.73 per year. Thats a measly $55.64 to $271.72 per month. According to the US Census Bureau (spreadsheet here),

the average (mean) annual household income in the US is

$69,677. Less than one percent of Vemma reps earn this.

The products

There are four Vemma product lines thus far: 1) Vemma, a

vitamin & mineral-fortified mangosteen-based drink that also

contains aloe; 2) Verve, a series of mangosteen-based energy drinks containing anywhere from 5 to 70 kcal and 40 to 160 mg

caffeine; 3) Bod-e, a series of products sold as transformation packs that include a vitamin & mineral-fortified protein shake, mangosteen & caffeine-based burn, fiber-based cleanse, mangosteen based rest which supposedly enhances the bodys nightly restorative processes, and thirst, a mangosteen-based, vitamin/mineral-fortified beverage aimed at hydrating and

providing electrolytes minus the high sugar content of typical

Alan Aragons Research Review October 2013 [Back to Contents] Page 13

electrolyte replacement drinks; 4) Next is a vitamin & mineral-

fortified, mangosteen-based beverage aimed at children 2-12

years of age. All four Vemma product lines have similar

ingredients with slight variations, but all contain mangosteen and

vitamin/mineral fortification. This product template is common

in MLM because its a proven hit. The underlying formula is to tout the benefits of some exotic fruit juice, and include it in a

line of products that cover the range of health/fitness goals and

insecurities of the general public. The recurrent thoughts I had

while reading through these product labels were, Wow, that caffeine could add up, and Wow, what a superfluous degree of vitamin and mineral fortification.

Scientific support?

Like any smart MLM, Vemma boldly claims that its products

have a solid foundation in research. They lean heavily on the

academic credentials of their product formulator and Chief

Scientific Officer, Ybing Wang. MD, PhD. But the question is,

how strong is the research evidence behind their products? You

would think that theres a mountain of research supporting Vemma by the way the sales reps glorify this aspect of it.

However, there are only 2 published studies examining the

Vemma product specifically. One examined immune response,

and the other examined bioavailability. Lets take a closer look.

Tang et al investigated the 30-day effect of Vemmas flagship product (the vitamin/mineral-fortified mangosteen-based juice)

on immune function and subjective self-appraisal of well-being.1

The investigators found that Vemma enhanced both innate and

acquired immune responses while lowering C-reactive protein (a

biomarker of inflammation). Subjective self-appraisals of overall

health status in the Vemma treatment were also signicantly improved compared to the control condition.

While these results are mildly interesting, they still lack any real

value. Why? Because the placebo control was merely fructose

and water. A much more practical design would have compared

Vemma with some widely commercially available fruit juice or

fruit juice blend taken with (or without) an equivalent

supplemental amount of vitamins and minerals. As it stands,

Vemma cant claim to impart exclusive health benefits. For example, concord grape juice which is inexpensive and widely available has been shown to benefit immunity and increase antioxidant levels.

2 And keep in mind, you can purchase concord

grape juice without having to endure a pushy sales speech.

The other Vemma study tested bioavailability and antioxidant

effects of a single dose.3 Antioxidant capacity increased, and the

bioavailability of -mangostin as well as B2 and B5 were observed. But once again, this was compared with a fructose

solution, and the same lack of practical relevance applies. Aside

from these two Vemma studies, a more extensive body of

research has been published on mangosteen itself. This raises the

question of whether mangosteens health effects are worth the investment. Thus far, the answer appears to be nope. Heres an excerpt from the conclusion of a recent scientific literature

review by Gutierrez-Orozco and Failla:4

Controlled intervention trials of the efficacy of xanthones in human volunteers, as well as characterization of the absorption, metabolism and elimination of these compounds,

remain quite limited. Also, the potential toxicity of chronic ingestion of formulations containing mangosteen pericarp and its extracts has received minimal attention. Despite the numerous health claims on advertising sites for producers and retailers of products and beverages containing mangosteen, there is insufficient scientific evidence at this time to support the use of mangosteen containing supplements as enhancers of health and useful adjuvants for treatment of various pathophysiological illnesses.

Cause for concern

What Vemma does particularly well is capitalize on the caffeine-

driven energy drink craze that has swept the younger generation like wildfire. According to a recent ISSN position

stand, energy drinks are the most popular dietary supplement in

the US adolescent and young adult population aside from

multivitamins.5 Seifert et al recently reviewed the adverse

consequences and extent of energy drink consumption among

children, adolescents, and young adults.6 Their cautionary notes

are worth quoting:

Energy drinks have no therapeutic benefit, and many ingredients are understudied and not regulated. The known and unknown pharmacology of agents included in such drinks, combined with reports of toxicity, raises concern for potentially serious adverse effects in association with energy drink use.

Concluding thoughts

The MLM business model inevitably makes you view everyone

you meet as means to increase revenue. Seeing people as

walking dollar signs is not the healthiest mindstate to dwell in.

Ive tried MLM for a short stint back in high school (more than 20 years ago), and Im hearing the identical sales script from the new generation of MLMs such as Vemma. When you combine

the desperate hustle of network marketing with relatively

ineffective products that carry the risk of adverse effects, you

have a good recipe for saying, no thanks.

References

1. Tang YP, Li PG, Kondo M, Ji HP, Kou Y, Ou B. blind, placebo-controlled trial. J Med Food. 2009 Aug;12(4):755-63. [PubMed]

2. Rowe CA, Nantz MP, Nieves C Jr, West RL, Percival SS. Regular consumption of concord grape juice benefits human immunity. J

Med Food. 2011 Jan-Feb;14(1-2):69-78. [PubMed]

3. Kondo M, Zhang L, Ji H, Kou Y, Ou B. Bioavailability and antioxidant effects of a xanthone-rich Mangosteen (Garcinia

mangostana) product in humans. J Agric Food Chem. 2009 Oct

14;57(19):8788-92. [PubMed]

4. Gutierrez-Orozco F, Failla ML. Biological activities and bioavailability of mangosteen xanthones: a critical review of the

current evidence. Nutrients. 2013 Aug 13;5(8):3163-83. [PubMed]

5. Campbell B, Wilborn C, La Bounty P, Taylor L, Nelson MT, Greenwood M, Ziegenfuss TN, Lopez HL, Hoffman JR, Stout JR,

Schmitz S, Collins R, Kalman DS, Antonio J, Kreider RB.

International Society of Sports Nutrition position stand: energy

drinks. J Int Soc Sports Nutr. 2013 Jan 3;10(1):1. [PubMed]

6. Seifert SM, Schaechter JL, Hershorin ER, Lipshultz SE. Health effects of energy drinks on children, adolescents, and young adults.

Pediatrics. 2011 Mar;127(3):511-28. [PubMed]

Alan Aragons Research Review October 2013 [Back to Contents] Page 14

Interview with Eric Helms about his latest peer-reviewed publication on protein needs of lean, trained athletes in an energy deficit. By Alan Aragon

____________________________________________________

_ Thanks so much for agreeing to do this interview in the midst

of sledging through your doctoral work. My first question is,

what gave you the idea or the impetus to ask the research

question (protein needs of lean/trained subjects in dieting

conditions)?

Alan, happy to as I'm between projects. This review was the

second chapter of my masters thesis which I recently submitted and my PhD doesn't officially start until January. Plus, the true

purpose of my research-based education is adding to the body of

knowledge in my field. This includes not just publication, but

dissemination and engaging the people interested in my work.

Your readers are exactly the folks I'm trying to serve and help,

so I see this interview as part of my academic and life goals!

As to where the research impetus came from, that stems from

my personal goals and goals of 3DMuscleJourney. Among these

goals, and my focus as a part of the team, is using science to

approach bodybuilding in an evidence-based fashion. To do so

we need researchers to ask questions relevant to the sport;

specifically questions where confusion and contention lie. I

decided to stop wishing more researchers would look at

bodybuilding related topics, get over my insecurities, and do it

myself (not to say I'm the only bodybuilding researcher out

there, but there aren't many of us).

One contentious question at the top of my list was related to the

debate over protein intake. There are smart people on both sides

of the fence who have very different opinions on

protein recommendations. Bodybuilders typically recommend

higher protein intakes than most scientists and nutritionists.

I believe that central to this difference of opinion is context.

Bodybuilders see the biggest physique changes during contest

prep, and this is also when nutrition is most important. The

experience of seeing your physique at it's peak during a period of

intense nutritional focus, almost always with a high protein

approach, influences the perspective by which bodybuilders see

nutrition (I know it has for me). Additionally, one of the biggest

gaps in the literature is protein intake in athletic populations

during hypocaloric periods. In essence, the primary experience

that influences bodybuilders to have a "high protein bias" is

woefully understudied. Bodybuilders primarily have anecdote to

argue their case, and their opponents have research that is at best

only semi-applicable to counter it.

So, in order to help out this impasse I decided to tackle this

understudied area with my thesis. In fact the title of my thesis is

"Exploring protein and macronutrient intakes in lean

bodybuilders during caloric restriction". To start any thesis you

have to become intimately familiar with the research that does

exist. The experience of sifting through all this research for a

few years culminated in this publication.

I remember how your recently published paper in IJSNEM

started out (way back!), as I had the privilege of you getting

my feedback & critique. I'm curious to know how you took

on the direction of conducting a systematic review, since its

original form - if I recall correctly - could have been

considered more of a narrative review. I like how the paper

is more sterile & concise now, but I also miss a lot of the

background detail that was in the original work. It's always

amazing how papers often evolve into completely different

animals once they hit publication. So, here's my question -

what would you say are the greatest strengths of your paper?

And on the other hand, if you didn't have any word limits or

obligation to focus so tightly, what aspects of

the paper would you go into more depth about?

My first masters wasn't research-based, but I learned to be an informed consumer and reviewer of research. That said, I had

never attempted a review of this scope. Thus, I started with an

organic, broad, comprehensive, and in hindsight, unorganized

approach. I dedicated hours every day, starting with the reviews,

working my way back through their reference lists, reading the

game-changing papers through the last four decades, reading the

underlying theoretical papers on metabolism and methodologies

related to protein, and then I went back and read it all again with

a renewed perspective and understanding.

A systematic review of dietary protein during caloric restriction in Resistance Trained Lean Athletes: A Case for Higher Intakes. Helms ER, Zinn C, Rowlands DS, Brown SR. Int J Sport Nutr Exerc Metab. 2013 Oct 2. [Epub ahead of print] [PubMed] BACKGROUND: Caloric restriction occurs when athletes attempt to reduce body fat or make weight. There is evidence that protein needs increase when athletes restrict calories or have low body fat. PURPOSE: The aims of this review were to evaluate the effects of dietary protein on body composition in energy-restricted resistance-trained athletes and to provide protein recommendations for these athletes. METHODS: Database searches were performed from earliest record to July 2013 using the terms protein, and intake, or diet, and weight, or train, or restrict, or energy, or strength, and athlete. Studies (N = 6) needed to use adult ( 18 yrs), energy-restricted, resistance-trained (> 6 months) humans of lower body fat (males 23% and females 35%) performing resistance training. Protein intake, fat free mass (FFM) and body fat had to be reported. RESULTS: Body fat percentage decreased (0.5% to 6.6%) in all study groups (N = 13) and FFM decreased (0.3 to 2.7kg) in nine of 13. Four groups gained or did not lose FFM. They had the highest body fat, smallest magnitudes of energy restriction or underwent novel resistance training stimuli. Two groups lost non-significant amounts of FFM. The same conditions that existed in the groups that did not lose FFM existed in the first group. These conditions were not present in the second group, but this group consumed the highest protein intake in this review (2.5-2.6g/kg). CONCLUSION: Protein needs for energy-restricted resistance-trained athletes are likely 2.3-3.1g/kg of FFM scaled upwards with severity of caloric restriction and leanness. SPONSORSHIP: No funding was provided for this research.

Alan Aragons Research Review October 2013 [Back to Contents] Page 15

At this point, I started doing more focused Boolean searches. I

ended up exhausting probably 99% of the research on protein

needs under hypocaloric conditions, and probably 2/3rds to

3/4ths of the published work on protein intake in athletes. I

wrote and edited as I reviewed, letting subtopics define

themselves. I plugged these sections into a semi-coherent first

draft, although looking back it was a review of everything

remotely related to the question rather than a clear paper that

could be applied in practice.

The first people to see it were folks like yourself: practitioners

with their proverbial ear to the ground of research. This was to

make sure I didn't miss important things in the field and that I

hadn't considered. The next step was getting it to my supervisors

who knew the peer review process and knew what academic

writing had to be. This process brought the word count down

from over ten thousand to just under seven. It also shifted away

from citing every piece of work ever published, to focusing on a

clear logic-chain leading to a conclusion.

When the dust settled it was a focused paper that I was proud of

and I submitted it to IJSNEM. At the time it was in fact still in

narrative review form. The transition into a systematic review

came after submission and I'll go into that further in answer to

your question about the peer review process.

As far as the paper's greatest strengths, I would say besides the

fact that it covers a very understudied topic in a systematic

fashion, the determination of protein intake by fat free mass

rather than total body mass is it's greatest strength. Believe it or

not, this also came out of the peer review process, so I'll save

further discussion on this topic for your question about peer

review as well.

Finally, as to your question about word limits and a tight focus,

I'm glad I had to tighten it. It made the paper more honest. For

example, before submission I had a section dedicated to studies

suggesting there might be benefits of high (over 2g/kg) protein

intakes for strength athletes even during non-hypocaloric

periods. The purpose was to illustrate that the "jury is still out"

on high protein intakes in general. However, it was the most

biased section and not relevant to the main point. I searched

specifically for papers showing the benefits of high protein

intakes, and while the fact that I found them is noteworthy,

presenting them in isolation is inherently an incomplete and

biased view of the literature and I'm glad I removed it.

I was also happy to trim down the section on methodologies of

determining protein requirements. I went into too much depth,

covered obscure methodologies, and got away from the main

point: we need to be looking directly at changes in body

composition and performance, not surrogate measures of protein

balance.

As you sifted through the literature, what were the most

common limitation(s) you found with the studies on protein

requirements for the population in question?

I could never "have my cake and eat it too". All the studies I

found were imperfect in their ability to answer the research

question on their own. Either they were on what I would call

"semi-resistance-trained" populations like recreational exercisers

or non strength athletes who do some resistance training, or

when they were on dedicated resistance-trained populations

something else was missing. For example, the length of the

interventions was incredibly short (1 to 2 weeks) or a high

protein intake was compared to a very low protein intake with

nothing in the middle.

The one study that was on highly trained natural bodybuilders

during contest prep that was 11 weeks long, and had a high

protein group compared to a moderately high protein group was

almost perfect. Except for one crucial thing, it was a study of

hypocaloric vs hypercaloric conditions not protein. Meaning

while the high protein experimental group was hypocaloric, the

moderately high protein control group was not! So while a great

study that did observe and record protein intake and body

composition changes in a relevant population, it didn't answer

the question. In fact no study alone has been able to answer the

question "what is the optimal protein intake in dieting strength

athletes?". So, the review looked at all the studies that met

certain criteria collectively to see what shook out. Essentially

looking at each study as an individual data point, each one filling

in the gaps where other studies were lacking.

In piecing the paper together, what were your most

significant "light bulb" moments? Were there any points

that you thought, "Ah-hah! I learned something new, and so

will the readers of this review."

The biggest one for me was when I looked at the study by Elia et

al., (1999). Seeing that lean individuals during starvation utilized

two to three times the amount of protein for energy that obese

individuals during starvation utilized really made some things

click for me. This study illustrates quite clearly that a caloric

deficit does different things in someone with higher body fat

than in someone with lower body fat. It illustrates that having a

low body fat level and being hypocaloric each independently

increase how much protein is used fo