If you see one bright red swan, you are not likely to give up a theory that says that all swans are white; you will instead go looking for the person who painted it.
Much is being said on this subject. Bet many are getting pretty fed up by now. But I still think this is an interesting discussion and so I will take this opportunity to add some thoughts. After all, the goal here is to find the truth; to find out how the world works. In that respect, I would also like to say that I do not agree with any one side in this discussion. Scientifically speaking, agreeing is not very scientific. That would mean confusing matters of opinion with matters of fact. Things are just what they are.
Chris Kresser is of course right in that there is no single cause of obesity. In animal studies obesity can be induced in a number of ways, just as in humans. The fat tissue is a large part of our body and it has a wide range of receptors and interesting signaling, so it should not come as a surprise that there are many ways to become fat.
If we are to look for a general cause, we could say that western, post agriculture lifestyle is to blame for obesity and our lifestyle diseases. But that does not mean you cannot get fat eating paleolithic foods, although if you did, you should blame your parents for the lousy chromosomes.
Neither carbohydrates nor food reward is able to explain all the observations. They both explain a part of the observations and so are both likely influential factors. Just how big a role each plays is an extremely difficult question to answer. Thus the current discussion.
The key question is: Why is not hunger down-regulated in humans becoming fat?
The Guru Walla
From what I can see, the Cameroonian Guru Walla is a bland food, overeating, fat gaining rite.
In the Guru Walla ritual, young Cameroonian men consume a diet made of red sorghum and cow milk (makes up over 95% of calories). The young men isolate themselves in different houses with a female attendant devoted exclusively to the preparation of Guru Walla meals. The diet and exclusion is supposed to lead to a certain level of purity. The men eat every 3 hour for 60 days, during which time body-weight can increase by an average of 17kg. Only 64-75% of the weight gain is fat .
Traditional food amongst these Cameroonians is about 75% CHO, 10% fat and 15% protein. During the Guru Walla it is 70% CHO, 15% fat and 15% protein.
The Guru Walla food is obviously fattening; at least if force fed and combined with minimal physical activity. The question we need to ask is: Would the Cameroonians be overweight if all they consumed was the Guru Walla diet?
It seems that the Cameroonians do not get fat because of the food itself. Rather they become fat because they force feed themselves. The newly gained weight is also lost after the ritual.
The reason I called the Guru Walla food bland, is that it most likely is very bland after the first few days. Try eating any one food exclusively for 2 months, and eat it even though you are not hungry (vomiting is also a part of the Guru Walla). The dopamine reward response should be minimal. Remember the Twinkie Professor who ate nothing but Twinkies, Oreos, donuts and similar crap but who lost 27 pounds in a 10 week experiment. He did consciously under eat, but my point is that we need to ask ourselves how lack of variation affects reward.
While food reward might help explain why we overeat at a biochemical level, there is little evidence to indicate that a fat loss diet needs to be unrewarding, if by unrewarding we mean less palatable. We also need to know if it is possible to unconsciously overeat (become fat) on rewarding foods if we have a working metabolism and the rewarding foods do not mess with our metabolism. If not, whatever caused the metabolism to go out of whack is the real problem.
Stephan’s bland food through a straw experiment does not necessarily support a theory claiming that the study participants lost weight because of an inherently unrewarding quality of that particular diet. The finding could easily also support the theory that eating only one food, no matter how rewarding it may be when consumed intermittently, will make people lose weight because the rewarding quality of that food declines with increasing intake.
So we need to know if people could lose similar amounts of weight eating other foods exclusively.
I am still having trouble seeing what’s the big fuzz about leptin. It is a signaling molecule. It signals energy surplus and the lack of leptin signals lack of energy. Leptin also increase fat oxidation. The leptin deficient animal models, that are obese, act and behave as they were starving and administering leptin normalize their behavior and induce weight loss. Either the body just needed to be told that it had stored energy to use, or we just needed to increase fat oxidation. If you increase fat oxidation by other means such as GH, ob/ob mice lose weight just as with leptin.
If for example high insulin levels cause leptin resistance, focusing on leptin does not add anything to obesity treatment. High insulin levels can also be caused (or at least be exacerbated) by factors other than carbohydrates. For example factors that messes with liver function.
“In particular, protein-rich foods such as beef can increase insulin secretion as much as certain starch foods such as pasta, or more.”
The quote takes the results from trials out of context. It is an unfair statement, just like “proteins are inherently satiating” statement. A few days of beef eating will likely lead to lower insulin than a few days of pasta. I’ve written some about satiating proteins here.
In overweight people, as in overweight animal models, the key issue seems to be a reduced fat oxidation. Reduced fat oxidation with a high energy intake cause fat deposition in most all tissues and also insulin resistance.
Anything that increase fat oxidation in overweight animal or humans, cause weight loss and reduced food intake.
Lessons from insulin resistance
Stephan claims that overweight people have high serum free fatty acids. This is not completely true, at least if we are to listen to Keith Frayn at . The claim may be true in general, but there are lots of overweight people with normal FFA levels. This however does not change Stephan’s argument. Generally the fat tissues of the overweight give out more FFA indicating adipose tissue insulin resistance.
Here is how we imagine insulin resistance to occur (roughly):
The pancreas has a direct route to the liver. The reason for this direct route is that the liver controls blood sugar level through its production of glucose. When blood sugar rises, the pancreas notice and secretes insulin. When the liver receives this insulin, glucose production is reduced. As the cells in the body are utilizing glucose for fuel, blood glucose level drop.
Somehow the liver becomes insulin resistant and keeps sending out glucose despite the insulin being sent from the pancreas. The reason seems to be inflammation and/or buildup of fat (NAFL). In this insulin resistant state, the muscles also fill up with fat. Once glycogen stores are full they become insulin resistant to avoid sugar poisoning, but keep taking up fatty acids. Because of the high carb diet and/or lack of physical activity the muscles do not burn fat and so it builds up. Also, there is some loss of muscle and liver mitochondria function and probably fatty acid transport into mitochondria.
The fat tissue takes up both glucose and fatty acids and expands if it takes up more than it gives out. The expansion of fat tissue eventually cause fat cells to send out stress signals (probably caused by endoplasmatic reticulum stress) and macrophages invade the tissue, gathering around dying fat cells. In this state, the fat tissue secretes a lot of fatty acids that wreak havoc around the body. But if free fatty acids are not burned they need to be re-esterefied. A high FFA level does not mean that we are not gaining weight or that we are losing weight (that more fat is leaving than entering the fat tissue). FFA are measured fasting and although the level might be higher in overweight and insulin resistant in that fasted state, this does not mean that over time more fat is leaving the fat tissue than are entering.
Stephan Guyenet takes the high FFA-level often observed in the overweight to mean that the fat tissue is insulin resistant and that they could not be gaining weight. This might be a wrong assumption. They have definitely been gaining weight and most overweight people are either weight stable or gaining weight. Is it impossible to gain weight while still having high FFA level?
Lean people also get insulin resistant. As do animals and humans with lipodystrophies. Many massively overweight do not become insulin resistant, and it seems that what causes the overflow of free fatty acids from adipose tissue is that it reaches its limit – a limit of course determined by both genetics and lifestyle.
In the insulin resistant state (metabolic syndrome), free fatty acids are usually high and fat builds up everywhere. Anything that increases fat oxidation helps. Pharmacological inhibition of the oxidation of fatty acids in the liver stimulates food intake in both humans and rats and stimulation of hepatic fatty acid oxidation reduces food intake, weight gain and adiposity in rats with diet-induced obesity .
FFA’s come from food, the liver or fat tissue. Carbohydrates are largely responsible for the amount secreted by the liver. At a cellular level, insulin resistance/metabolic syndrome seem to come from a high total energy intake. There is a surplus of both glucose (glycogen) and fat and the body can’t handle it all. Reducing the dietary fat load helps (at least if hypocaloric), but reducing dietary carbohydrate is the most efficient treatment to date. The question, though, is still why these people overeat.
“…for insulin to cause fat gain, it must either increase energy intake, decrease energy expenditure, or both.”
“If calories and protein are kept the same, high-carbohydrate meals cause equal or greater satiety than high-fat meals, and equal or less subsequent food intake, despite a much larger insulin response)”
Insulin will reduce hunger as long as there is energy coming from ingested food. Once that flow of energy stops or is reduced, a high insulin level cause hunger. In order for insulin to cause overweight, the level only needs to be high enough for allowing fat oxidation to be less than fat storage in that particular individual over time.
Injecting both glucose and insulin reduce hunger. Injecting insulin alone increase hunger. Long term satiety is better with low carbohydrate diets than high. We need to remember that we adapt to burning different fuels. If we normally eat high carb and suddenly eat high fat we are likely to be poor fat burners and thus more likely to get hungry. This might also explain higher leptin levels after high fat meals in acute feeding studies.
“If blood glucose decreases enough, it activates a system called the «counter-regulatory response», designed to maintain blood glucose at all costs to protect the brain from the effects of hypoglycemia. Part of this response is hunger and increased food intake. However, this system is not activated except in severe hypoglycemia, which is rare except in diabetics, thus it is not relevant to common obesity.”
This quote seriously needs references. It seems very unlikely.
These are just some thoughts. Nothing more.
1. Pasquet P, Brigant L, Froment A, Koppert GA, Bard D, de G, I, Apfelbaum M: Massive overfeeding and energy balance in men: the Guru Walla model. Am J Clin Nutr 1992, 56: 483-490.
2. Taubes G: Insulin resistance. Prosperity’s plague. Science 2009, 325: 256-260.
3. Ji H, Friedman MI: Reduced capacity for fatty acid oxidation in rats with inherited susceptibility to diet-induced obesity. Metabolism 2007, 56: 1124-1130.
Much is being said on this subject, but not much of it is of a very skeptical nature. Glad to see you weigh in on the subject.
An perhaps if we all ate through a straw we would lose weight! No-one has mentioned method of consumption yet.
Nice post. I also reacted to the lack of references to the last statement, as it seems highly unlikely. Why would this system even exist if it was only relevant in diabetics?
It seems to me that Guyenet is doing exactly what he accuses Taubes of (and vice versa, I guess), avoiding a lot of inconvenient facts.
Think Stephan got caught in the moment there. Wasn't as waterproof as some of his other writings. I'm still looking forward to his future posts and elaborations on food reward.
Nice job Pal–the Ensure study with the rats is interesting, but I've never actually perused it, so I can't really comment.
Nice post, Pal. One thing you bring up that I think is very important is the element of time. In obesity, long-term effects are usually opposite the short-term effects. It might be a disease of over-adaptation.
This is why talking about molecular pathways is so risky … they interact with other molecules and the body in such complex ways that it's hard to predict what altering any molecule will do in the long run.
As for why so much fuss is made over leptin, it's a molecule whose manipulation can reproduce many of the features of obesity. Manipulating insulin pathways doesn't give you anything like obesity, but manipulating leptin pathways does. Leptin resistance induces insulin resistance, but insulin resistance doesn't induce leptin resistance.
Since the first task of any research scientist is to come up with an in vivo animal model, leptin models were very important.
Paul, the time aspect sure is important. I've been thinking more about it recently, and it easy to get caught up in short term effects.
Leptin is of course very interesting, and I cannot see much evidence that insulin resistance induces leptin resistance. It was meant more of an example. I have an RSS feed going on pubmed articles on leptin so I am eagerly awaiting more pieces for the puzzle.
Pal that is because it precisely the opposite way in which it occurs. LR always predates IR. Leptin acts on three levels, hypothalamus, liver, and the muscle layers. Paul's point about timing is also very relevant and rarely spoken of. Leptin also is tied to ciracadian clocks of the tissues it acts upon. The sleep researchers Luis DeLecea and anti aging researchers at Albert Einstein in NYC are uncovering some pretty interesting findings about these issues. Nice post.
Good point about sleep. How do we know LR always predates IR? I haven't read much of the literature about this.
Great blog. But should it not be «imre _lakatos_»
Thanks, yes of course. «Lakatos»