I recently attended a lecture by Dr. Arya M. Sharma here at the University of Washington. Dr. Sharma is a Canadian clinician who specializes in the treatment of obesity. He gave the UW Science in Medicine lecture, which is a prestigious invited lecture.
He spent a little bit of time pointing out the fallacy behind conventional obesity treatment. He used the analogy of edema, which is an abnormal accumulation of fluid in the body.
Since we know that the amount of fluid contained in the body depends on the amount of fluid entering the body and the amount of fluid leaving the body, the treatment for edema is obvious: drink less, pee more.
Of course, this makes no sense. It doesn't address the underlying cause of edema and it will not help the patient. Yet we apply that exact same logic to fat loss. Since the amount of energy contained in the body (in the form of fat) depends on the amount entering and the amount leaving, the solution is easy: eat less, move more. Well, yes, if you can stick to that program it will cause fat loss. But that's equivalent to telling someone with edema to drink less water. It will cause a loss of fluid, but it won't correct the underlying problem that caused excessive fluid retention in the first place.
For example, if you have edema because your heart isn't pumping effectively (cardiac insufficiency), the heart is the problem that must be addressed. Any other treatment is purely symptomatic and is not a cure.
The same applies to obesity. If you don't correct the alteration in the system that causes an obese person to 'defend' his elevated fat mass against changes*, anything you do is symptomatic treatment and is unlikely to be very effective in the long term. My goal is to develop a method that goes beyond symptomatic treatment and allows the body to naturally return to a lower fat mass. I've been doing a lot of reading and I have a simple new idea that I feel confident in. It also neatly explains the results of a variety of weight loss diets. I've dropped a few hints here and there, but I'll be formally unveiling it in the next couple of months. Stay tuned.
* The body fat homeostasis system. The core element appears to be a negative feedback loop between body fat (via leptin, and insulin to a lesser degree) and the brain (primarily the hypothalamus, but other regions are involved). There are many other elements in the system, but that one seems to set the 'gain' on all the others and guides long-term fat mass homeostasis. The brain is the gatekeeper of both energy intake and energy expenditure, and unconscious processes strongly suggest appropriate levels for both factors according to the brain's perceived homeostatic needs. Those suggestions can be overridden consciously, but it requires a perpetual high degree of discipline, whereas someone who has been lean all her life doesn't require discipline to remain lean because her brain is suggesting behaviors that naturally defend leanness. I know what I'm saying here may seem controversial to some people reading this, because it's contrary to what they've read on the internet or in the popular press, but it's not particularly controversial in my field. In fact, you'll find most of this stuff in general neuroscience textbooks dating back more than 10 years (e.g., Eric Kandel and colleagues, Principles of Neuroscience).
117 comments:
Hello Stephan,
Looking forward to the future posts on this. I have few questions
In your past posts on altering ones set-point, you've mentioned low carb diets as one means to this end. Peter at Hyperlipid has posted (in his potato post) that if one has a "broken liver", they might need a low carb diet.
If a person is not completely metabolically deranged (T2 diabetes, morbidly obese, etc), do you think that by avoiding the primary modern dietary offenders - wheat, fructose, vegetable oils, soy - but continuing to be moderate carb intake (as opposed to LC/VLC) that one can achieve a healthy set point.
I suspect the rate of weight loss might be faster with low carb, but if one is not in a hurry for rapid weight loss and not completely metabolically deranged, would you expect them to eventually lose the excess weight? Again, my assumption is that the moderate carbs exclude things like fructose, wheat, etc.
Or does one need to go low carb in addition to extirpating the neolithic agents of disease so as to give ones liver a chance to heal, even if not completely broken?
Perhaps the answer requires clarification on your definition of a "broken liver" and shades of grey in between healthy and broken?
Thanks so much!
Aravind
You're killing us all with anticipation Stephan, I hope you know that! :)
Is it anything to do with flavourless calories a la Seth Roberts perchance?
Tease.
Hi Stephen,
Excellent analogy, I think that it's a really effective way to quickly describe weight metabolism and regulation.
Did anything else stand out to you in Dr. Sharma's Presentation?
Very interested to hear your idea simple new idea!
Interesting. You think melatonin is stronger or weaker than the leptin? All I know is in Miami is it much easier to stay thin!
What Tuck said!! Can't wait.
Aravind,
your definition of moderate carb intake without wheat, fructose, vegetable oils and soy is pretty much low carb.
I had success with such protocol and I have some metabolic disorders - borderline metabolic syndrome and possible hypothyroidism. I don't eat wheat, potatoes, rice and corn, 0-1 fruit per day usually kiwi or apple. I eat vegetables of all kinds basically as much as I want, 20++ eggs per week, all meats. Fats: grapeseed,flax,fish,sesame,palm,coconut,lard,butter. Lots of diary. Lots of all types of nuts.
I exercise ~ 20-30 minutes every 2nd day (push ups, weight and similar), and I walk average 45 mins per day. No alcohol, only black wine 1 glass per day. Other drinks include avg 2 coffies per day, 1 white tea & 2L of watter, 2 cocoa drinks (with water only and stevia). I use bunch of supplements every day - megadoses of B,C & D, Carnitine, Q10, Iodine, K2, Mg, Multi, Probiotic, Policosanol, etc..
I loose 3-5 kg per month so I gues its close to what you want. My pal had the same result. I aproximate carb intake at around 75-100g per day.
The drink less, pee more analogy is fantastic. I can't understand how litteraly everybody around think obesity is about character. The other analogy, used in interesting free book "Hackers diet" is that saying to obese people to eat less is like saying to people who don't see very well not to take glasses but exercise natural sense of sight (or something like that). The obesity is disease and while it depends a lot on personal lifestyle, that can be said about almost any other disease.
Its not about quantity of food but quality.
Apple for instance has around 16g of fructose. Its a lot of fructose, almost equals 1 can of Coca Cola. Whats not imediately obvious is that its loaded with GLUT4 inhibitors (flavonoids), fiber which slows down fructose absorption, Vitamin C which is glucose competitor and so on... Sugar beat contains policosanol which is well known supplement for weight loss. All natural stuff comes with poison and antidot which all get lost after food is processed.
So, if you manage to remove most of the industrial food from your diet and use fresh grocery stuff (organic or not, it doesn't matter) you will have no problem loosing weight given that you don't have some extreme metabolic disorder.
@majkinetor
Thanks for the comments. I'll make this response specific to me. I am not a strict paleo eater in that I continue to consume rice and lentils, which are needless to say high carb sources - I am of South Indian descent so this is in my DNA. The food is prepared in a manner that Stephan and Weston Price would approve of :-)
Throw in tubers and I can easily get over 100-120g of carbs per day. I do not consider 100+ grams to be low carb. Note I am pretty strict about the wheat, oils, fructose.
I am 41 years old, 5'11", and started the year at 195 lbs. By mid Feb I weighed 180 lbs. Today I weigh 177 lbs (my weight graduating college 20 years ago was 175 lbs, which was still overweight). So the weight loss has tapered noticeably, but still is progressing at a snail's pace. My target is 165 lbs (which I've never been in my adult life on SAD). I am in no hurry because my goal is health and wellness...the weight loss is an ancillary benefit.
Having said that, I know I am not at a healthy set-point currently based on % BF, waist, etc. If I need to cut the rice/lentils to resume the weight descent, then fine. But if I stay the course and crawl towards it, this is my preference rather than some austere measure simply due to impatience.
This ties to my question to Stephan about the definition of a "broken liver". Maybe my liver isn't broken, only fractured :-)
Regards,
Aravind
I, too, look forward to your future posts regarding this topic.
I have had great success both for myself (an active, lean, genetically mesomorphic male) and for my family (all obese, inactive, genetically endomorphic NW Europeans) with a “cyclical carb” diet.
My family tried the zone, which worked for a long while (my mother , for example, lost about 50 lbs in 6 months). We then tried a paleo Atkins-like approach, which provided a bit more weight loss (which may have been water anyway), but stalled within a month. Most of my family needed to lose another 50-80 lbs., and so this was not good enough.
IMO, the simplest model required for accuracy considers 3 hormones: insulin, cortisol, and leptin. This is more complicated than Sisson’s or Taube’s approaches which focus exclusively on insulin. But the added complication is needed…and actually works!
Long story short, insulin should be kept as low as possible. However, too low of carb intake (especially when active) leads to ever-so-slight hypoglycemia which requires cortisol to take part in stimulating gluconeogenesis from the liver. The trouble is that cortisol slows metabolism and promotes the accumulation of intrahepatic fat (fat stored within the liver) which is perhaps the greatest contributor to insulin resistance. Thus, keeping post-prandial insulin low by avoiding carbs is not necessarily productive long-term.
And actually, one of the complications is that consuming any specific set amount of carbs (whether low or moderate or whatever) will lead to the same result. Your body is very good at adjusting its use of carbs (as it is protein, via oxidation) to your input (provided the carbs are paleo, and do not mess with hormonal regulation like wheat, etc.). The consequence of this is that even a moderate-carb diet will begin to stagnate since activity greater than expected will result in slight hypoglycemia. Basically, your body adjusts to your carb intake as “baseline”, and then when your activity level requires more sugar than “baseline” your body gets stressed, resulting in insulin resistance and a slower metabolism.
The solution that I’ve found is to keep carbs low to moderate (think low but not ketogenic) most of the time. And then, on hard workout days, double or triple the carb intake and lower the fat intake. So, non-workout days are low carb, moderate protein, moderate fat. Workout days are moderate to high carb, low fat, low to moderate protein. The fat should be kept low when carbs are high since, again, your body will fine-tune carb oxidation in response to intake, but extra fat consumed concomitantly will then be stored. In fact, calories should be a little higher on the workout days too. The added benefit of this, besides preventing insulin resistance, is spiking leptin (which is secreted primarily by adipose tissue in response to glucose), which will further increase metabolism and fat burning, and may play a role in longevity, etc.
For those who don’t workout, just have one high carb day per week. You can think of it as a “cheat” day if you like, but the food should still be paleo (so think potatoes, sweet potatoes, bananas, etc.).
If fat loss is the goal, total calories should still be kept at 20-25% below maintenance on non-workout days, with workout days being about maintenance (maintenance requirements in Cal estimated at 12-15*bodyweight in pounds).
But you don’t have to count things: low carb days should be dark meat and veggies, and high carb days should be light meat and starches. It’s that simple. This is a paleo cyclical-carb diet.
This plan seems to work for fat and thin people, alike. This has helped me go from 12% to below 8% body fat without ANY hunger or difficulty and only 3 workout sessions per week. And, my endomorphic family members (including old ones and young ones) are now very near their ideal weights after, in each case, nearly 100 lbs of weight loss. Again, without pain or hunger. The weight loss was steady at 1-2 lbs per week.
I wonder, Stephan, is this along the lines of what you have in mind?
@aravind: Similar build to you, just 10 years ahead. When I turned 29 I **might** have been close to 200 -- but didn't own a scale. Started to watch my food, lost a few pounds, and measured myself around 195. After a year, was in 165-170 range. 10 years, kept mostly in that range. Sometimes as high as 180 -- living in hotel for two months with no exercise.
Be patient. It might take 2 years or so to really reset your body's setpoint.
Another point about weight loss it takes longer to lose a beer gut. I was a 34, now running about a 29-30, which is partially exercise but partially just liver shrinkage.
So be patient, and remember this is about health, not weight.
@Charlie,
I have no issue being patient as I noted previously, so I am with you regarding a long term focus. In Peter's Hyperlipid post on the all potato diet, he stated the following -
"The more of a problem you have with obesity the less likely you are to lose weight or experience appetite normalisation (translates as access to adipose tissue calories). Ultimately the ability to live on varied macronutrient ratios comes down to how broken you are, especially your liver. Why a broken liver requires low carbohydrate eating is another post."
So again, my ultimate question to Stephan is his take on this statement from Peter, and why I am seeking his definition of a "broken liver" - T2 diabetes/obese vs something less deranged (i.e. 20-30 lbs overweight)
Regards,
Aravind
Is it possible that the body of a pre-menopausal or menopausal women doesn't want to be thin? I am 50 years old and live in ketosis because it keeps me mentally balanced and free from health issues and problems I had in my pre-low-carb days (having leg edema was one of many -doctor told me it was typical for my age and gender and prescribed diuretic).
Stephan,
I know your main focus is on body weight but do you think acne is also due to some type of deregulation in the body?
Looking forward to this Stephan. I am getting more and more confused as to what causes obesity/being overweight - to me it now looks to be mainly veggie oils and not eating enough food, both slowing the metabolism and pushing the body into a storage mode.
2 CelticPhoenix
Thanks for details. Didn't think about that but you are probably right - body is adapting/optimising fast, so shifting seems like good idea. I do have cheat day, but that means I just add starchy or sugary food, without removing fat. I'll try to follow your guide when my wasting stops. I am pretty close to my BMI < 25 tho, with this diet.
About cortisol, it can substantially reduce weight in some people (not everybody is affected, some people get opposite). Stress made me loose around 10 pounds in less then month, although I wouldn't recommend intentional stressing for reducing your weight due to health problems. However, if there is nothing you can do about it (i.e. its about time) you can use it in your advantage.
Also, you said something that needs to be underlined: The goal should not be to loose weight, but to get healthy. That equals to loosing weight on the long run. Opposite is usually not true - most people become malnourished and sick and poisoned by following some of the popular restrictive diets.
This is somewhat in response to Aravnid.
I've been reading this blog for quite a while now, as well as a few other health blogs, most of which favor a low-carb diet for people with poor glucose control and/or metabolic syndrome.
Last May I found that I'm diabetic or prediabetic depending on how you squint.
With a BMI of 25, I eagerly embarked on a low-carb diet and it helped control my blood sugars to a degree - though my fasting sugars and between-meal sugars rose. After six months on this diet my A1C was down to 6.0 from 6.4. Not as much a I'd hoped. I lost about 20 pounds.
I developed some other health problems that I tried to address with a low-fat diet. It's gluten-free, but does include oats and legumes. I've now given up caffeine as well. My blood sugars have improved substantially - my fasting bg is now routinely between 95 and 105 and 1 and 2 hour pp between 85 and 105 (sometimes up to 125 at one hour). (I can still catch spikes a the 30-minute mark, though.) I've lost another 10 pounds and my tendency is still to lose rather than gains. I'm not particularly hungry. Most of my calories are carbs, though I try not to eat a lot of high-glycemic carbs (like potatoes) at once.
It does seem that my set-point has changed, since I'm eating to appetite most of the time and my BMI is 20 - the skinniest I've been since I was 20 (I'm now 45). I get less hungry than I ever have - less hungry than on low-carb or a "regular" diet.
I don't mean this as advice - just information.
P.S. to Aravind, following on my previous post. If my liver is broken, it's kind of hard to detect, though I find it hard to get clarity on it. My liver enzymes are normal and it is a normal size on an ultrasound.
I don't have and have never had other symptoms of metabolic syndrome. My triglycerides have ranged from 44-48 for years, my HDL ranges from moderate to high and my LDL is low. My blood pressure is a low normal.
It could be that my liver was getting insulin resistant (I'd guess due to a combination of long-term stress, sleep issues, and genetics, rather than diet) with the only sign being impaired glucose tolerance.
My psychology textbook says that body fat accumulation is the result of the breakdown of homeostatic systems. Yep it seems like those who are paying attention know this stuff.
If anyone reads this, what about the thyroid? If the thyroid is low or if thyroid hormones aren't doing their signaling to the cells, but leptin is still working properly can it still cause people to be limited to a certain amount of energy output per day?
The problem I have with this is that if I'm retaining water, I can take a diuretic ... problem solved.
There's no pill that can cause fat accumulation to reduce as quickly.
Fluid balance is just that - regulated by intake and excretion of a very small molecule.
Fat balance? Intact fats are not excreted in any significant manner. They must be oxidized to make their way out once they've been absorbed.
If you can find the key to releasing all the fat and having it EXIT the body, you'll be rich Stephan!
I reset my weight set point once. I spent 2 weeks in Europe walking a ton and eating delicious European food that was not Paleo. I figured I would gain 5 pounds but I ended up going from 153 to 138 and staying around there for a year. Very curious how I did this!
It will be interesting to see what Stephen comes up with: so far, following his and Dr. Davis' suggestions has not only gotten me nowhere on weight loss, my health is rather the worse for wear, so candidly I'm not waiting with bated breath. Mind you, my problems are not their fault -- but people like Stephen and Dr. Davis don't deal with outliers, but rather with group performance, where the nonconforming result is going to get discarded as unwanted noise. Whether there's any answer for me at all I have no idea; I do, however, clearly understand at this point that low carb (wheat-free/grain-free, paleo, whatever iteration you choose) is NOT a universal panacea, and it can have some unfortunate effects and consequences.
As a registered nurse, fluid restrictions + diuretic therapy is definitely effective to control conditions of cardiac diseases/CHF related edema. People start off with a BNP that's sky high and with proper therapy (iv lasix + fluid restrict) you see that number improve (as well as objective evidence of heart failure such as coughing/bloody sputum, shortness of breath, edema, activity intolerance, dropping O2 sat, etc).
I don't know where you get the idea that fluid restrictions + diuretics do not help control CHF. This is false.
True, it won't cure the underlying pathophysioloical cause of the heart failure (e.g. abnormality in the anatomical cardiac structures) BUT it will control the result. This is similar to how a low calorie, low carbohydrate diet will control the secondary diseases of diabetes. If you control your sugar by avoiding carbohydrate and reducing calories, you won't end up on dialysis, with multiple toe/foot amputations, with neuropathy, with all encompasing infections, with severe heart disease and heart attacks and strokes.
Diabetes and obesity, just like heart failure, can be controlled by adherence to a low carbohydrate, low calorie diet. No, you cannot cure the underlying physiological defects but you can prevent the natural consquence of uncontrolled disease (the aforementioned sequellae of diabetes and obesity as described above).
It's not controversial to say that there is something wrong with the body of an obese person or a diabetic that makes them that way. I see this every day of my life as a nurse, as well as a person who has severe obesity that I am controlling well with a low carbohydrate diet, calorie controlled diet.
Diabetes is NOT caused by high carbohydrate intake, however high carbohydrate intake absolutely 100% makes this disease worse in the vast majority of diabetics.
Many diabetes are severely diabetic even when eating nothing, or hardly anything at all. I've seen severely obese patients who were not eating as much as some much thinner people I know. These are real diseases which are not so flippantly caused by wheat or sugar or the moon being in libra. There are widespread defects in the body causing them.
However, that doesn't mean one should not do what they can to control the illnesses. Don't eat carbs. Don't eat a lot of calories. Your weight will improve and your diabetes will as well in a lot of cases. No it won't cure you, but it will control the illness.
Golly, some interesting interpretations of the post popping up in these comments. I liken the Edema Therapy analogy to most other symptom-oriented treatments - I tend to use fungal infection as my example, since wiping out the symptoms through medical processes rarely stamps out the underlying infection...
As someone who may or may not have reset their fat set point by late 2009, only to see all the weight come rocketing back after being prescribed a drug for an injured nerve, I'd be very keen to play guinea pig for your advice/program. I'm overweight, for sure, but have nothing to suggest metabolic derangement beyond my body having adjusted to carrying extra fat since my pubescence. I've just spent time healing myself and my attitude to food, and am ready to hit the road back to weight loss, especially with a sense of long-term success!
So, I can wait until you release your info, or you can email me now to get ahead and you can use my results later on... ;)
GGP
@Stephen-I like that analogy although the complexity of being overweight is far greater than edema IMO.
I too have reset my set point (a theory I think is correct-I've gone from almost 200 lbs to about 145, and have stayed there for years now). Much of it, however, I think is mental, as I have learned to find comfort in not being full, discomfort in being full and satisfaction in being lean and sticking with the eating habits that have gotten me there (maintenance calories or less). I can still eat a house if I let myself, but I don't. It's kind of like the Tony Robbins "pleasure/pain" idea. It's as much of a mental set point as a physical one for me.
Carbsane wrote:
There's no pill that can cause fat accumulation to reduce as quickly.
Some claim that HCG is just that.
Megaera wrote:
... people like Stephen and Dr. Davis don't deal with outliers, but rather with group performance, where the nonconforming result is going to get discarded as unwanted noise.
Its how science works. The science doesn't cover 100% of cases. Low carb is never claimed as universal panacea. Mercola for instance supports it but explicitelly states that there are people who don't do well on LC and he insists on 'nutritional typing'. In your position I would log my entire day, every little thing, from watter drinking to peeing for at least 2 months. Without complete log, its hard to say how entusiastic you had been about your diet. Doing my own logs, I see I underestimated my carb intake by about 200%. If the protococl doesn't work, I would examine the data troughtly, see if there are stuff I could do better. If that fails, I would switch to different protocol and do the loging again. Its a lot of work, but you get more efficent doing that each next day. Computer tools are must and adequate input that is configured right for advanced computer parsing.
ItsTheWooo2 said
I don't know where you get the idea that fluid restrictions + diuretics do not help control CHF.
Nobody said that. Its stated that it does help control it, but not cure it as it doesn't adress underlying problem.
ItsTheWooo2 said
This is similar to how a low calorie, low carbohydrate diet will control the secondary diseases of diabetes.
This is not the same. LC might cure hormonal imbalance that led to T2DBM and correct food craving/hyperinsulinemia/insuline resistance.
ItsTheWooo2 said
Diabetes is NOT caused by high carbohydrate intake.
It IS caused by high CH intake combined with (epi/meta)genetic factors and/or environmental triggers and/or nutritional deficiencies.
ItsTheWooo2 said
Many diabetes are severely diabetic even when eating nothing, or hardly anything at all.
The rules are different once patophysiology is activated. I would like to see somebody becoming T2DM by eating nothing.
ItsTheWooo2 said
These are real diseases which are not so flippantly caused by wheat or sugar or the moon being in libra. There are widespread defects in the body causing them.
Any disease can be cured by removing or introducing adequate nutrient. Its the basis of nutrigenomic science. The problem is to find the adequate nutrient.
I like were you are going with this. It matches my experience and sence of what is going on with my own weight. I look forward to more evedence and thoughts.
"The rules are different once patophysiology is activated. I would like to see somebody becoming T2DM by eating nothing."
Sure diabetes can be triggered by eating almost nothing.
http://www.ncbi.nlm.nih.gov/pubmed/8777329
Majikinetor: I will do you the courtesy of assuming you're not really trying to sound quite as patronizing as you do: rest assured that given the years I have struggled with weight control (notice, not weight loss -- I have abandoned that front, now I'm just desperately trying to forestall gain, and doing so with less and less success) I have spent vast amounts of time on notebooks, graphs, computer programs, etc., lovingly, drearily, noting, charting, weighing, measuring, intake, since 'way back in the bad old days of the absolute, hateful assurance that "if you just eat less and exercise more, THERE'S NO WAY YOU WON'T LOSE WEIGHT." Can't tell you how desperate I used to get over that one. Threw out about six-seven years worth of calories/exercise records last year, pathetic crap that it was, all that wasted time. And that was just the REALLY old stuff. Nothing current. Dude, you have NO idea.
majkinetor said...
Carbsane wrote:
"There's no pill that can cause fat accumulation to reduce as quickly."
Some claim that HCG is just that.
= = = = =
But it seems those claims are not substantiated:
http://www.obesitypanacea.com/2009/04/human-chorionic-gonadotropin-hcg-for.html
...numerous...studies have shown conclusive evidence that HCG does not enhance weight loss, reduce hunger, or increase the sense of well-being. For example, a meta-analysis in the British Journal of Pharmacology examining all of the research on HCG concluded that:
"there is no scientific evidence that HCG is effective in the treatment of obesity; it does not bring about weight loss or fat redistribution, nor does it reduce hunger or induce a feeling of well-being."
(For those who, like me, did not know what HCG stands for, it is Human Chorionic Gonadotropin.)
JBG said...
majkinetor said...
Carbsane wrote:
"There's no pill that can cause fat accumulation to reduce as quickly."
Some claim that HCG is just that.
= = = = =
But it seems those claims are not substantiated...
Indeed. If there were such a pill there would be no epidemic. Even if death were a considerable chance of a "side effect". HCG diets are also extremely low calorie.
Sorry, I think Stephan is off base trying to equate fluid balance with fat mass here.
@CarbSane-
Stephan's point as I understood is focusing on symptomatic treatment vs addressing the underlying root cause of the problem. Notwithstanding the fact that analogies are blunt instruments at times, it works just fine IMO.
Given your penchant for tautologies, your comment is not surprising.
Regards,
Aravind
@Stabby thryroid is akin to the gas pedal in metabolism. The car would still work but you have no ability to speed up or slow down based upon needs. The liver is the engine. It is the seat of metabolism and the hypothalamus is the engines microchip that controls the homeostasis. I hope this helps you get a 30000 ft view. Mito Al gave you a 30 ft view that will confuse most not steeped in neuroanatomy. Dr K
Stephan I am not sold on a set point but I have an open mind. I do believe that leptin signalling is far more important than insulin is initially. Once insulin resistance sets in the ball is already rolling down hill. Leptin resistance always preceeds insulin resistance in the human. After insulin resistance occurs than invariably we have adrenal resistance come into play and this rise in insulin and cortisol simultaneoulsy send p53 the epigenetic signals for growth and glycation among other pathways of apoptosis. The genome initially tries to protect itself by inducing apoptosis but eventually the sustained assault of the high insulin and cortisol levels induce cancer formation via epigenetic effects by shortened telomeres and of oncogenes and tumor suppressor that begin to react to the higher levels of TNF alpha and NF kappa beta and IL6. Cancer is basically a failure to communicate issue correctly between mitochondria and the DNA. The shorter the telomere of the cell the closer to death it is via apoptosis. More growth occurs because cells are driven thru the cell cycle because of high levels of the growth like hormones insulin and IGF 1. We see its effects via DNA methylation and acetylation of histone proteins in chromatin. The body normally takes out these cells via apoptosis but cant when no stems cells are left to replace the others. Then the remaining cells with short telomeres are doomed to continue to face the onslaught of IGF1 and insulin to force it to divide. A cell with a shortened telomere makes errors in mitotosis and hence cancer is the result. That is why all cancers generally walk in tandem with high insulin and cortisol levels. The whole process starts with leptin resistance. Dr K
You got my attention with this. "The core element appears to be a negative feedback loop between body fat (via leptin, and insulin to a lesser degree) and the brain (primarily the hypothalamus, but other regions are involved)."
I recently finished writing a 3 part blog examining how just this loop might very well be involved in Abrupt Onset Type 2 diabetes better known as Ketosis Prone Type 2 diabetes.
http://ketosisprone.blogspot.com/2010/11/abrupt-type-2-diabetes-onset-and-1st.html
Though I was examining the coming and going of a 1st phase response it would seem that this "loop" might be part of the same mechanism.
"I've been doing a lot of reading and I have a simple new idea that I feel confident in. It also neatly explains the results of a variety of weight loss diets. I've dropped a few hints here and there, but I'll be formally unveiling it in the next couple of months."
You suck.
Okay, not suck. But this is going to bother me like a piece of corn in my teeth until you spit it out for me (weird analogy?). Why the slow reveal???
I wonder if it has something to do with hormesis...
@Majkinetor: It’s a small point but you can’t underestimate anything by more than 100 percent. Also, your host’s name is Stephan, not Stephen.
Majkinetor:
"Any disease can be cured by removing or introducing adequate nutrient. Its the basis of nutrigenomic science. The problem is to find the adequate nutrient."
That is just patently false.
M-Al:
@ The two villages in Papau New Guinea. Interesting. Maybe the difference was in their gut flora. There have been some articles out recently about how some people's gut flora predisposes them to overweight. Another layer of the onion.
@ Daddy's epigenetics. You got me trying to remember my husband's diet and weight at the time our daughters were conceived. I have three-year-old fraternal twins. Since age one, one has clearly been more disposed to putting on chub, and the other toward relative leanness. The difference is subtle so far, but I wonder and worry how it will play out for our chub-prone one, especially with diabetes on both sides of our family (and neither diabetic party being remarkably chub at diagnosis).
Hi Carbsane,
You probably know that there are multiple anti-obesity drugs already in existence, that have been on the market past and present. The problem is, they aren't very effective. Why? Because they don't target the homeostatic system.
Drug companies are getting wise and working on drugs that increase hypothalamic leptin sensitivity but none have cleared the FDA yet. I hope I'm not on this earth the day the majority of Americans are on an anti-obesity drug.
Hi John,
I think the problem many people have with the word "setpoint" is semantic. It's not an immutable thing that defends the same amount of fat mass under all circumstances. Like the thermostat in a house, it can be changed to defend a different setpoint. The body fat setpoint defends energy balance within a qualitatively similar diet and lifestyle context. It can change in response to changes in both dietary and lifestyle factors. I'll expand on this more soon.
Hi Brock,
Sorry, the idea has been a long time coming and it will take time to develop on the blog. I don't want to go off half-cocked but I think you'll find it was worth the wait.
Type 2 diabetes may have an immune system link.
http://www.physorg.com/news/2011-04-type-diabetes-immune-link.html
Apparently, you can develop antibodies toward your own fat cells, inducing insulin resistance.
I wonder how much the correlation between Type 2 diabetes and other autoimmune disorders has been researched.
The hygiene hypothesis, lack of vitamin D, and genetics come into play as predisposing some people to autoimmunity. Everyone's been blaming carbs and fat for diabetes. Maybe weight gain just triggers an underlying tendency to an autoimmune response, the way gluten triggers celiac disease or alfalfa sprouts can trigger lupus-like symptoms. It's a trigger but not the "cause."
It's wrong how excited I am for the follow-up to this cliffhanger post!
s, your story sounds like Seth Roberts' experience, and how he started to develop the Shangri La diet. You might want to check it out!
Thanks Steph I'll check that out!
"In the first three weeks of his diet, Mr. Voigt estimates that he was only eating 1,600 calories per day. Aha! That's why he lost weight! Well, yes. But let's look into this more deeply. Mr. Voigt was not deliberately restricting his calorie intake at all, and he did not intend this as a weight loss diet. In my interview, I asked him if he was hungry during the diet. He said that he was not hungry, and that he ate to appetite during this period, realizing only after three weeks that he was not eating nearly enough calories to maintain his weight*. I also asked him how his energy level was, and he said repeatedly that it was very good, perhaps even better than usual. Those were not idle questions."
"The fact that he didn't experience hunger or fatigue implies that his body did not think it was starving. Why would that be?"
"You see this same phenomenon very clearly in rodent feeding studies. Changes in diet composition/quality can cause dramatic shifts in the fat mass setpoint (5, 6). Mr. Voigt's appetite would eventually have returned to normal once he had stabilized at a lower body fat mass, just as rodents do."
"Another possibility that I've been exploring recently is that changes in palatability (pleasantness of flavor) influence the fat mass setpoint. There is evidence in rodents that it does, although it's not entirely consistent. For example, rats will become massively obese if you provide them with chocolate flavored Ensure (a meal replacement drink), but not with vanilla or strawberry Ensure (10). They will defend their elevated fat mass against calorie restriction (i.e. they show a physiological starvation response when you try to bring them down to a lower weight by feeding them less chocolate Ensure) while they're eating chocolate Ensure, but as soon as you put them back on unpurified rodent pellets, they will lose fat and defend the lower fat mass. Giving them food in liquid or paste form often causes obesity, while the same food in solid pellet form will not. Eating nothing but potatoes is obviously a diet with a low overall palatability."
I found this interpretation of Voigt's potato diet very interesting... Maybe there are some hints we can pull from here?
@Stephan
Looking forward to your ideas - I'm guessing palatability and NADs in novel amounts/ densities in processed food.
@Carbasane
You said:
"The problem I have with this is that if I'm retaining water, I can take a diuretic ... problem solved."
Are you serious?
Your ankles are perhaps less swollen and you may be less short of breath, but I assure you the giant scar in your myodardium or your leaking nephrons or your failing liver is not repaired by taking a diuretic.
(it could be nephrotic syndrome or hypoalbuminemia as well - but I am sure you knew that with all the papers you have read)
Maybe failure to imagine all the impossibly complex mechanisms in living organisms is what keeps you perseverating on the CICO tautology.
I think Stephans' quoted analogy is perfectly apt.
And there is simply no conceivable way that there is not a setpoint mechanism that regulates intake of food, any more than there is not one for oxygen or water. Any of these homeostatic systems can be overridden somewhat, but they are always there.
Leptin resistance? I think is caused by fructose - but is it permanent?
Dietary changes to effect Amylin? I'm wondering if milk products are involved?
Other dietary effects on Amylin and Leptin resistance?
Somehow I'd missed the paragraph about the chocolate Ensure before (from Stephan's post about the potato diet). Fascinating! So rats like chocolate, too.
Poor rats - I can think of tastier things than chocolate Ensure.
There are so many factors to obesity and our modern life seems to favor them all.
Yesterday I was in a waiting room where the TV was showing Rachel Ray. Between the ads and the show, there were continuous prompts to think about highly caloric, refined-carby food (which Rachel Ray then described as "healthy"). Magazines are the same way - especially women's and kids' magazines. I can't imagine that having food flashed before your eyes every five minutes wouldn't trigger hunger.
@Stephan & All: I'm in no way contesting that we have homeostatic systems at play in weight regulation. I just know from my own experiences and reading and discussing with countless others their experiences, that it's so much more than just some dietary agent that somehow upset the turnip cart and sent the turnips rolling ever faster down the hill of metabolic chaos.
@Stephan: Yes, I'm well aware of the fact that anti-obesity meds are largely ineffective. But, if one is looking at a homeostatic model, would you not include appetite suppressants as being targeted to part of that system?
IAC, that wasn't really my point so much as fluid balance is far more instantaneous and manipulatable than tissue balance (for lack of a better term). Ionic and water transport across membranes and in and out of the body is largely regulated subconsciously and is relatively rapid - requiring no change in chemical structure, etc.
To use the Drink Less, Pee More analogy to ELMM, one must also consider Drink More, Pee Less. Umm... except at extreme levels (there is such a thing as water toxicity as I'm sure you're aware) I could drink more and more and more and it wouldn't cause edema. It might even help to alleviate it. There are surely limits on peeing less. Hydration is a far more short term situation. You die sooner from lack of water than lack of food.
But fats must be esterified and hydrolyzed to be transported across membranes and oxidized to CO2 to be excreted. If only we could pee or poo the fatty acids down the loo!
So even if one were to just look at the triglyceride/fatty acid cycle for fat storage/mobilization, which would be analogous to fluid balance regulation, stimulating lipolysis only shifts the form of the lipids, it doesn't get rid of them.
Also in the edema analogy, it would be darned difficult to produce edema in a healthy body. However even lean folks can be enticed (compensation for study participation) to induce a state of adiposity. Although most will return to their former states after study end, it does take a while, and if they were forced to maintain the elevated weight for a period of time, I suggest the return to normalcy might well be delayed or incomplete.
Anyone who has suffered through eating disorders, as I and countless others have, can tell you that, whatever setpoint our bodies are naturally dialed in to defend, it is shockingly easy to override. Not only would fluid balance be difficult to impossible to override (especially in the "positive") w/o impending death, I'm not sure I know any who have tried. Such is the nature of obesity that goes unmentioned by those seeking a single underlying etiologic cause or dietary agent.
@Kurt: Might it be possible to have a comment from or conversation with you where you don't always argue the end-stage disease state and presume me to be on my deathbed from massive organ failure? Has your wife never gotten a little bloated around that time of the month? Are her kidneys failing? C'mon!! My mom gets edema in one calf from an injury. I used to get swollen ankles when I was fat. It doesn't happen anymore.
A goodly portion of overweight adults start out normal weight through their 20's or 30's even. Then they start to pack on a few pounds. Those fatty acids need to be oxidized to make their way out. Otherwise why not just suppress insulin for a few days and reverse the obesity?
A question for you both: If it were possible to switch leptin sensitivity on in the obese, do you think that would solve the problem?
@Kurt
Judging from Stephen's recent posts, I think you're right.
When I read this post it reminded me of some stuff he wrote in his 'Potato Diet Interpretation', the most relevant being:
"Another possibility that I've been exploring recently is that changes in palatability (pleasantness of flavor) influence the fat mass setpoint."
This makes sense in the context of a variety of diets success on weight loss.
And of course novel density of NAD's in the diet:
"One possibility is that cutting the wheat, sugar, most vegetable oil and other processed food out of Mr. Voigt's diet was responsible for the fat loss. I think that's likely to have contributed. Many people find, for example, that they lose fat simply by eliminating wheat from their diet."
Stephan,
Regarding setpoint, it would help to distinguish:
a) The target point of the feedback system.
b) The (average) settling point of the feedback system.
For a thermostat this would be a) temperature set by the user, b) average temperature the user ends up with.
My (wild) speculation is that for the lipostat the target point is largely fixed.
However, the settling point is highly variable, because any feedback system is very sensitive to measurement errors in the feedback path.
Example: feedback measurement below actual value → settling point above target point.
Leptin measurement seems to be hindered by insulin. Insulin appears to act on the same neurons in the arcuate nucleus as leptin (NPY and α-MSH). And as an energy signal, insulin is postprandial/urgent, while leptin is long term/less urgent. So, it sounds plausible that insulin signalling will override leptin signalling.
If true, it means that fasting insulin can affect long term fat mass. Not so much because of inhibition of lipolysis, but more because fasting insulin can prevent the hypothalamus from "seeing" all the leptin. This would cause the lipostat to settle above its target point.
My current hypothesis is that liver health is key in weight management.
Liver health ↑ → fasting insulin ↓ → leptin measurement error ↓ → healthy energy balance.
This model seems to explain several observations: staying lean on high calorie diets, fructose's impact on fat mass, rats getting fat on ad libitum lard, weight gain due to refining and/or high palatability, etc.
John
Carbsane,
"But fats must be esterified and hydrolyzed to be transported across membranes and oxidized to CO2 to be excreted"
Yes, and in a leptin sensitive person high leptin will cause the hypothalamus to set that in motion.
If you have access to a recent copy of Lehninger Principles of Biochemistry, chapter 23 covers lipostat theory and leptin action with nice illustrations. These can also be downloaded as a PPT (in a .zip file).
Lipostat/leptin figures start at slide 56 (fig. 23-33). Slide 58 (fig. 23-35) gives a nice overview of the hypothalamic regulation of energy balance.
"Otherwise why not just suppress insulin for a few days and reverse the obesity?"
Robert Lustig, in his interview with Jimmy Moore, talked about how this was done in obese children. They suppressed insulin with drugs, and the obese children automatically started moving more and eating less. No conscious effort or discipline required, just a properly functioning lipostat that regulates energy balance.
John
Might-ochondri-al
You said
"In rodent models, for example, a sire fed a highly fattening diet up-regulates 21 genes and down-regulates 56 genes in the daughter; with the notable end result being less pancreatic islet volume and inadequate Beta cell potential."
Do you have a link for this please.
At a lecture on epigenetics, it was suggested the gene switches were reset at conception, which if correct makes me wonder how the father would influence the gene settings.
Would it not make sense for the mother to be the primary influence, her diet, and the environment she experienced, setting the genes in the foetus to maximum the survival chances of the infant by preparing it for the food and conditions it could expect in life.
Thanks Stephan for your great posts and every body for the great information and debate on this blog.
@Stephan
You wrote: "I think the problem many people have with the word "setpoint" is semantic. It's not an immutable thing that defends the same amount of fat mass under all circumstances. Like the thermostat in a house, it can be changed to defend a different setpoint. The body fat setpoint defends energy balance within a qualitatively similar diet and lifestyle context. It can change in response to changes in both dietary and lifestyle factors. I'll expand on this more soon."
I'm looking forward to your expansion on this (as well as your elucidation for a treatment of obesity...in fact I look forward to your posts, in general).
I'm not sure the problem with "setpoint" is semantic, and may be fundamentally different from "settling point," for example. There is a competition of forces and negative feedback loops at play, but the way I tend to see it is there's no ultimate regulator of the level of fat accumulation. 'Just nature and the environmental forces that effect it.'
I also picked up a comment from Dr. Harris [@Kurt G. Harris MD] on one of your prior posts where he wrote: "I think a set-point is the only possible explanation for normal people having stable weight without counting anything.”
If you replace the words ‘stable weight’ in Dr. Harris's comment with a multitude of outputs, be they body temperature, total body water, blood glucose, for example: Do we have a thermostat, hydrostat, and glucostat, respectively? Or do we have control systems, feedback loops, which do not imply a set point, rather they settle at numbers that we can generally predict, and it appears as though a set point is involved?
http://segamartinez.blogspot.com/2011/03/set-point-versus-settling-point.html
It might be semantic, but I'm not so sure.
Stephan wrote: "For example, if you have edema because your heart isn't pumping effectively (cardiac insufficiency), the heart is the problem that must be addressed. Any other treatment is purely symptomatic and is not a cure."
I wouldn't say that our heart is fighting our hydrostat, rather the cardiac insufficiency is leading to a cascade of feedbacks that ultimately lead to edema. We want to address the problem, i.e, the heart, not the 'hydrostat.'
@John
Thought-provoking comments. And if it's all about liver health, you would have to imagine that alcoholics have an unhealthy energy balance?
Also, I posted about Lustig's study on octreotide, and lowering insulin levels:
http://segamartinez.blogspot.com/2011/04/robert-lustig-does-low-insulin-cause.html
@Carbsane
Stephans' quote is as follows:
"For example, if you have edema because your heart isn't pumping effectively (cardiac insufficiency), the heart is the problem that must be addressed. Any other treatment is purely symptomatic and is not a cure.
The same applies to obesity. If you don't correct the alteration in the system that causes an obese person to 'defend' his elevated fat mass against changes*, anything you do is symptomatic treatment and is unlikely to be very effective in the long term."
My expansion of the analogy is the same as Dr. Sharma's and Stephans'. Neither of them is talking about perimenstrual puffiness. We are talking about the kind of edema it would be legitimate to treat with diuretics, the kind affecting oxygen exchange in the lungs and not just a little ankle swelling. Your rebuttal to Stephan is the one entirely missing the point, as you are the one confusing a touch of transient ankle swelling in a normal person with the pathologic edema that is caused by heart failure, end stage liver disease or nephrotic syndrome. In all of these cases, a diuretic provides symptomatic relief but does not address the ultimate cause of the edema.
Extending the metaphor back to diet, the difference between perimenstrual symptoms and pulmonary edema is like the difference between weighing yourself after a meal and actual fat gain over time. Transient vs more permanent.
You claimed the analogy to edema was not apt, and this is because you are failing or refusing to understand what edema actually means medically - the way Drs. Sharma, Guyenet and Harris are all understading it, and the reason we all think the analogy is apt.
We are not talking about perimenstrrual puffiness or about weighing yourself after a piece of pie.
Nice discussion, but all the toing and froing over the aptness of the analogy misses the point IMO; namely, that fatness is not inherently pathological.
Fatness of itself, is merely energy storage.
Now, given that the bulk of our evolutionary history is spent trying our darnedest to stave off starvation long enough to reproduce successfully, why do we still see fatness as an 'unnatural' state.
Given an abundant food source, fatness is perfectly natural, as are all the eating behaviours that support it (eating highly palatable so-called 'junk' foods, eating until stuffed, eating quickly etc.).
It's this very abundance of food that is the unnatural 'pathogenic' agent, not our eating response/s to it.
Now, since it's unlikely that food is going to become scarce any time soon, we're stuck with an unnatural food abundance.
As such, we require an unnatural response.
Low fat dieting sure is unnatural.
But so is avoiding tasty sugary fatty confections when they're available.
And so is 'formal' exercise.
Bottom line; your body 'wants' you to be fat, because it still perceives the danger from starvation as being way more serious than the diseases of civilisation.
There's NOTHING you can do to change that.
But if you want to employ some 'unnatural' manoeuvres to affect your body weight and body composition, then pick one that works for you.
Trying to isolate the one (or two, or three) factor that will 'trick' our body into settling into homoeostasis at a body composition that we find aesthetically pleasing (when all it really wants to do is to store ample energy for the famine that will never come) is hubristic IMO...not against the gods, but against millions of years of evolution.
For most people, looking like a supermodel will, and ought to be, hard work.
Cheers
Harry
I guess I have to articulate better in language even a doctor will comprehend then Kurt. ;-)
In order to be apt, an analogy must fit what we observe clinically as you are so enamored of reminding us.
So let's see. Fluid balance: Fluid in = Fluid out + Fluid retained. And Sharma is trying to make the analogy to energy balance: Energy in = Energy out + Energy stored.
Well, here's what we observe:
Fluids: If we drink more, we pee more and if anything, those prone to edema from certain (but not all) causes, may actually retain less water. Conversely if we drink less, we tend to pee less. I don't know about you but I tend not to drink a whole lot of fluids before a long car trips for a reason! Normal folks can drink a LOT more than needed and not retain more water. Same if one finds themselves deprived of fluids. A physiologically dehydrated person doesn't shrivel up to nothing (before dying!). Lastly, we can do little if anything that I'm aware of to alter urine volume output independent of diet. I suppose sweating out fluids in a sauna might qualify, but that's just changing the exit route.
Now Energy: If I eat more my body MAY expend a little more energy (TEF) and/or my metabolic rate MAY go up a little bit. In overfeeding studies, subjects may expend a bit more, but they predictably add
weight/store energy. And the opposite occurs for calorie restriction - weight IS lost even with a compensatory decrease in energy expenditure. Add to that the fact that we CAN intentionally increase energy expended (exercise/activity) independent of diet.
We can simplify this further. Fluid balance is a process involving transport only. Energy/mass balance is one of both transport and transformation (chemical reactions/metabolism).
So, I don't think it takes an MD or PhD after one's name to see how there analogy here simply is not apt. Perhaps you need to embrace your inner reasonably well educated child?
I guess I have to articulate better in language even a doctor will comprehend then Kurt. ;-)
In order to be apt, an analogy must fit what we observe clinically as you are so enamored of reminding us.
So let's see. Fluid balance: Fluid in = Fluid out + Fluid retained. And Sharma is trying to make the analogy to energy balance: Energy in = Energy out + Energy stored.
Well, here's what we observe:
Fluids: If we drink more, we pee more and if anything, those prone to edema from certain (but not all) causes, may actually retain less water. Conversely if we drink less, we tend to pee less. I don't know about you but I tend not to drink a whole lot of fluids before a long car trips for a reason! Normal folks can drink a LOT more than needed and not retain more water. Same if one finds themselves deprived of fluids. A physiologically dehydrated person doesn't shrivel up to nothing (before dying!). Lastly, we can do little if anything that I'm aware of to alter urine volume output independent of diet. I suppose sweating out fluids in a sauna might qualify, but that's just changing the exit route.
Now Energy: If I eat more my body MAY expend a little more energy (TEF) and/or my metabolic rate MAY go up a little bit. In overfeeding studies, subjects may expend a bit more, but they predictably add
weight/store energy. And the opposite occurs for calorie restriction - weight IS lost even with a compensatory decrease in energy expenditure. Add to that the fact that we CAN intentionally increase energy expended (exercise/activity) independent of diet.
We can simplify this further. Fluid balance is a process involving transport only. Energy/mass balance is one of both transport and transformation (chemical reactions/metabolism).
So, I don't think it takes an MD or PhD after one's name to see how there analogy here simply is not apt. Perhaps you need to embrace your inner reasonably well educated child?
@John, I'm glad you brought up Lustig. His observations are the closest to being analogous to fluid imbalance. As Harry points out, most energy imbalances (e.g. obesity, anorexia) are NOT pathological - at least from a metabolic point of view.
Lustig works with children with hypothalamic obesity: A rare side effect of brain surgery resulting in hypothalamic dysfunction and corresponding hyperinsuinemia. This hyperinsulinemia results in the kids feeling sluggish and having voracious appetites.
The radiation and/or surgery results in hypothalamic and downline pancreatic dysfunction. This is rare amongst a rare subset of the population - e.g. it's not informative as to the causes of obesity amongst the general population.
Yes, reverse the pathological hyperinsulinemia - pharmaceutically I would add - no amount of low carbing would work in this situation - and normal homeostasis of the triglyceride/fatty acid cycle is restored.
This is not the problem for the diet-induced obese. They have increased availability of free fatty acids, fats are not "locked away". Non-oxidative glucose disposal is impaired because of overnutrition/NEFA excess.
Might-o'chondri-AL
MANY thanks for that, and your really helpful explanation (more basic reading required on my part)
"In the next wave of changes the germ cells altered & then re-methylated de-novo (ie: "erased" some initial programming)."
In the lecture (which I struggled to understand) it was suggested that most of the initial programming was reset.
But clearly from the trial you posted some influence of the fathers gene expression may remain in females.
Much of the detail is beyond my knowledge, but the implications are fascinating, and rather scary even if primarily driven by the conditions in utero).
Did you see the second comment
http://www.nature.com/nature/journal/v467/n7318/full/nature09491.html#/supplementary-information
Any thoughts?
Again many thanks for you excellent and thought provoking contributions.
Stephan, I hope you're a regular reader of Emily Dean's blog Evolutionary Psychiatry. She's recently made me very happy writing a couple of posts on the endocannabinoid system and the implications of excess omega 6s in the diet wrt appetite and obesity.
Not sure where you're going re fat homeostasis, but compliance on any way of eating would certainly be easier if it doesn't involve potentially synthesizing THC-like chemicals courtesy of high carb/high veggie oil foods.
Cholescystokinin and gut brain signaling:
http://www.ncbi.nlm.nih.gov/pubmed/19345244
"Endocrine cells of the gastrointestinal tract act as aluminal surveilance system responding to either the presence of absence of food in the gut lumen. Collectively, their secretory products regulate the course of diigestion and determine the delivery of nutrient to the gut by controlling food intake."
Thus it appears that food inake to a degree regulates the setpoint.
The appetite suppressant cholecystokinin (CCK) is secreted by the gut in response to the presence of undigested food at the ileum at the end of the small intestine. The primary trigger of the "ileum brake" is fat. Increased secretion of CCK results in inhibition of transit of food through the gut and results in reduced appetite and reduced food intake. As little as 3 grams of fat infused at the ileum increased CCK synthesis in a dose dependent manner.
Thus it appears that the reduction of food intake observed in those on a high fat diet, compared to those on a low fat diet, is due largely to triggering of the ileal brake in response to fat.
Old folks, even those in good health, frequently experience unwanted weight loss as they age. Apparently their setpoint is reset because of increased secretion of CCK as well as increased sensitivity to CCK.
(From PMID 20703055, 20590826)
Jack C,
That is interesting. I also recall reading that CCK signalling is disrupted in people with diabetes and in people with untreated celiac disease. This can lead to a dysfunctional gallbladder, which relies on CCK to tell it to squeeze that bile through.
I've done nothing but lose weight on a low-fat diet, which is high in soluble fiber. On a low-carb, high-fat diet, my weight loss was slow. On a WAPF diet (high fat, high carb), my weight gain was rapid and my appetite greater than it is now. I have mild diabetes (which put an end to WAPF for me). In January I had my gallbladder out.
I wonder if my CCK was not working so well, so I wasn't getting the signal to stop eating or to squeeze that gallbladder. I wonder if gallbladder dysfunction could be a sign that you won't get the appropriate "stop-eating" message from fat in your diet.
Might-o'chondri-AL
Thank you for all your comments, which are always informative and thought provoking, and must take a great deal of time - and we all have limited time. Better a rushed post that no post from my perspective (-:
You know a very great deal more than I do.
There are many who think the father has a role.
I have no idea who is right in the epigenetics debate, and do not have the knowledge to from an opinion.
I totally agree there is still so much to learn.
I've been thinking about altering the set-point. I did notice that when I started low-carbing, the set-point seemed to reset itself about 60 pounds below where it had been previously.
When I began eating lots of nuts, the set-point seemed to go up by about 10 pounds. When I added two tablespoons of coconut oil in the morning, it went back down again. I'll be keeping an eye out for the possibility that it's not just willpower but that certain foods can reset the setpoint.
Carbsane & all,
Let's take a lard fed rat as an example. My (highly simplified) guess on the Carbsanity explanation:
Calorie excess ↑ → fat mass ↑ → NEFA ↑ → insulin resistance → metabolic syndrome. (Please correct me if I got this wrong.)
My lipostat/liver hypothesis was inspired by Chris Masterjohn's choline series (Nov 2010).
From that, the criteria for fatty liver seem to be:
1) Provide the liver with high energy.
2) Do NOT provide the liver with nutrients it needs to process that energy.
It's a bit like burning lots of gasoline in an engine, without providing oil or coolant.
The liver eventually converts its unused energy to fat, and makes it available to the rest of the body by exporting it into the blood. But fat is not soluble in blood, so the liver packs it into VLDL, for which it needs nutrients like choline. No choline → fat stays in the liver.
A rat on a calorie dense, nutrient/choline poor diet seems to meet the criteria: fatty liver → liver insulin resistance → fasting insulin ↑ → hypothalamic leptin measurement interference ↑ → energy balance shifts to "move less, eat more" → calorie excess ↑ → fat mass ↑ → NEFA ↑ → insulin resistance → metabolic syndrome.
My hypothesis doesn't challenge the NEFA/IR idea. It just tries to explain why the rat ate beyond its caloric need: impaired lipostat function due to fatty liver.
The hypothesis would predict that a rat on a similar diet but with sufficient choline would retain normal lipostat function, causing it to eat within caloric needs. Not because choline is satiating, but because it keeps an organ crucial to metabolism from getting clogged.
Highly palatable food? This seems to override short term satiety signals → risk of a high calorie-to-nutrient/choline ratio ↑ → risk of fatty liver ↑ → etc.
Food refining? This usually reduces nutrients and increases calorie density. So, duh!
Fructose more fattening than glucose? Fructose is nearly completely disposed of by the liver, whereas most glucose is disposed of outside the liver. So in a choline deficient context, fructose would lead to fatty liver faster. Glucose disposal is a bit like burning gasoline outside of an engine: the engine's oil and coolant status is irrelevant in that case.
John
Helen, I think you hit the mail on the head when you asked if CCK not working properly could prevent getting signal to stop eating or to squeeze the gall bladder.
To quote from the abstract "Abnormal small-intestinal endocrine cells in patients with irritable bowel syndrome."
"Conclusions: The low densities of secretin and CCK cells in IBS-diarrhea patients may cause a functional pancreatic insufficiency as well as inadequate gallbladder emptying, as these hormones stimulate pancreatic bicarbonate and enzyme secretion and CCK stimulates as well gall bladder contraction.----"
When CCK secretion is adequate (or more than adequate) the transit food through the gut is slowed or even stopped so it is difficult to continue eating. It is a signal that is hard to ignore.
http://www.ncbi.nlm.nih.gov/pubmed?term=20300845
@CS
I am not instructing "us", I am instructing you, as you are the one who is perpetually confused, and who thinks you know much, much, more than you do.
You said:
"We can simplify this further. Fluid balance is a process involving transport only. Energy/mass balance is one of both transport and transformation (chemical reactions/metabolism)."
You really have no idea what you are talking about and everything you write just demonstrates it further.
Water is partitioned into various compartments - IC, EC, and insterstitial, under hormonal and neurohormonal control and within relatively wide parameters of intake that do not need to be consciously monitored under normal conditions.
Stored energy including fat is also created and partitioned under neuro -hormonal control and in a NORMAL individual, is relatively independent of conscious knowledge of caloric value or macronutrient ratio. I use myself as just one example. I never count, weigh or measure my food and my weight only goes up just a little if I lift weights a lot. I don't accidentally get fat even though I live in a "food abundant" environment. I don't accidentally lose fat mass because I forget to eat, either.
I also don't accidentally get pulmonary edema from forgetting to measure my water intake or from peeing too much.
If you weigh 300 lbs that is pathological, not an accident related to forgetting to stop eating.
If you have pulmonary edema and swollen ankles, that is pathological and not due to accidentally drinking too much water.
I know you just don't get it and you never will. You're destined to be forever stuck on high school physics.
@CS
You said:
"I don't think it takes an MD or PhD after one's name to see how there (sic) analogy here simply is not apt. Perhaps you need to embrace your inner reasonably well educated child?"
I guess you would be calling Dr Sharma and Stephan stupider than children here as well, then?
I just want to be clear on the long, long list of folks that you are so much smarter than.
Please teach us more!
I am sure you've read a few papers from pubmed about fluid balance and how it is regulated. I'm sure it must be much simpler than those nephrologists and ICU internists think it is.
@Carbsane
"most energy imbalances (e.g. obesity, anorexia) are NOT pathological - at least from a metabolic point of view."
Are you just teasing me now? Stop it!
I can only respond to a limited number of your outrageously moronic statements in one evening.
@Kurt: You really need to find what's missing in your diet that causes you to react the way you do. The sarcasm was directed at you.
The typo, BTW, should have been "the" not "there" - can't edit comments.
So you think anorexia,as we use the term - yes I'm aware that certain conditions can lead to wasting - develops because someone's metabolism goes haywire? That was my point. The development of the obese state - storing excess intake in adipose tissue - is not pathological in most cases. It is normal physiological function. It is when this normal process breaks down that problems occur. Drs. Frayn, McGarry, Boden, Bays etc. who have spent distinguished careers studying this are all wrong I suppose.
The analogy thing doesn't even require an understanding of fluid balance, however. The point is that for two things to be analogous certain criteria must be met. Those criteria are not met by the observable differences between the two systems.
Drinking too much doesn't cause edema. Eating too much will cause obesity.
@John: It's not *my* hypothesis, it's the hypothesis of the culminations of the life works of folks like Frayn, Bays and Boden. With a crap load of evidence in support, I might add.
You may be interested in: http://carbsanity.blogspot.com/2011/03/why-we-get-sick-fat-lessons-from.html
http://jcem.endojournals.org/cgi/content/short/89/2/463
@Kurt: I can only respond to a limited number of your outrageously moronic statements in one evening.
Then don't respond. I can only respond to a limited number of your outrageously obnoxious statements.
What is it about pointing out the flaws in making the analogy here that got your boxers so bunched? Afraid someone else might agree with me if you don't pull your "I'm a doctor" card for trump?
Carbsane wrote: "You may be interested in: [link]"
I follow your blog, so I already read it. I also read the February version without the "sick".
Stephan's comment in that version was very appropriate in my opinion: "No one studies the health effects of unrefined high-fat diets in rodents to my knowledge".
Like I said, I'm not challenging the NEFA hypothesis. I just think it's only a small part in a much larger system. And I don't think that anyone can ever understand the behaviour of an entire system by only zooming in on a small part.
However, some seem to think they can by zooming in on insulin. Others seem to think they can by zooming in on fructose. And to me you appear to do a similar thing with NEFA.
I prefer to zoom out and see how I can fit together all the small parts like NEFA, insulin, leptin, choline, etc. to hopefully get a better insight in the entire system.
That zooming out resulted in my lipostat/liver hypothesis. Perhaps it's highly inaccurate, but for the moment it seems to fit many observations very nicely :-)
John
John, the high fat diet in that study was mostly lard (5.6% soybean oil/40% lard). Some refined, but hardly can be dismissed as being Crisco or somesuch. My generation was not raised on home rendered lard and tallow alone.
In a prior post you stated the liver is the engine. My zoomed out view is that the liver is the combination recycling plant (packing up chylo remnants etc.) and back-up battery (gluconeogenesis) not the energy supplier for the body. Each cell has its own engine - mitochondria.
NEFA is not a dietary agent here. Levels are properly determined by well regulated fat tissue independent of dietary intake. However dietary fat is to NEFA in a person with "sick fat" as dietary carb is to hyperglycemia in diabetic/IR individuals. Dietary fat will add to circulating NEFA when fatty acids liberated from chylo are not efficiently trapped by adipocytes.
Most seem to have no problem acknowledging the bad effects (e.g. glycation) of chronic hyperglycemia. For some reason they don't want to even acknowledge those of chronic elevated NEFA.
"In a prior post you stated the liver is the engine"
No I didn't. That would be ridiculous, because that is not my view of the liver at all.
I said that providing the liver with high energy, while not providing it with nutrients to process that energy is a bit like burning gasoline in an engine, without oil and coolant.
I was trying to illustrate the absurdity of doing this to the liver, which obviously didn't come across. But how you can read that as me saying that "the liver is the engine" is beyond me, certainly given words as "is A BIT like".
My (way too simplistic) analogy for the liver: a processing and distribution plant. In other words, a lot of the food you eat passes through the liver. The liver will process the food and distribute the output of the processing to the body. And if the distribution part doesn't have the resources (e.g., choline) for a high demand, the processed output just piles up. And this can set in motion a whole cascade of problems, like a screwed up energy balance, which ultimately results in IR, elevated NEFA, obesity, etc.
So to make it explicit: when you eat a lot of nutrient poor high calorie food, indirectly you dump a lot of work onto the liver without supplying it with the resources necessary distribute the end product. So it just accumulates in the liver, making it sick. And I think a sick liver is an effective way to create metabolic problems.
John
My apologies Capital J John, it was a lowercase j john who made that statement and I confused you two.
I have 2 Alans that have commented on my blog and have confused them. Pretty sure there have been at least two Johns as well. It gets confusing.
I agree with everything you say in your post. But part of dumping too much nutrition into the liver seems to be the release of NEFA from it's proper storage depots.
Moral of story: Be kind to your liver ;-) I think we agree there?
Looking forward to the conclusion of your research. (Or even a sneak preview.)
"Moral of story: Be kind to your liver ;-) I think we agree there?"
Most certainly.
"But part of dumping too much nutrition into the liver seems to be the release of NEFA from it's proper storage depots"
I was thinking along the same lines. This made me realize that my liver/lipostat hypothesis wasn't zoomed out enough → revision 2 of the hypothesis ;-) The central idea remains the same, the model just becomes more elaborate.
(***)
Energy in the body has 3 possible destinations, depending on energy type and context: muscle cells, fat cells, or the liver.
Muscle cells are, from the viewpoint of the liver, an end site of energy: no energy flow from muscle cells to the liver. Only exception: lactate (Cori cycle).
Verdict: fatty liver potential of energy going into muscle cells seems nearly zero.
Fat cells are, from the viewpoint of the liver, a conversion site of immediate energy into time release energy (NEFA). So the immediate energy that goes into fat cells, is no threat to the liver. However, when it is released as NEFA lateron, it could still be a threat, if the NEFA dose is high.
On the other hand, high NEFA will cause tissue insulin resistance, i.e., some glucose disposal pathways are closed down. This is liver friendly, as this lowers the liver's gluconeogenesis burden. This type of insulin resistance should not affect fasting insulin levels, therefore leptin signalling should not be impaired. And as high NEFA suggests more fat mass, leptin would be high as well, and the hypothalamus would switch to "eat less, move more" energy balance. That would reduce the likelihood of eating and therefore additional fat mass and NEFA. Plus, the increased metabolism would cause more NEFA to be used.
Verdict: fatty liver potential of energy going into fat cells seems medium to low in normal situations, but very high if leptin signalling is impaired.
Energy not handled by muscle or fat cells will go to the liver. The energy that the liver doesn't use, can become fat or ketones. Ketones are water soluble, and can therefore be exported into the blood as is. Fat on the other hand, requires choline for export. If not available, fatty liver → liver insulin resistance → blood glucose ↑ → all insulin levels, including fasting levels ↑ → impaired leptin signalling → energy balance to "eat more, move less" → energy in body ↑ → vicious cycle.
Verdict: nutrient status seems to determine fatty liver potential of energy going into the liver.
Note that as the liver exports energy it doesn't need, we loop back to (***).
Hmmm, the old revision was shorter ;-)
John
"You seem to be looking for choline to be a dietary determinant"
I can understand that it may come off that way. So just for clarity: it is not my intention to look for a (single) dietary determinant for fatty liver. I don't think going bottom-up is useful here. I tried to approach it top-down, and choline just happened to pop up as an important factor, based on the limited information I have.
My hypothesis was the result of me recently asking myself the question: how can I consolidate rats getting fat on an ad-libitum lard diet with the idea of a leptin based lipostat? Immediately I thought of insulin/leptin interference and what Chris Masterjohn said about fatty liver: any source of liver energy can potentially cause it, if there is no choline (or related substances).
And so an extremely simplistic hypothesis was born: liver health is crucial (low fasting insulin), and nutrients like choline seem a very important factor. It seems to explain several observations quite nicely: Matt Stone raising metabolism by overfeeding on a nutrient dense diet, people getting fat on a calorie dense but nutrient poor diet, rats eating beyond caloric need on a nutrient poor ad-libitum diet, etc.
My hypothesis can be flat out wrong. Seemingly explaining several observations doesn't make it true. Gravity seems nicely explained by the idea that all matter continually expands from its own center. Just imagine a big circle (= earth), and at some distance, a small circle (= an object above the earth's surface). When both circles expand at the same rate, relative to each other they stay the same size. But as they expand from their own center, they eventually collide. So for the (also expanding) observer, the small circle seemingly got attracted to the surface of the big circle → gravity. Does that mean everything is expanding? I doubt it, but it's a nice hypothesis.
And even if my hypothesis were somewhat true, then I still believe the actual story to be more complex. And I think you illustrate that very nicely. Unfortunately my knowledge base at this moment is too limited to fully grasp your writing. But I think I understand some bits and pieces. For example: if higher mTOR1 activity limits ketogenesis, it is clear that the risk of developing fatty liver is higher, as ketogenesis is a "fat free" way of exporting energy.
Note that next to fasting, one can also include more medium-chain fats (e.g., coconut oil) to increase ketogenesis.
About PPAR-α co-factor 1 and FXR: if I understand correctly, this seems to allow some clearance of liver fat into bile. Interesting: to get rid of this liver fat as bile, you need to *eat fat* to stimulate gall bladder emptying.
Question: does mTOR1 affect the pentose phosphate pathway, and thereby NADPH levels? If so, that would seem to fit a speculation of mine about ketogenesis.
See http://bit.ly/gEbBZa and http://bit.ly/eTc96m
Thanks for your thought provoking comment.
John
I like the way you think John.
Hi John,
Since I recently had my gallbladder out and I looked into it, you only need to eat 10g of fat a day to stimulate gallbladder emptying. One shouldn't be on a no-fat diet, but that is still pretty low-fat.
edit:
add "acetyl-" before "CoA" in the last sentence ... mention is thus of "cytosol acetyl-CoA".
@CS
Once again you evade the point that you are not just disagreeing with me, you are saying both Stephan and the lecturer he referred to are wrong and you are right.
As usual, I have demonstrated you don't even understand what you are criticizing. You are wrong. The metaphor is quite apt. You just don't get it.
Kurt, what is it that bugs you so much that you need to troll after me on the internet for merely expressing an opinion.
I don't think the analogy is apt. Yeah, I think they're wrong and I'm right. Could I be wrong? Sure.
Nothing in your "educating" posts countered what I said:
You said:
"We can simplify this further. Fluid balance is a process involving transport only. Energy/mass balance is one of both transport and transformation (chemical reactions/metabolism)."
You really have no idea what you are talking about and everything you write just demonstrates it further.
Water is partitioned into various compartments - IC, EC, and insterstitial, under hormonal and neurohormonal control and within relatively wide parameters of intake that do not need to be consciously monitored under normal conditions.
Stored energy including fat is also created and partitioned under neuro -hormonal control and in a NORMAL individual, is relatively independent of conscious knowledge of caloric value or macronutrient ratio.
What part of that counters what I said? Partitioning of water involves JUST transport. Partitioning of energy between usage and amongst stores involves both transport and transformation.
We need not oxidize water to eliminate it from the body. That's a HUGE difference compared with fats, or carbs or proteins for that matter.
Nothing confused about that.
Hi @Kurt,
I guess I have an issue with the use of 'set point' in the explanation of both 'fluid-in/fluid-out' and 'calories-in/calories-out.'
Are we fighting a hydrostat when we consume too much water, and therefore more is excreted - or - does water get partitioned via hormonal mechanisms and feedback loops where our water volume generally settles at a number that we can generally determine?
Stephan wrote: "For example, if you have edema because your heart isn't pumping effectively (cardiac insufficiency), the heart is the problem that must be addressed. Any other treatment is purely symptomatic and is not a cure."
I wouldn't say that our heart is fighting our hydrostat, rather the cardiac insufficiency is leading to a cascade of feedbacks that ultimately lead to edema. We want to address the problem, i.e, the heart, not the 'hydrostat.'
http://segamartinez.blogspot.com/2011/03/set-point-versus-settling-point.html
Helen,
I didn't know 10 grams of fat is enough to stimulate gall bladder emptying. That indeed is not a lot.
Might-o'chondri-AL,
thanks for the extensive answer. My current knowledge is way too limited to fully appreciate all the knowledge you packed into it, but I will certainly re-read it a couple of times to let it sink in a bit more.
John
@CS
Anyone who has read, say, Guyton's physiology, or done clinical anesthesia or ICU work, or has any knowledge of the renin angiotensin system sees the obvious parallels that I and Stephan and Stephan's lecturer all see.
It is opaque to you and I imagine it shall remain so.
And who is the troll? You are now systematically ruining blog comments in blogs I formerly read with pleasure for years.
Who showed up here and made a comment critical of the original blog post?
You did.
Please go away. I'll give you some cookies and a free copy of GCBC if you just go back to your blog.
Stephan,
i hope your mystery revelation doesn't include.... something you're going to sell.
Great stuff, Stephan. Hopefully scientists will understand better how fat cells behave in different parts of the body etc. A full and complete explanation of the fat cell lipid exhange mechanism is at the heart of what we need to know, I think. The chemical behavior of fat cell receptors etc.
On a side note , I was wondering what you think of the hormone adiponectin as a future obesity treatment?
There was a study published in Nature Medicine on this.
Take care,
Raz
Kurt, considering that you trolled my blog with derogatory comments for several weeks, I don't see that you're in any position to tell me where I should post on the internet. I only posted at Peter's initially to clear up some misconceptions as a bunch of childish, mostly men over there were trashing me needlessly.
Both Stephan and Peter have commented on my blog (Stephan in agreement at times, disagreement others). I happen to disagree with Stephan here. What's it to you? Or is your idea of interesting discussion mostly just adoring "nice post ****" and "I agree!". We learn nothing if we don't question our own beliefs.
Perhaps I think Stephan is overly wedded to some automatic regulatory system, and perhaps I'm too overly wedded to non-physiologic reasons per se why we overeat and get fat. And perhaps - almost certainly - the truth lies somewhere in between.
As to Guyton - it's one of the texts I saved from my college days. We used it in advanced A&P and lab where we manipulated fluid balance in rabbits.
I know a lot more than you think I do, but you know everything so nobody but you is entitled to their opinion. Get over yourself please. Stop harassing me around the internet because you don't like my comments where "you read". You are the only one fouling comments here.
I agree with Dr. Kurt Harris 100 % about CarbSane. Sums up my feelings perfectly. These anti- Gary Taubes people need to stop bashing him .
They are clueless. They will never admit there is much more to be learned about body fat regulation and morbid obesity.
She's acting like a troll.
I applaud Gary Taubes for getting the ball rolling in the right direction. He deserves credit and respect.
I also repesct Stephan a lot, as well as Dr. Sharman. I am always pleased to listen to their podcast to try to learn more. They admit unknowns.
Hey guys, although I appreciate a spirited discussion, I think this one has become unproductive. I'm not going to allow any more comments through on this thread that are personal or insulting. Please feel free to continue discussing/debating the subject of the post in a respectful manner.
CarbSane, you are wrong that "eating too much will cause obesity".
Obesity is NOT a simple condition of eating too much. Genuine science has soundly demonstrated this.
Furthermore, there is a HUGE variation in how people respond to calories.
The body works AGAINST US in obesity - it is a disease state. The growing research on unfortunate gut flora and obesity is showing strong support to this.
Fat cells go into HEARD MODE and are NOT cooperating.
My bodybuilding brother grossly overeats a lot of the time, but he remains LEAN.
It is not good for his health, but he remains lean, and certainly NOT fat at all.
Dr. Sharma, and Dr. Friedman are VALID sources of obesity information.
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