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Sthira,

 

Yes, I think that was Michael's point - eat fruit because it is good for you rather than because statistics show it would be good for world health (i.e. other people).

 

Regarding the YouTube personality DurianRider that you speak of. I hear he is a very nicer person in person. But he certainly does play an a$$hole on YouTube and may have gone off the deep end as of late - I stopped watching him about a year ago when he really seemed to get mean, stop talking much about a WFPB diet and worst of all, became boring. Plus I really do dislike his gross, revenue-generating videos. He and especially now Freelee, make a pretty good living off of YouTube ad revenue. Perhaps you should consider it Sthira! :-)

 

To his credit, DurianRider (aka Harley Johnston) has probably encouraged more people to try a whole-food, plant-based vegan diet than anyone else on the planet, with the possible exception of a few exceptional individuals - i.e. Michael Pollan and the good Drs. Greger, Furman, Esselstyn, Bernard, McDougall, Pritikin etc. Considering Harley was a messed up Australian hoodlum, he's done alright for himself, and the planet.

 

So don't knock an in-your-face, bombastic style. Sometimes being an a$$hole is what it takes. Skillful means...

 

--Dean

 

P.S. But don't that this to imply I don't actually hate Saul's guts. He makes me so angry!!!!

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Saul,

 

:)xyz

 

My favorite vegan guru is probably Dr. Pollan.

 

  --  Saul

 

I hope that silly smiley was meant to cover your own post, not just my heartfelt diatribe hurled your way. The reason is that you've outdone yourself once again, perhaps setting a record for the most wrong statements in a sentence of under 10 words.  Michael Pollan is neither a vegan (not even a vegetarian), nor is he a Doctor, even the kind you (and I) are - i.e. the one's that don't actually help people. According to his biography, Pollan has a BA from Bennington College and a Master's degree from Columbia, both in English.

 

But I will say one thing, Pollan's pithy statement - "Eat (real) food, not too much, mostly plants" has done more to get across the message of how simple it can be to eat a healthy, whole-food, (mostly) plant-based diet than just about anyone else. I give him a lot of credit for that, despite his proclivity for consuming the flesh of innocent sentient creatures.

 

--Dean

 

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Sucralose (and Probably Other Sweeteners) Promote Hunger via Insulin - Dopamine - AMPK - NPY Pathway

 

Hold onto your hats folks, the whole sucralose and non-nutritive sweetener saga may have just gotten a whole lot more complicated...

 

The title of this new study [1] (popular press articles here and here) pretty much gives it all away: 

 

Sucralose Promotes Food Intake through NPY and a Neuronal Fasting Response (full text)

 

In it, researchers spiked the food / drink of mice and flies respectively, with sucralose. They used the flies to figure out the pathway, but first the mouse data (which they put last in the paper). They tested sucralose feeding in two types of mice, wild-type and NPY-knockout mice (NPY-/-). WT mice who were fed a little jelly candy (I kid you not) in addition to normal chow for a week ate over 50% more (unsweetened) regular chow (with no candy) on the 7th day than did mice who didn't get the daily treat for the week.  Remarkably, the NPY-knockout mice who received the sucralose jelly candy for seven days didn't eat any more regular chow on the seventh day than did the knockout mice deprived of the daily sucralose candy (right graph below):

 

XJ8MKex.png

 

In short, sucralose consumption appeared to dramatically boost the appetite and hence food intake of mice, and the effect required intact signalling via the hunger hormone NPY.

 

The pathway story they teased apart using the fruit flies is amazing as well, and quite complicated. They basically ran a long series of sucralose feeding experiments with various mutant flies to figure out the details of the pathway involved. The basic experimental paradigm was the same as the mice - feed flies either their normal food or their normal food + sucralose for a few days. Then, remove the sucralose and see how much they eat over the subsequent 24 hours, and correlate that with the genetics or the treatment they gave to the fly to see what intermediate compounds are critical for the observed increase in appetite.

 

Here is what they found at the highest level, in their own words and without all the complex pathway intermediate names:

 

[O]ur data support a mechanism where an imbalance of
sweetness versus caloric content of a diet simulates a fasting
state and triggers a sensory and behavioral response that increases
caloric consumption.

 

That "behavioral response" that manifested (in the flies at least) as follows:

 

Our results show that sucralose pretreatment triggers an increase
in appetite and sucrose receptivity and promotes hyperactivity,
insomnia, and sleep fragmentation, behaviors that are
consistent with a mild starvation or fasting state (ref).

 

Interestingly, that sounds consistent with a CR mimetic response.

 

Here was more on the metabolic and behavioral effects of sucralose feeding on the flies:

 

Sustained sucralose ingestion did not cause a significant
change in body weight (Figure S1C), triglycerides (Figure S1D),
glycogen (Figure S1E), or resting hemolymph glucose (Figure
S1F). However, sucralose-treated flies did show impaired
glucose tolerance in an oral glucose tolerance test (Figure 1F).
Furthermore, flies became hyperactive after 4 days of sucralose-sweetened
food (Figure 1G).., and sucralose-treated animals also
exhibited sleep fragmentation (Figure 1H) and reduced total
sleep (Figure 1I). Elevated energy expenditure caused by
increased activity and altered sleep behavior may explain why
these animals do not significantly expand energy stores despite
increased caloric intake. Of interest, similar effects (i.e., altered

sleep behavior and insomnia) have been reported in human subjects

ingesting [non-nutritive sweeteners] (Roberts, 1988). These data show 

that, in flies, prolonged ingestion of sucralose-sweetened diet triggers

broad physiological changes similar to effects reported in rodents
and human studies.

 

Unfortunately they didn't report on all these same behavioral measures for the mice (just the flies). But as seen above, the effects of sucralose exposure on appetite were recapitulated in the mice, at least in mice with intact NPY signalling. 

 

So how exactly did it work (i.e. what was the pathway)? Here is the best summary I found in the full text:

 

Thus, long-term ingestion of sucralose-sweetened food activates neuronal AMPK, which acts within dopamine and NPF-producing [equivalent of NPY-producing cells in mammals - DP] cells to promote hunger.

 

To clarify, "NPF" stands for neuropeptide F, which the authors say is "the fly ortholog of the potent mammalian appetite-stimulating neurotransmitter neuropeptide Y (NPY)".

 

Stepping back, all this stimulation of hunger might be bad for weak-willed normal people, and might explain why sucralose (and other non-nutritive sweeteners) are associated with a certain amount of weight gain (compared to water) or at least not as much loss (compared to drinking sweetened beverages) as one would expect due to calorie compensation. But for strong-willed CR folks, at least on the surface this might actually sound pretty good. That is, as long as you can control your calorie intake despite the increased hunger to avoid overeating like the mice and flies did, or if you don't worry about eating lots of calories if you expend them in physical activity / cold exposure to maintain a net calorie deficit ☺. 

 

Why might it sound good? Because whether or not you think NPY and the hunger hypothesis has any merits, it's pretty well established that upregulating the AMPK energy deficit sensing pathway is beneficial, and likely a part of how CR works. 

 

So if you're tricking the body into thinking it's operating at a calorie deficit using sucralose to boost AMPK, and subsequently boosting hunger via NPY, mightn't that be a good thing?

 

Perhaps, but the one thing I saw in the paper that might give one pause is shown in this master diagram (Figure 5J):

 

RzotmUH.png

 

See the "IPC" at the top that appears to serve as the master regulator orchestrating all these effects? That stands for "Insulin-Producing Cells". And the "InR" links coming out of IPC stand for "insulin receptor". So in short, via a buttload of experiments, the researchers found that sucralose consumption seems to somehow stimulate insulin release. I'm pretty sure, but not positive, that the authors showed (or at least think) that the insulin-producing cells that were involved are located in the brain, and not the pancreas or elsewhere peripherally1. The resulting increased insulin is detected in the brain by three different types of cells (neurons?), each of which is critical for this whole shebang. One of the types (Dop+) are dopamine-producing cells involved in motivation & reward. The second type (labelled Oct+) are octopamine-producing cells. Octopamine is apparently "related to norepinephrine, [and] is a major neurotransmitter in the insect reward pathway (ref) and can promote gustatory reward in flies (ref)."

 

The third type of brain cell involved are the NPF+ cells, which are the equivalent of the cells that produce the hunger hormone NPY in mammals. The NPF [=NPY] then sensitizes the sweet taste receptor GF64+ on the tongue, which makes food more palatable to the flies and increases their caloric intake.

 

What appears to be happening might be described teleologically as follows (note - I'm making the following up, not the authors - hence no italics):

 

Sucralose (somehow) elevates insulin in the brain. This would normally be associated with the presence of food, since insulin is normally released when there is glucose in the bloodstream. But since sucralose is sweet but without calories, there is no glucose. So the energy deficit sensor AMPK is upregulated in dopamine and NPY-producing brain cells. Apparently, when in dopamine and NPY-producing cells there is a convergence of this pairing of conflicting signals, namely insulin which says "there should be food around here somewhere!" and the energy deficit detector AMPK which says "nope, we got no food!", the dopamine and NPY-producing cells kick into gear, producing and releasing their respective neurotransmitters/neuropeptides, dopamine and NPY. The dopamine and NPY subsequently increases food-related motivation and hunger, thereby boosting food intake.

 

In short, in my (perhaps naive layman's) interpretation of the above diagram, the "bait and switch" effect of sucralose (or perhaps any non-nutritive sweetener) says "there should be food around here somewhere, but I'm not gettin' any, so try harder (body) to go out and find it!".

 

So in flies at least, sucralose boosts AMPK (probably a good thing?) and NPY (maybe a good thing if you buy the hunger hypothesis) but it does so by increasing insulin level and insulin signalling in the brain (maybe a bad thing?). The potential downside of the latter would seem especially troubling given the observation I glossed over earlier that "sucralose-treated flies did show impaired glucose tolerance in an oral glucose tolerance test."

 

Speculating, perhaps this extra insulin signalling in the brain as a result of sucralose consumption might somehow interfere with insulin signalling elsewhere in the body, triggering a reduction in insulin sensitivity and impaired glucose metabolism?!  See what I mean - both quite confusing and potentially troubling...

 

Let's see how the author's interpret all this, using quotes from the discussion section, to see if it clear up this ambivalence:

 

Here we show that sustained sucralose
ingestion activates a conserved neural fasting response. This
response integrates pathways that govern feeding, gustatory
reward, and energy sensing that together modify how sweet
food is perceived. In conditions of fasting, or when the sensory
sweetness of food does not match the caloric content for a sustained
period, a compensatory response is activated that alters
taste sensitivity and feeding behavior accordingly.

 

That doesn't sound bad - sucralose mimics fasting, which might mean it would trigger a CR-like response.

 

Interestingly, given previous findings (discussed in the first post in this thread) that sucralose and other sweeteners act by altering the microbiome of mice (my emphasis):

 

We found no role for the microbiome in our system. This
may be a result of the lower overall diversity in commensal gut
microflora in the fly compared to mammals (ref).
Instead, our data support a mechanism where an imbalance of
sweetness versus caloric content of a diet simulates a fasting
state and triggers a sensory and behavioral response that increases
caloric consumption.

 

The "no role for the microbiome" statement was supported by experiments I didn't discuss, in which they found that both normal and germ-free flies showed the same appetite boost from sucralose. So it looks like this appetite boosting effect is independent of the obesity-promoting gut microbiome changes reported in the opening post of this thread...

 

But then things get complicated and confusing when it comes to the role of insulin in all this, and its implications:

 

In the fly, insulin signaling was integrated
at the systems level, with insulin acting upstream of octopamine,
dopamine, and NPF [NPY] in this response. Interestingly, we
found insulin required for the orexigenic [appetite stimulating]
effect of sucralose, and chronic activation of insulin-producing
cells was sufficient to mimic this effect.
 

Next the authors talk about some really confusing effects of circulating insulin and insulin-receptor knockout in mice, which I'm leaving out (pg. 84, righthand column). They basically throw up their hands on generalizing from flies to mice regarding the insulin involvement, saying:

 

This suggests a more complex regulatory network of insulin action
in the mouse brain, though the phenotype of rodents lacking the
insulin receptor specifically in NPY+ neurons remains to be seen.

 

But they do go on to talk about insulin signalling impairment in diabetics that seems relevant here:

 

In line with our results in the fly, exogenous administration as
well as excessive and prolonged release of insulin (like under
conditions of type 2 diabetes) paradoxically gives rise to the
sensation of hunger, which in the early phase occurs on the
background of normal glycemia. Importantly, insulin therapy
can cause weight gain, and this is most likely occurring through
increased energy intake (Ryan et al., 2008). Moreover, a role for
insulin in promoting increased food intake is also consistent with
human data, where dysregulation of the insulin system through
clamping could increase hunger, food intake, sucrose sweetness
intensity, and the overall perceived pleasantness of sugar
taste (Rodin et al., 1985). Similarly, we found the insulin system
was upregulated following a sucralose diet, while glucose
tolerance was reduced, and an identical response has been
observed in rats fed a saccharin diet (Swithers et al., 2012) or humans
that have consumed saccharin (Suez et al., 2014) or sucralose
(Pepino et al., 2013).

 

So that doesn't sound very good, particularly in light of our ongoing discussions (here and here) about impaired glucose tolerance that many of the skinniest CR folks seem to exhibit.

 

The authors mention saccharin above, and earlier in the fly experiments they mentioned a non-nutritive sweetener called L-glucose had the same appetite-stimulating effect as sucralose in the flies. So whether good, bad or indifferent, it looks like this may be an effect of sweetness / sweeteners in general, and not sucralose specifically.

 

Moving towards their final summary, the authors give a pretty good overview and put their results in context in this paragraph:

 

Prolonged ingestion of a sucralose-sweetened diet triggered
an activation of neuronal AMPK, and we found, for both fasting
and sucralose responses, AMPK was essential within dopamine and
NPF-producing [i.e. NPY-producing] cells of the gustatory reward system. 
These effects are similar to data from the mammalian system, where
activation of neuronal AMPK in the hypothalamus has also
been shown to increase appetite and regulate NPY expression
in response to starvation (ref). Mammalian
NPY is a potent regulator of food intake, especially during food
deprivation, and is a critical mediator of insulin’s control on
whole body energy homeostasis (ref). Through our
systematic dissection of the sucralose response in flies, we
identified the conserved NPF/NPY system as a critical downstream
component of the sucralose response and confirmed a
conserved role for NPY in promoting food intake in response to
sucralose-sweetened food.

 

 

Finally, they discuss some implications:

 

Despite inclusion in thousands of products, and consumption
by billions of people, the molecular effects of ingesting synthetically
sweetened food are not well understood. Moreover, there
is conflicting evidence from both human and animal studies as
to whether or not synthetic sweeteners interact with overall physiology
or regulation of energy homeostasis. Our results show that
prolonged consumption of a sucralose-sweetened diet promotes
hunger and changes how animals perceive nutritive sugar. This
involves layered neuronal regulation through conserved metabolic
regulatory pathways that we report are also novel components
of a neuronal response to fasting. Importantly, in mice,
NPY was also critical to mediate increased food intake following
chronic ingestion of sucralose-sweetened food, and a similar
mechanism may also mediate these effects in humans.
 

Sorry for all the long quotes, but this one is a real head-scratcher. Coming to the end, I'm still not sure whether these results suggest sucralose (or non-nutritive sweeteners in general) are likely to be a good thing or a bad thing for CR folks. 

 

Fortunately for us, Michael's megamuffin recipe has always and continues to contain a whopping 2g of sucralose per batch, so it seems he'll be personally quite motivated to go over this one with a fine-toothed comb. ☺

 

So all I'm really hoping to do with this post is set the stage and provide (hopefully) helpful pointers in expectation of a better-informed interpretation of the implications of this study from Michael, or anyone else who'd care to chime in with an informed perspective (which excludes you Saul, sorry).

 

But one thing that does seem certain, sucralose and probably other non-nutritive sweeteners may not be metabolized completely or at all in the gut, but that doesn't seem to prevent them from having pretty dramatic effects on metabolic processes and particularly hunger.

 

--Dean

 

1Michael or anyone else who wants to dive into the weeds on where the insulin was coming from, the discussion is on page 76, bottom of the right hand column. I'm pretty sure they think/showed it's from insulin-producing cells in the brain.

 

----------

[1] Cell Metab. 2016 Jul 12;24(1):75-90. doi: 10.1016/j.cmet.2016.06.010.

Sucralose Promotes Food Intake through NPY and a Neuronal Fasting Response.

Wang QP(1), Lin YQ(1), Zhang L(2), Wilson YA(2), Oyston LJ(1), Cotterell J(1), Qi
Y(2), Khuong TM(1), Bakhshi N(1), Planchenault Y(1), Browman DT(2), Lau MT(1),
Cole TA(1), Wong AC(3), Simpson SJ(3), Cole AR(4), Penninger JM(5), Herzog H(6),
Neely GG(7).

Full text: http://sci-hub.cc/10.1016/j.cmet.2016.06.010

Non-nutritive sweeteners like sucralose are consumed by billions of people. While
animal and human studies have demonstrated a link between synthetic sweetener
consumption and metabolic dysregulation, the mechanisms responsible remain
unknown. Here we use a diet supplemented with sucralose to investigate the
long-term effects of sweet/energy imbalance. In flies, chronic sweet/energy
imbalance promoted hyperactivity, insomnia, glucose intolerance, enhanced sweet
taste perception, and a sustained increase in food and calories consumed, effects
that are reversed upon sucralose removal. Mechanistically, this response was
mapped to the ancient insulin, catecholamine, and NPF/NPY systems and the energy
sensor AMPK, which together comprise a novel neuronal starvation response
pathway. Interestingly, chronic sweet/energy imbalance promoted increased food
intake in mammals as well, and this also occurs through an NPY-dependent
mechanism. Together, our data show that chronic consumption of a sweet/energy
imbalanced diet triggers a conserved neuronal fasting response and increases the
motivation to eat.

Copyright © 2016 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cmet.2016.06.010
PMID: 27411010

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I've recently read the Segal & Elinav book 'The personalized diet'. The ideas therein exposed have been discussed in a couple of threads in thsi forum.

 

 

They dedicate the last part of chapter 5 in their book on the effects of artificial sweeteners such as aspartame, saccarin and sucralose.

 

The amazing long-term effects observed on lab rats seem to be glucose intolerance, via a detrimental influence on the gut microbiome.

 

Such effects have also been observed by the authors on humans, but not all people (another support to the theory of the high inter-individual variability in response).

 

The NAS studied were commercial formulations of saccharin, sucralose, aspartame, diluted in water.

 

Artificial sweeteners induce glucose intolerance by altering the gut microbiota
  • Nature volume514pages181186 (09 October 2014)
  • doi:10.1038/nature13793
Received: 27 March 2014 Accepted: 28 August 2014 Published: 17 September 2014

 

 

Edited by mccoy

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The cited authors in the book provide details on their experiments on human volunteers. 50% of'em displayed glucose intolerance after assumption of NAS, the mechanistic explanation provided is that some strain of gut bacteria in the presence of NAS secrete metabolites which cause an inflammatory response similar to that occurring after the intake of a large amount of sugar.

 

Stevia is considered a natural sweetener. They don't cite erythritol, which is found in small amounts in nature.

Edited by mccoy

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