Well, it's quite easy. You just rearrange their digestive system to virtually join their stomach to their colon. Tatarinni wrote the paper. Eat, have a bowel movement, eat some more, poo some more. Maybe you have to eat sitting on the loo. Once patients have "adapted" to their bilio-pancreatic diversion they can get down to as few as 3-5 bowel movements a day, allowing them to leave the bathroom occasionally.
This is what you do (I added the red arrow for clarity):
Total remaining absorptive gut is about 250cm long. This works for weight loss. Tataranni's paper is fascinating as it gives us a picture of the metabolism of eight post-morbidly-obese women who are close to an ideal BMI and who have been that way for over two years.
You need the caveat that these people have a markedly maligned digestive system, so may not represent their metabolic state pre-obesity, but they are very interesting never the less. You also could make an argument that these people, given a normal digestive system, would rapidly become obese again. So perhaps they may really tell us something about people who are pre-obese.
The most striking aspect is that they are NOT insulin resistant. Fasting insulin and fasting glucose are quite, quite normal. Their resting metabolic rate is indistinguishable from that of control women.
But they are not quite normal. The response to a 75g oral glucose load shows markedly increased insulin sensitivity.
Let's just emphasise: Post-obese women with long term sustained normal bodyweight have a significantly increased sensitivity to insulin during an OGTT compared with never-obese women.
Fasting free fatty acids are lower, as you might expect, albeit ns in a group size of eight.
Obviously, with limited access to FFAs, the control of metabolic substrate supply at the cell surface must be managed by manipulating GLUT4s using a glycolysis derived input, which of course means mtG3Pdh as the CoQ input to resist insulin's action. This means there must be enhanced glucose (or insulin) induced thermogenesis to achieve this insulin resistance. Here it is in the aftermath of an OGTT:
The excess energy expenditure is, in part, heat generated by the in-putting of high energy NADH electrons to the CoQ couple without pumping protons.
I floated the concept that glycerol-3-phosphate might be a core protectant against caloric overload on an individual cell basis in the last post, by inducing insulin resistance. I also suggested that the other related function might be the diversion of excess calories to lipid storage, phosphorylated glycerol being essential for intracellular triglyceride formation.
So here we have another interesting set of graphs from Fig 5:
The first striking thing is that in post-obese people an oral load of 75g of glucose induces a respiratory quotient of greater than one. Second is that, during this time, lipid oxidation becomes negative. It was only ever half that of the never obese controls to begin with. As the authors comment:
"After the oral glucose load, the RQ increased more in P0 [post-obese] than in C [control] subjects, reaching values > 1. Thus, lipid synthesis exceeded lipid oxidation in P0 subjects 45 min after the oral glucose load and continued to do so for 40 more min".
What is happening is that these women accept glucose in to their cells very easily. The glucose is converted to pyruvate, this is decarboxylated via the pyruvate dehydrogenase complex to yield CO2 which increases the RQ. The acetyl CoA formed is exported to the cytoplasm as citrate. Obviously the citrate is formed by combining acetyl CoA with oxaloacetate, the latter can also be derived from pyruvate but this time via carboxylation, and hence the TCA never turns. Oxygen is never consumed. RQ >1.0.
So these post-obese women are exquisitely sensitive to insulin, in particular they are remarkably efficient at de novo lipogenesis and at the inhibition of lipolysis.
Were they like this before becoming obese? I think so. Why they might be like this is interesting to think about from the mitochondrial point of view.
Might there be any way of controling their weigh gain without the need for gross malabsorption secondary to removing most of their gut?
Well, you could take insulin out of the equation by simple ketogenic eating and see what happens...
I was going to leave this as an interesting snippet but there are a few add-ons to these ideas.
Some artificial models of this effect are available from various "pre-obese" rodent models. I had a think about them here.
Edward emailed me a link to this paper about a post-obese case report from Dundee. This man has a normal digestive system, he simply didn't use it for 382 days.
Look at the glucose levels in Table 1:
NB, these glucose levels are all very, very low. The authors feel that these values are real. Perhaps he may have been morbidly obese, yet still insulin sensitive. You need to have retained some insulin sensitivity to attain massive obesity without limiting weight gain by the transition to diabetes. But anyhoo, the trends are what interested me.
What we need to look at is the first column, fasting glucose levels. If we ignore day 355, where there was some sort of a hiccup, FBG was around 35mg/dl. This is quite low but the chap was in extended starvation so this might not be surprising. This is the level of glucose under deep, deep physiological insulin resistance. Ignore day seven value of re-feeding because metabolism will, in all probability, still be far from normal and the chap was only consuming liquid glucose at this time.
Instead I looked at day 55 of re-feeding, while he was on 1000kcal of a mixed diet. His FBG was very low, about two thirds of what it was during fasting. This chap, like the Italian enterectomy women, was very, very insulin sensitive. Insulin drives fat storage as well as hypoglycaemia.
He kept the weight off for at least 5 years. Two points: This chap was a psychological outlier! Second is that 1000kcal/d, if it is Food based, is a LC diet even if it is also a low-everything-else diet too.
Enjoy the winter festivities!
Peter
When I hear post-obese my first thought would be their adipocyte cell number. Something tells me these women have a substantially larger number of adipocytes, so their insulin sensitivity at a cellular level would be explained by having a ton of seemingly empty cells.
ReplyDeleteI haven't looked specifically at thermogenesis in starved individuals, but it would make sense that DNL would be much higher in a starved cell, as it cannot afford to waste any food energy. Hence why dieters are always cold.
ReplyDeletehttp://www.ncbi.nlm.nih.gov/pubmed/19887594
This was one of my favorite studies in a long time. Mice subjected to 30% calorie restriction ( which is around what most "dietitians would recommend ) had massive DNL in the postprandial state.
The mice were oxidizing 367mg of fat per day but only had access to 92mg of fat per day from the diet. The missing 275mg of fat per day was being synthesized in the adipose tissue in the postprandial state.
immediately after food was provided, fatty-acid synthase expression increased
50-fold in calorie-restricted mice, leading to values nearly threefold
higher than ad-libitum controls
A persistent question in this field is what causes the exaggerated anabolic rebound in weight reduced patients, is it the calorie restriction or the emptying of the adipocytes?
Peter thank you for addressing the unique state of post obesity; it's almost never spoken about by teh shoddy 2 bit paleo gurus out there who would sell fantasy fairy tales that they have the magic cure for obesity.
ReplyDeleteI am extremely insulin sensitive meaning to say, I respond with exaggerated response to any challenge that is insulinogenic. I seem to have exaggerated SNS response to insulin (e.g. eating a large, moderate carb meal will cause insomnia, activation, and tremor that lasts many hours). Even paleo darling food like coconut, I have observable hypoglycemic symptoms because the MCTs -> insulin that promotes a drop in blood nutrients. NORMAL PEOPLE are supposed to feel full from coconut; I get hypoglycemia because I am so sensitive to the insulin of MCT.
Once I did challenge self with 50 gram dextrose and blood glucose dropped to 40. I was thinner then, so perhaps would not be so egregious now.
Post obese people MUST follow a VLC diet if they hope to feel even slightly normal, sadly most prefer to eat 2 lindt truffles crash diet, binge on carbs, regain all weight, and then write an entire authoritative blog stating that carbs have nothing to do with weight control, it should seem.
The only people I've known who have a sort of relaxed/not eating disordered exercise obsessive weight loss strategy are people on low carb diets like me. We don't set ourselves up to fail by viewing VLC diet as some kind of punishment or deprivation either. Low carb is really the only way we can be sorta normal.
I have whole twitter feed/ instagram account filming the yummy stuff I eat. Better than cutting up my guts and being knife edge from binging from hypoglycemia... or being big fatass anonymous internet warrior diet expert pretending I am deprived / setting myself up for failure by romanticising eating bagels or whatever.
I eat this, its delicious, and I'm skinny, I'm happy about that. THe cake is made of cream cheese, sour cream, walnuts, eggs, splenda, sugar free jam. It tastes really good. Even this will make me gain weight however; most people would have ZERO appetite and chornic ketotic nausea eating stuff like this .(more)
I tend to think obesity is like a "scar" of the endocrine system. Insulin causes obesity from an endocrinological perspective; insulin promotes the wild adipocyte hyperplasia that causes these insulin supersensitivity defects which set post obese up for failure. The reason post obese people are insulin supersensitive is because of a large volume of hypotrophic adipocytes which respond to insulin in exaggerated fashion.
ReplyDeleteAdditionally, hypotrophic adipocytes do not make normal amounts of leptin, and the leptin insufficiency of post obesity ablates the sympathetic nervous system, T3, and general fat oxidation which further promotes obesity and hypersensitivity to glucose oxidation, fat storage. This informs the finding that weight reduced peopel have very low rates of fat oxidation ; low leptin gimps the sympathetic nervous system, fat oxidation is arrested, thyroid hormone peripherally is hypoactive, people feel lethargic and hungry and store fat very easily. This is observed in sympatholytic drug like beta blocker. Leptin is master of sympathetic tone for obesity.
The first observation of injecting leptin, was sweaty palms and an inability to sit still, within seconds of taking leptin. Why? Hypersensitivity to sympathetic stimulation; naviete to leptin.
Insulin causes obesity in a cycle. Insulin fertilizes preadipocytes into adipocytes, condemning peopel to higher body weight. Attempt to reduce adipocyte size, fat tissue is only supersensitive to even trivial insulin. Adipokines like high adiponectin (that *darling* of obesity research) and low leptin only promote further adipogenesis when dieting people refeed. This is how carbsane happens... cyclical dieting and insulin binging into morbid obesity.
Wooo got to be obese the old fashioned way: innate defective endocrine system, which is probably why it is easy for me to adhere to therapeutic diet. I didn't start out eating disorder insane, I was unlucky enough by genetics to be messed up, but I easily accept and understand the neuroendocrine regulation of these things and the unmitigated advantage of very low carb diet to circumvent the broken insulin/adipose dynamic of trying to reduce body fat.
I would say the obese don't express these defects before obesity, unless the obesity is central related to defective leptin or downstream leptin actor, SNS/PNS or something of this nature. Most fat asses just have frank massive hyperinsulinemia that promotes crazy hyperplasia of adipocyte, which is now PERMANENT because attempting to deflate a normal sized adipocyte is no different than an ormal weight person staving themselves. Obesity of some degree or other is now a normal weight stable constitution even on a low carb diet (which only arrests the hyperinsulinemia and progression of obesity).
Again, thank you peter for your wonderful blog for many years now, and not being stupid,
Wooo
@Icedcoffee - Yes, in a cycle; the adipose hyperplasia induced by massive hyperinsulinemia makes obesity a normal weight stable constitution of a healthy body (the commonest route to obesity is hyperinsuilnemia in a predisposed individual; contrary to the food rewardian perspective, central defects which induce a functional starvation state in spite of obesity are rarer).
ReplyDeleteEven when hyperinsulinemia might be corrected (if it ever its...) the adipocyte hyperplasia is as permanent as might be exaggerated IGF1 excesses like extreme growth/height/deeper voice pitch and all of these growth hormone axis excess signs, which are ubiquitous in the children of uncontrolled diabetics. Insulin is the most intimate activator of IGF1, growth hormone excess signs would be permanent even if hyperinsulinemia is corrected, or exogenous (as in the case of a developing fetus).
Growth hormones, insulin, also promote adipogenesis, growth of adipocytes, and this is permanent as well.
If one attempts to "go on a diet" and make themselves lose weight, they might succeed if they are actively endocrine disordered and afflicted with hyperinsulinemia prompting wild nutrient swings in bloodstream. However, if weight is stable, if they are entirely healthy, it is much more likely the adipose is what it is and they simply have hyperplastic fat tissue, perhaps from prior exposure to hyperinsulinemia, perhaps from a history of weight cycling/binging and starving, perhaps even before birth.
A person with hyperplasia of adipose attempting to reduce the size of adipose will trip the adiponectin/leptin feedback cycle and will be rewarded with a massive neuroendocrine imbalance not that much different from a person without obesity also trying to lose weight.
There are so very many ways a body with hypotrophic adipocytes conspire to elevate weight back to preferred set point (largely mediated by leptin feedback).
Oh wait, nevermind. I meant to say it's all about the reward of diet and carbs have nothing to do with a therapeutic intervention for obesity. Sorry.
@Kindke the sad thing is we , humanity, already know the answers to all these questions. Leptin, adiponectin, the actual hypotrophic adipocyte itself, and the altered levels of adipokines, is responsible for the "post obese" state.
There is a reason fat asses on diet like wooo are obsessed with caffeine... anything catecholaminergic, sympathetic stimulating. It makes us feel normal to correct the chronic fat oxidation deficits of being at a reduced weight.
I can tell you , as a 23 year old kid i figured all of this out just by reading and not being stupid. I travelled states in spite of my avoidant personality to test my hypothesis; I lost so so much weight / felt totally normal taking leptin they were going to throw me out of the trial unless I maintained weight.
I wasnt trying to lose fat; I merely chronically follow a weight loss diet and was normalized with leptin so fat loss happened a lot. In baseline leptin deficient state, it only promotes very slow fat gain... with normal leptin, rapid and massive fat loss.
I old crone now, but I still become a bit angry when I think about how for about a year or two I never had to think about my weight like a normal person. It was nice.
We know these things; no one cares, because all medical research is in service of corporate interest, not benefit of humanity, which means to say profit seeking.
ReplyDeleteThere is no profit in applying a very low carb diet and leptin injection. The latter is not at all profitable, and unlike something like insulin therapy for type 1 diabetes, it is hardly a life or death proposition being a size 16 instead of a svelte size 2, so the essential necessity of leptin for post obese patients is something absolutely no one cares about (except for the 3 obese people intelligent enough to understand it, me and sid and maybe thats it).
This is actually very common in medicine/corporate profit machine. Very necessary life enhancing treatment simply suppressed because it is in NO ONES benefit to popularize the therapy.
Consider GH deficiency. Routine therapy is to treat with GH until hypophyseal maturity and then terminate. This in spite of the fact it is well documented adult GH deficiency promotes metabolic disorder, depression, miserable quality of life (just like leptin deficiency). The only reason GH deficients are not maintained on GH is because the medical/corporate industry/insurance complex stands to lose BIG TIME if they have to pay for a lifetime of GH of replacement...and subjective quality of life for the few GH deficient patients is just not compelling (forceful...) enough to get the standard therapy to change.
This is PAR FOR COURSE in medicine. Treatments which are not profitable, which are economically detrimental, are swept under rug.
Corporate pharma and insurance companies are often adversaries here, but they join forces to be a dynamic duo of oppression of patients when it comes to expensive , not for patent highly effective therapies. Like GH replacement, or leptin replacement.
Psych patients probably have it worst, with all evidence things like vitamin D and a simple fish oil pill can stop psychosis... no one gives crap, ZERO psychiatrists give fish oil to schizophrenics, all are condemned to ineffective, quality of life reducing tiny pills with fancy names that begin with Z or W that sell best.
It's the Woo. I can't say I entirely comprehend what you guys are on about but I need some advise please. I lost 45kg using LCHF almost 2 years ago. I eat the same still and exercise the same as well but find my weight slowly picking back up again. Are you saying leptin injections will prevent regaining of weight? I really don't want to go back where I was and am a bit desperate. I am a T2DM. Thank you. Peter
DeleteHi all, I have no problem with the concept of the shrunken adipocyte and the relative/absolute leptin deficiency related to this. But in some ways life is far more complex than this. As I’m still in the Protons vein my current line of thought asks: What might be happening in the adipocytes of a teenager about to ballon in to full blown obesity? How might such an individual become hypersensitive to insulin? They hide this through storing dietary palmitate in their adipocytes so they store fat without need for insulin controlled DNL/palmitoleate formation. While you are putting dietary fat in to adipocytes there will be no palmitoleate signal to maintain that (enhanced) insulin sensitivity systemically. The increased insulin sensitivity is thus hidden during weight gain and weight stability at hypertrophic adipocyte size. It only shows when people are starved to normal bodyweight. So I’m back to looking at complex I and what might go wrong here. I’m particularly looking at why insulin signalling (controlled by a nano molar pulse of H2O2 via superoxide from complex I) might be enhanced. Why this might be maintained life long, moving from superoxide damage to complex I (possibly subunit ND6, very close to FeS N1a) to the damage done to mtDNA. I have no idea if this will pan out. The whole of the Protons thread has no fixed plan. It’s all me looking to see how stuff might fit together.
ReplyDeleteSpecifically re starvation/DNL to conserve calories: This makes the enhanced metabolism immediately after an insulogenic (small) meal paradoxical unless you are looking for what has broken. Broken complex I can only be (partially) bypassed by DNL to palmitate then palmitate’s beta oxidation to maximise ETFdh FADH2 input, downstream of complex I. Or using (thermogenic) mtG3Pdh.
Heteroplasmy is as common in obese adipocyte mitochondria as it is in PD/AD neuron mitochs, i.e. very common.. There are serious mitochondrial issues in all of these tissues. Complex I, delta psi and superoxide… High level signalling is for the gravy train-ers.
Peter
Peter, Woo,
ReplyDeleteYou are both trying to make me feel bad for eating that roast potato on Christmas day.
I feel no guilt. My excess of shrunken adipocytes agree.
Hi Top,
ReplyDeleteWooo would know great deal more about this than I would. But I would look at fatty acid composition of diet. Omega 6 PUFA, the preferred fats of cardiologists, should be avoided. Ditto trans fats but probably for very different reasons.
David, the occasional burst of superoxide is probably a good, hormetic, thing. A bit like buying Pacific salmon for the Fukushima effect. Just picked up 12 fillets today, half price!
No guilt is good. So is occasional superoxide.
Peter
@ItsTheWooo
ReplyDeleteJust to understand you correctly. Are you saying that you have hyperinsulinemia (although I don't really understand that when you say you're extremely insulin sensitive)?
@ItsTheWooo
ReplyDeleteJust to understand you correctly. Are you saying that you have hyperinsulinemia (although I don't really understand that when you say you're extremely insulin sensitive)?
I have severe hypoglycemia, and at the hospital I found out I even have nocturnal hypoglycemia - in the 40's during the night. I never woke up in the middle of the night though. Doctors don't have a clue on why this happens and are misformed about everything related to hypoglycemia without having diabetes. At first they didn't even believed me before they did tests. Now I started to research on my own and eat a low carb high fat diet and one thing that really helped me is eating a high protein breakfast. I believe this is a leptin issue because I was a bit overweight as a child and anorexic when I was 16 years old... I lost 15kg in 3 months and was always cold. I am 23 years old now and I regained all the weight I lost..
ReplyDeleteFollowing a sort of a leptin reset I no longer have nocturnal hypoglycemia and my episodes during the day are pretty much gone. what really confuses me is that I want to use coconut oil to become fat adapted more quickly but that seems cause me hypoglycemia. Is this possible? And if so why does this happens? I really would like to understand what was going on with me specially because in the hospital they wanted to do a pancreatic catherism and refused to accept other options.
sorry for my english, I am from Portugal.