I am optimistic that everyone can acquire an attractive and healthy body composition, including women of a certain age. I’ll discuss what I think is the best strategy for that in future blog posts. First, some ground work.
Obesity and weight regulation is a complicated subject, and I have to confess upfront that I am not thoroughly conversant with the literature. I still learn new things every time I delve into the journals. Occasionally, I will I write posts (like today’s) that look into journal articles and molecular pathways related to obesity. This helps me explore ideas and learn. Hopefully you’ll have some fun following along.
A good starting point for an investigation into obesity would seem to be the issue of how weight regulation works in a healthy person. How does our body keep itself at its ideal weight?
Now all the problems our body has to solve, had to be solved about 2 billion years earlier by the first eukaryotic cells. Formed by the merger of fat-eating mitochondria with glucose-eating bacteria, single-celled eukaryotes had to regulate their various metabolic pathways to keep themselves from becoming too fatty or too lean (and to control the urge of mitochondria to eat their hosts!). Then, when multi-cellular organisms developed, these cellular-level mechanisms were the building blocks available for organism-level weight regulation.
So we can simplify the subject a bit by looking at individual cells. And here CarbSane gets a huge “hat tip” for finding a fascinating paper that neatly summarizes how an individual human muscle cell controls its fat and glucose levels.
Obese Cells on High-Carb Diets
The paper dates from 2004, looks at muscle cells, and has the latinate title of “Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity.” [1]
We can (loosely) translate “de novo lipogenesis” as “fat creation from glucose,” “lipotoxicity” as “too much fat” and “glucolipotoxicity” as “too much glucose in a cell that has too much fat.” So the paper is examining cells that are:
- fat;
- eating a high-carb diet; and
- disposing of excess glucose by converting it to fat.
Sounds familiar! How do these cells control their weight?
Cells Follow the Same Strategy as the Body
Glucose can be toxic and it feeds bacteria, so excess glucose is removed from the body as quickly as possible. First, it’s stored as liver and muscle glycogen; beyond that it is mostly converted to fat by de novo lipogenesis.
The main organs which do that conversion are the liver and adipose tissue, but this paper points out that muscle cells do it too:
The recent recognition that de novo lipogenesis might have relevance for lipid homeostasis in skeletal muscle stems from the realization that Sterol regulatory element binding protein-1c (SREBP-1c), a member of the family of transcription factors that regulate the expression of genes involved in lipid storage in liver and adipose tissue, is also present in skeletal muscle at a level close to that observed in the liver,41,42 … [M]ost fascinating are the very recent demonstrations that glucose alone (in the absence of insulin) can stimulate de novo lipogenesis in skeletal muscle cells….
[I]t is clear that de novo lipogenesis, although low in skeletal muscle, can be markedly stimulated in muscle cells, particularly under conditions of high glucose (and/or high insulin) concentrations. [1]
So muscle cells convert glucose to fat just as liver cells do. Indeed, they convert glucose to fat even without any insulin stimulation, just to get rid of it – but they dispose of glucose most aggressively when stimulated by insulin.
The likely reason for this is to help the body avoid glucose toxicity:
Extrapolated to conditions of postprandial elevation in blood glucose and insulin (particularly after a high-carbohydrate meal), de novo lipogenesis in skeletal muscle, like in the liver, could also contribute to blood glucose homeostasis by disposing some of the excess circulating glucose as muscle triglycerides, particularly if the glycogen stores are full. In other words, de novo lipogenesis in myocytes may provide another sink for glucose disposal through skeletal muscles. [1]
Insulin gets the muscle cells to take in more glucose and do more of this glucose-to-fat conversion. So insulin is a glucose disposal hormone. Muscle cells respond to it as an act of charity to the rest of the body.
But if muscle cells are storing fat that they manufacture from glucose, they risk becoming obese. How do they get rid of excess fat?
That gets us to the other latinate phrase in the title, “lipid oxidation,” also known as fat burning, and a key hormone, leptin. The authors write:
It is now well established that the adipocyte-derived hormone leptin, which is well known for its central role in body weight regulation in part via its control over thermogenesis, 52–55 also plays an important role in blood glucose homeostasis and in the protection of insulin-sensitive tissues against excessive ectopic lipid storage by regulating the partitioning of fatty acid away from storage towards oxidation. 56–58 [1]
Leptin is released by adipose cells in proportion to the amount of fat they are storing. High leptin levels mean “I’m obese, help me lose weight”; low leptin levels mean “I’m skinny, please don’t waste any fat, we may need it.”
Leptin helps the body regulate its weight, by two mechanisms:
- Leptin promotes fatty acid oxidation, or the burning of fats.
- Leptin triggers thermogenesis, “creation of heat,” which warms the body and causes it to lose energy.
In short, leptin causes the body – and individual muscle cells – to transform fat into waste heat, thereby slimming down the cells and the body.
What happens if you stimulate normal muscle cells with both leptin and insulin? This situation occurs in a healthy person with too much fat (leading to high leptin) who has eaten a high-carb meal and has lots of extra blood glucose to get rid of (leading to high insulin). The insulin triggers the glucose-to-fat conversion pathway, the leptin triggers thermogenesis – but the effect is compounded because the insulin amplifies leptin activity:
[W]e found that leptin could directly stimulate thermogenesis in skeletal muscle via ObRb,62 and that this thermogenic effect of leptin, which requires PI3K activity (since it is inhibited by wortmannin), is potentiated by insulin, a potent activator of PI3K. [1]
This makes sense: the body really wants to get rid of the excess glucose, which is toxic, but high leptin means it’s already fat and doesn’t want to get fattier. So if you’ve got too much fat and too much glucose, you really, really want to turn up the waste heat generator.
So eating some carbs, by increasing after-meal insulin, will actually tend to increase fat oxidation and waste heat generation. That is, it will lead to more calories out, at least for a few hours after a meal. Whereas a zero-carb diet, by keeping insulin low after meals, might tend to tamp down postprandial waste heat generation.
If you read CarbSane’s post, you’ll see that this is what got her excited. (Maybe it would also excite Matt Stone, advocate of the carb-overfeeding-raises-body-temperature thesis.)
We shouldn’t jump to the conclusion that eating lots of carbs is good for weight loss, since carbs may also increase appetite and calories in, or have other effects such as generating a transient glucotoxicity. But we should keep this thought in the backs of our minds: Not every response to dietary carbs works against weight loss.
The paper notes that it’s not only leptin that stimulates thermogenesis. Other hormones – including adiponectin, which is also released by adipose cells, stimulate the same thermogenic pathways.
One can also entertain the interesting possibility that, in skeletal muscle, this substrate cycling is also activated in response to other hormones and neurotransmitters (eg, adiponectin, catecholamines) particularly since adiponectin, as well as adrenergic agonists, can also stimulate AMPK activity, glucose utilization and fatty acid oxidation in skeletal muscle or adipose tissue.61,66–69 This substrate cycling between de novo lipogenesis and lipid oxidation could therefore constitute a thermogenic effector in skeletal muscle. [1]
Adiponectin is a favorite hormone of Dr. Kenneth Tourgeman of the blog Nephropal. High adiponectin levels are associated with good health; obesity is associated with low levels of adiponectin. Adiponectin, among other effects, increases insulin sensitivity – thus it would tend to promote thermogenesis not only by its own action, but also indirectly by enhancing insulin amplification of leptin-induced thermogenesis.
What If The Cell Became Hormone Resistant?
As a thought experiment, we can imagine what would happen if our healthy muscle cell became metabolically damaged – if it became resistant to some of these hormones.
If it became leptin resistant, then it would no longer dispose of excess fat via thermogenesis. The fat would collect and the cell would become obese.
If the cell remained leptin resistant but insulin sensitive, it would gradually kill itself through obesity. So leptin resistance would naturally lead to insulin resistance as the cell protects itself against lipotoxicity.
Once the cell becomes insulin resistant, then it no longer disposes of excess glucose by fat conversion. Glucose levels might become elevated. This corresponds to the condition in the body as a whole that we call metabolic syndrome or prediabetes.
High glucose levels, of course, lead to glucotoxicity or poisoning by excess glucose. The pancreatic beta cells, which produce insulin, are especially subject to glucose poisoning. Thus, prediabetes in the body, continued long enough, leads to loss of these cells and diabetes.
We can imagine two kinds of diabetes:
- If the insulin resistance developed as a consequence of leptin resistance, then we’d have an obese diabetic.
- If the insulin resistance developed without leptin resistance, then we’d have a skinny diabetic.
Conclusion
I like this paper a lot because it gives us a look at the key hormonal pathways involved in obesity, but in a very simple model – a single muscle cell.
It suggests that possible causes of obesity are leptin resistance and adiponectin deficiency, and that if we want to fix obesity, we may wish to look for a diet which increases leptin sensivity and/or adiponectin level.
References
[1] Dulloo AG et al. Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity. Int J Obes Relat Metab Disord. 2004 Dec;28 Suppl 4:S29-37. http://pmid.us/15592483.
via this link:
Great compilation of studies and links. My mom definitely has the age related weight loss issues mentioned by some of your commenters and I look forward to reading your future posts regarding solutions to leptin resistance and adiponectin levels.
Hi James,
I’m not saying I have those solutions! Only that (a) I do have some ideas about possible approaches to long-term, healthy weight loss, and (b) as I look for more ideas, I’m going to keep an eye out for ways to influence leptin and adiponectin.
Best, Paul
I’m thrilled you’re tackling this subject. If/when you start looking at appetite, here’s a link to a presentation made by a senior resident at Case Western Reserve that I recently found — and find fascinating! http://bit.ly/gD4deV
It explores the role of the endocannabinoid system and obesity. The pot/munchies link is compelling enough, but I got almost giddy reading that arachidonic acid is a precursor to anandamide, one of the ECS agonists.
Apparently research to find a good pharmaceutical to act as an antagonist hasn’t been successful (the ECS also manages pain, which you don’t want to block!). Alas, seeing what happens if people eat fewer omega 6s won’t be researched, as it can’t be patented!
Thanks, Beth!
I wonder in how many people appetite is the problem. It seems like some of our low-carb readers don’t really have a strong appetite for food, they just aren’t losing weight no matter what they do.
Best, Paul
Paul, I hope there won’t be a quiz on this post.
I thought leptin resistance usually refers to the brain’s inability to recognize the body has enough energy. That is, leptin resistance (or lack of leptin like the ob mice) will lead to excessive calories in. Also, how much “calories out” can actually be attributed to thermogenesis? Regarding fat oxidation, seems like the first order effect for burning fat is to keep carbs (glucose or ethanol) levels low.
I’ll give you credit for using “calories” only twice in your post, albeit bolded. 😛 But, I think your post addresses the fundamental problem of weight control as hormonal balance, not energy balance. Energy will always be balanced; it’s a natural law. Stating it offers no insight. The magic happens with the hormones.
Chris Masterjohn’s lecture on heart disease at the 2010 WAPF conference, available for download from Fleetwood, briefly talks about how thyroid hormone influences leptin status.
I actually found that adding starchy tubers to my diet not only turned on thermogenesis, but it also halved my caloric intake without hunger (which I measured on FitDay just to be sure).
This could be because a big sweet potato seems more filling, or it could be due to leptin going down to Kitavan-levels, but I simply didn’t feel the urge to eat. Calories in went from around 3000 to 1700 per day. This could also be because carbs displaced the fat I was eating, which carry much more Kcal per gram.
Paul,
Great post!
I’m happy to see that you have been reading CarbSane’s blog. It is a goldmine of information, much of which is ignored by most other lowcarb/paleo blogs. She has written a lot about lipotoxicity and the dangers of excess NEFAs. I’m very interested in seeing your take on this.
–Larry
Wow.
That was amazing.
Thanks for the article.
I guess this is why most traditional meals contain something with carb along with the meat and fat.
Hi erp,
No quizzes! This course is graded pass/pass.
Hi js,
Yes, obesity researchers think that leptin resistance in the brain is a big part of obesity.
However, there’s no reason people can’t become leptin resistant elsewhere, and it’s clear that obese people are metabolically damaged/altered throughout the body – in liver, in adipose tissue, in muscle cells, in the brain. So I think it’s premature to place blame in only one spot.
I don’t think thermogenesis is that important, and anyway it’s regulated in other ways than this. I was interested in this paper in the first place because of the demonstration that de novo lipogenesis occurs in muscle, which solved a problem for me since I knew glycolysis in muscle was going to be evolutionarily selected against, yet muscle disposes of excess glucose at a fairly good clip.
I agree that the problem is fundamentally a biological derangement that is controlled at the molecular level. Even the hormones as a totality provide too narrow a view of the problem, but they are a good window into it since there are relatively few of them.
Hi Jeremy,
Thanks, I’ll look for it.
Hi gunther,
I had exactly the same experience. I suspect your body was making you eat more to resolve a glucose deficiency; the body is programmed to conserve protein in glucose deprivation, it wants you to get it from food. Once you satisfied it, your body was well nourished and the excess hunger disappeared.
I think on balance lower calorie intake is a good thing, given the benefits of calorie restriction (as long as there’s no malnutrition) for longevity. A good rule of thumb is that lower calorie intake is good if there’s no hunger, bad if accompanied by hunger.
Hi Larry,
I agree, CarbSane is great. Not very commercial though.
There’s a box about lipotoxicity in the book, we make the point that it’s never been observed apart from metabolic syndrome. It’s part of the metabolic derangements associated with obesity. It’s an important point that fat metabolism is affected also in obesity and related conditions.
Hi Anand,
I think meals contain carbs because that is health-improving. Some glucose, plant-based nutrients like potassium, some glucose calories, and some fiber to maintain a commensal gut flora are beneficial.
One reason I avoid molecular pathways posts is that it’s too easy to over-generalize from a few molecules – even important ones like hormones.
Best, Paul
Paul,
Great information.
I am trying to understand the implications of one sentence you wrote: “Leptin is released by adipose cells in proportion to the amount of fat they are storing.”
So Leptin, is released based on rate of storage vs. how much fat has already been stored? If this is the case, you could have a “skinny” fat cell that is getting fat pumped into it quickly, triggering a release of Leptin?
Also, if I read correctly, you don’t need full glycogen tanks (muscles and liver) for your skeletal muscles to convert excess glucose to fat? In response to insulin the muscles try and do their part to remove glucose (not just store glycogen).
Thanks in advance.
…Tim
AMAZING post Paul! I’m going to edit that post of mine to link to this 🙂
Oops, hit Submit too soon.
Wanted to add that looking at this from a single cell “intake”-“output” is really a novel way of looking at things. To js290, I would say that hormones TRY to maintain the energy balance, but energy balance is NOT always the status. Here’s where Paul basically looked at the muscle cell much like a small model for the body. Liver and adipose cells can have mass fluxes – they both uptake and export (excrete) glucose and fatty acids. But muscle cells do not, to my understanding. The energy in is a one way street. Once the glucose or fatty acids have been transported into the cells, they are either stored or oxidized. So we have a neat little single cell model for CICO which does hold no matter what TFLOT-deniers tell you. Substrate futile cycling seems to be the way our muscle cells TRY to compensate for being “overfed”. Once we individually flirt with and exceed our body’s capacity to store lipid excesses in our fat tissue, the excess NEFA released from adipose tissue necessarily “overfeeds” our cells –> lipotoxicity.
The fact that any of us get obese (or severely emaciated) demonstrates that those “magic hormones” are not magic at all. They do what they can to balance CI with CO and vice versa through appetite signalling and energy expenditure up & down-regulation. But they are only able to do this within a relatively small buffer zone.
Hi Tim,
Sorry, I guess I didn’t write that very well. Leptin is proportional to total adipose mass, not to the flux. So when your fat mass goes up, your leptin levels will rise and stay elevated, even after you stop adding fat mass.
Leptin levels may vary across individuals. So I don’t want to say that a more fat person necessarily has higher leptin levels than a less fat person. But there is a strong tendency for that to be the case.
Re your second question, how glucose is disposed of is a complicated question. Glycogen creation is faster than fat creation, so even if both are operative, glycogen manufacture will tend to dominate when glycogen stores are low. Also, the insulin dependence is different, I would bet that glycogen creation can happen at a high rate on very low levels of insulin but fat manufacture happens at a high rate only when insulin levels are high.
So I think to a good approximation, muscles will put glucose into glycogen if they can, and only when glycogen is full will they do a lot of fat manufacture.
Hi CarbSane, Thanks!
The Kitavan study and Lindeberg’s human paleo diet trials seem to definitively show that a high (paleo) carb diet lowers leptin. Lower leptin equals lower hunger.
Carbs go up to 95% of the diet in some parts of Melanesia, with no insulin resistance or obesity. Lower levels of protein also seem to lower food intake, as shown in studies with rats, mice and flies (this is why they have to be “pair fed” in order to see if protein restriction is the reason caloric restriction works to lengthen lifespan). This does beg the question of whether moving to a paleo diet actually ends up being a caloric restriction diet (or at least a lower calorie diet).
Once you’ve gotten away from industrial foods, maybe there is a lot of leeway between high carb or high fat diets, but in all cases long-term weight loss seems to boil down to simply quelling your hunger.
Paul, yeah, I posted that ECS link in the broader context of obesity, not the specific “not losing weight on low-carb” kind. Re the latter, I’ve wondered whether the issue might be one or the other (or both) of too much protein or omega 6s from veggie oil. Eating more protein than you really need is just providing glucose through a back door. And I’m with Kurt Harris re too much linoleic acid in terms of not ideal for health in general.
Jenny has some interesting thoughts re low-carb not working here: http://www.phlaunt.com/lowcarb/19060149.php
Hi gunther,
I agree that hunger is key – I’m going to talk about that a lot in upcoming posts. One should never be hungry; and should eat a diet that enables you to restrict calories without hunger.
I am most familiar with studies claiming the protein is satiating and that high-protein diets reduce food intake. (These are linked frequently by Paleo bloggers promoting lean-meat-and-vegetable meal plans.) I find these plausible, at least in the short term, because personally I find those meals unappetizing. Of course the long-term may be a totally different thing, and weight-loss on low-carb diets tends to be fast early but converge toward that seen on other diets during long-term studies.
I also agree that carbs per se (if they are from “safe starches” and unaccompanied by food toxins, as in Kitava) should not be a problem for a healthy metabolism. I worry however that metabolic derangements may make carbs hard to handle, so I wouldn’t recommend a 95% carb diet to an already-obese person. I also worry about malnutrition in micronutrients from an unbalanced diet with insufficient animal sources. But in moderation I think safe carbs are a healthy part of a weight-reducing diet for the obese.
Hi Beth,
Yes, agreed. Omega-6 fats are strongly obesity-inducing. A lot of the low-carb Paleo types may be getting toxic levels of protein as well.
Jenny is a treasure. I tried to read all of her stuff at one time but it seems like there’s always more. Thanks!
Thanks very much for the clarification on leptin production as a function of overall fat in storage vs. fat being stored. Makes more sense.
…Tim
Hi Paul, I think protein is initially satiating for those looking to lose weight (which is to be expected since these people are usually coming from restricting all sat fat for the Ornish-style plan which never worked for them), but it becomes boring and perhaps expensive over the longer term. That and the fact that weight loss usually stalls on high protein due to the glucose “back door” that protein represents. I’m not even sure that glucose (through carbs or through protein) even causes weight gain. It may be that overabundance of protein itself is a signal causing autophagy and cell scavenging to cease and downregulation of certain fat-burning factors, causing the body to accumulate fat for some reason. In the end, calorie intake usually creep back up and high protein/low carb stops working.
I agree that a 95% carb diet is not a good approach, but it is good to know that it doesn’t cause outright disease in a healthy paleo context.
Malnutrition is a tricky thing, since it sometimes stimulates autophagy. Perhaps any TEMPORARY nutrient scarcity in the body will cause cells to scavenge what they need from cellular “junk”. The problem, á la Art Devany, seems to start when we do this chronically. Malnutrition would occur perhaps only when the body has no more reserves of the nutrient in need. Then autophagy stops and you’re hurting yourself.
In the end, it seems hunger is the decisive factor as to whether a dietary program works or not. As you say, when hunger is low, it’s a sign things are metabolically working!
Hi gunther,
I agree. I personally eat a moderate carb low protein diet, and I think there are subtle health risks to too much protein that might add up over the years and decades. As you say, high protein does downregulate autophagy, which is a big issue for immunity.
If you’ve read our book, you know I recommend the same diet for people trying to lose weight.
I suspect we’re going to get the answers about what works for weight loss empirically, before the molecular mechanisms are even half worked out!
Best, Paul
Paul,
You state “Omega-6 fats are strongly obesity-inducing.”
I never quite understood this statement. What makes an omega 6 uniquely fattening vs. an omega 3 or a saturated fat? Don’t they have the same effect on insulin, the same calories, etc.?
Thanks so much.
In reading about autophagy in your book and the various post comments, I was left thinking that it is a good thing. So I’m doing more research on it and came across information that seems to indicate that autophagy could have some serious potential downsides for certain tumors. Since most of us have precancerous cells and possibly small cancerous tumors not yet discovered, I’m curious if you have any thoughts as to potential downside of autophagy through ketogenic diets?
http://cancerres.aacrjournals.org/content/66/19/9349.full
Hey Paul,
Great post, as usual.
This may explain to some extent why some of my patients don’t do lose weight as expected with IF Eating a little, especially some carbs, may stimulate thermogenesis and help them shed some pounds. An interesting question is what accounts for the variance in individual responses.
Erich: n-6 fats are pro-inflammatory, and inflammation contributes directly to obesity.
I’m hoping that higher protein (I typically eat more protein than carb calories even now upping those carbs to ~300 cals) is not detrimental in the long haul, because it is my holy grail for “effortless” maintenance.
Perhaps some stints of high fat, low carb IF here and there might be a worthwhile experiment.
Erich,
In his latest interview, Dr. Kurt Harris points out that n-6 fats are pro-inflammatory. Excessive n-6 may be the driving factor behind developing insulin resistance, which is then exacerbated by elevated insulin levels from high carb diets.
Hi Erich,
It’s not a calorie effect, it’s a toxicity effect. And omega-3 can induce obesity too.
In addition to the pro-inflammatory effects of omega-6 that others have mentioned, polyunsaturated fats react with alcohol or fructose to create an obesity-inducing toxic mix.
We give examples in our book of studies in lab animals. It’s no coincidence, I think, that the modern obesity epidemic has coincided with simultaneous increases in the consumption of fructose and vegetable oils.
Hi Annie,
Some complications have emerged, but by and large autophagy is protective against cancer. As your linked article states, generally autophagy needs to be downregulated if cancer cells are to survive, so typically all cancer cells have lost genes for autophagy. Moreover, upregulating autophagy generally kills the cells.
The quick summary is that cancer cells will induce some autophagy if they need it to survive, but every time it happens they risk dying, and if you induce it by diet, you will probably substantially lower your cancer risk.
For people without cancer, I think autophagy is even more important because it enhances viral immunity and viruses are a leading cause of cancer.
However, some cancer therapies may work better in the absence of autophagy, or in the absence of vitamin C, etc., so cancer patients should always consult their oncologist about how to modify their diet to make chemotherapeutics work most effectively.
Hi Chris,
I don’t want to put too much importance on thermogenesis for weight loss, because body temperature is independently regulated, so more heat generation in the muscle cells doesn’t necessarily translate into more heat from the body as a whole.
I think a more persuasive case for carbs comes via the zero-carb dangers series and the possibility that a very low-carb diet invokes protein-and-glucose-conservation mechanisms including downregulation of metabolism.
I think it’s very desirable to go low-carb (<600 calories/day) for weight loss, but going too low-carb can backfire, especially if protein intake is also low.
Hi CarbSane,
I don't think there's anything wrong with the levels of protein (I believe) you eat. We say anything up to 600 calories/day protein is safe. I think nitrogen toxicity is the main problem and there's a fairly broad range of protein intake before you reach that.
Hi Paul
Another brilliant post which helps me add to my naïve model of my condition, which is good BTW. I have been on the full PHD for 6 months with good results, however it still worries me as it goes against conventional wisdom and leaves me with some anomalies I do not understand. Pre diet I was lean and clinically healthy, post diet I am lean and healthier by most indications and feel better than in years. I have posted before so will not repeat details as my specifics seem to not to be of general interest to others here. The main anomaly is that I have increased my energy intake (during the last 2-1/2 months) by about 500Cal/day (to about 2700 of which abut 500 are from glucose), yet I am not gaining weight. The diet is not insufficient in vitamins & minerals, I supplement per recommendations in your book and there are no observations or clinical indications of serious inflammation. Yet the weight is not increasing and when it falls (which it easily can with extra exercise) below a critical value and/or I consume dairy, my joints immediately begin to complain, which suggests under nutrition. The complaints are merely aches or pressure sensations which many would not consider a problem but they are good leading indicators of my general wellbeing. The other anomaly is that my fasting blood glucose is fairly high, about 100mg/dL by lab analysis (sometimes higher on my home meter). Some say this BG level may be “physiological” but I don’t know if that is at all explanatory. The other anomaly, a good one this time, concerns a huge and unmistakeable improvement with nocturia/polynuria which I can correlate with fibre restriction with good certainty. This last comment is to encourage you to post on fibre and effect of gut-flora size, please. From your reasoning it seems that I may be somewhat insulin resistant. If so, are there ways back? Also my rising temperature averages about 97.1degF, suggesting that thermogenesis is not a big factor in my metabolism (yet?). But there are no symptoms suggesting hypothyroid issues. Thank you again.
Morris
Hi Morris,
I wouldn’t consider 100 mg/dl as physiological insulin resistance if you’re eating 500 glucose calories a day. Personally I have to eat under 200 glucose calories a day to get my fasting glucose near 100 mg/dl (I was around 105 mg/dl when zero-carbing). At 500 calories/day I’d expect more like 90 mg/dl.
But people vary and I’m not sure how to interpret it. You could do a home oral glucose tolerance test, measure every 20 minutes after a 50 g dose and see where it peaks. That might be more informative.
The joint issues could possibly be immune related. The dairy suggests that – perhaps a dairy sensitivity. I’m not sure how to account for the joint aches when your weight falls, but perhaps you are losing glucose-water-lubricants from your joints (cf our recent discussion of water weight losses).
If fiber was causing problems, it could be that endotoxins or other bacteria-related toxins are also involved in the joint issues.
There are ways to improve insulin sensitivity and you’re doing many of them. Exercise helps. You might try mixing in some intense exercise like resistance exercises for muscle building.
Also, I think coconut oil might do you good. It lowers blood sugar, raises HDL, may help improve gut bacteria, conserves glucose in case that is a problem, and probably improves insulin sensitivity. You could try adding more if you’re already taking it. Since you would prefer to gain weight, extra calories shouldn’t bother you I would think.
Fiber and gut flora size – I’ve sort of posted on that. I think an intermediate quantity is good — enough to raise immune defenses and create a commensal community to keep out pathogens, but not so much as to produce a lot of endotoxins. That’s why I favor some plant foods, but not excessive vegetables, and do not recommend prebiotics.
Best, Paul
@Paul: Thank you so much for your insights. I’m interested in experimenting with a protein restricted ketogenic diet to see what if any impact it may have on my large uterine fibroids. I got the notion because my gyno mentioned that the newest theory surrounding fibroids is that they may be of a viral origin. He is close to retiring and has followed thousands of fibroids. Some do respond to hormone treatments but the response is often symptom relief — not actual shrinkage. Changes in diet often bring symptom relief to women but MRIs would reveal no change in fibroids or continued growth and multiplication. Ultrasounds can vary from week to week depending upon how the measurements are taken and especially what is happening during the menstrual cycle. An MRI can show entirely different measurements from recent ultrasounds.I’ve tested this myself. Many women just assume their fibroids are gone because symptoms have abated. It’s also a fallacy that they necessarily shrink after menopause. The uterus shrinks so bulking may seem less but ask surgeons and they will tell you that it’s a fallacy that they necessarily shrink after menopause. Since I have experienced no symptoms whatsoever suggesting hormone imbalance (no pain or cramps at all, no heavy bleeding), I am interested to see if diet-induced autophagy could help cause some shrinkage. I credit long-term low carbing for helping me to avoid the horrible painful endometriosis my mother suffered with and the type 2 diabetes both parents and only sibling suffer with, however, my low-carb ketogenic diet has never been protein-restricted. So I’m interested in testing out periodic protein restricted ketogenic fasts to see what happens.
Hi Annie,
I think that occasional ketosis and intermittent fasting is a good idea.
Be careful — ketogenic diets imply low carb, while protein restricted means you won’t have enough protein to replace the missing glucose. For safety, you should keep carbs+protein at 600 calories per day or higher.
Therefore, do protein restriction on days when carb intake is high, and eat protein on ketogenic days.
If I recall the literature correctly, fibroids are associated with a lot of mast cell activity and inflammation. So it’s important to minimize omega-6 and eat salmon.
Vitamin D and especially vitamin K2 are also important. Vitamin K2 helps normalize fibrin. All our supplements are probably valuable.
Best, Paul
Morris,
“Yet the weight is not increasing and when it falls (which it easily can with extra exercise) below a critical value and/or I consume dairy, my joints immediately begin to complain, which suggests under nutrition. The complaints are merely aches or pressure sensations which many would not consider a problem but they are good leading indicators of my general wellbeing.”
This sounds much like overtraining to me. If you say “Exercise” what do you mean specifically? How intense/how often?
It’s a myth that there’s no overtraining but just undernutrition. Overtraining is real and can lead to the symptoms you name. And (assuming you don’t want to gain fat) muscle grows when you rest (enough!) after intense exercise and not during the exercise!
Hi Franco
Thanks for the comment. My exercise regime has not changed from pre-PHD and is not too strenous, about 2-3 hrs total/week of which most is moderate effort cardio with some resistence. The odd thing is that pre-PHD, with the same exercise effort, if I increased calories my fat would easilly but slowly increase, but not now. I would like to think that the extra energy is going into useful work as opposed to fighting pathogens but cannot find a plausible mechanism. That said I feel great, perhaps some adaptations need to come to completion.
Morris
Hi, Paul, you say: Of course the long-term may be a totally different thing, and weight-loss on low-carb diets tends to be fast early but converge toward that seen on other diets during long-term studies.
Those long-term studies you quote refer to “intent to treat” analysis, which is likely why there is a convergence. The convergence is likely not due to the loss of effectiveness of the diets (I say likely because the authors didn’t provide a separate analysis), but rather to other reasons(i.e. non-compliance likely being at the top).
Annie, the latest on autophagy is that it is inhibited by BOTH amino acids (protein) AND insulin (as in insulin spikes) through the insulin-amino acid-mTOR signaling pathway. Therefore, if you want to induce autophagy to the fullest you should keep both proteins and carbs low for the time period you want autophagy do some cleaning up. Intermittent fasting allows you to do that while remaining on your low-carb diet or adapting Paul’s version. Or, IMO, you can do 24-48 hour fasts once a week or month, whatever works for you.
Hi Poisonguy,
Good point. However, as you say there may have been convergence even without the intent-to-treat analysis; also reduced compliance with the low-carb diets may indicate something unsatisfying about the low-carb diets tested.
Ideally, we’d want a diet that both normalizes weight and is so pleasing that people will want to stay on it.
Thanks for the good advice to Annie!
Thank you for your help Paul and Poisonguy.
Poisonguy,
When you say fast for 24 to 48 hours — do you mean total water only fast or adding coconut oil?
I regularly find it very easy to fast for 16 hours with nothing but water and black coffee or unsweetened tea (I generally only eat 2 meals per day) so adding a few more to make 24 would be very easy. Is coconut oil supposed to increase autophagy more than simply zero calories and just using zero calorie beverages such as water, black coffee & unsweetened tea?
One thing I’ve noticed during fasting is that my energy seems to increase. A while back I exerimented with eating one meal per day — nothing at all and then just one big supper. I felt fine energy wise during the day and indeed, sometimes quite “wired.” I’m thinking that was likely due to low blood sugar stimulating release of stress hormones and hence the wired feeling. I stopped the one meal per day because my fasting glucose was rising and I think this is because of stress hormones. Also, one huge meal in the evening is not conducive to restorative sleep for me. I have no issues falling asleep but always feel groggy and sluggish the next day.
Hi Annie,
I recommend taking coconut oil on long fasts. It reduces the stress of the fast and will enable you to extend the fast without reducing autophagy. It is especially helpful for the brain and nerves.
Water and electrolytes such as salt should be taken as well. It’s OK to add some low-calorie vegetables like leafy greens if you want also.
Your experience with one meal a day is interesting. I wonder what would have happened if you’d been able to eat at midday instead of in the evening.
Best, Paul
What Paul said. I developed my fasting regimen based on his advice and his book (although I’ve never been able to down the full 6 fl.oz of coconut oil–after 3 fl.oz, my gag reflex starts getting an itchy finger).
When I fast (other than the daily 16-18 hrs intermittent fasting window), I do the coconut thing and drink water. Since I’ve lost my love of straight coconut oil, I’ve found that I can have as much as I like when I mix it into coconut cream (the cream emulsifies the oil). The best mix I found is a 2:1 ratio of cream to oil (100 g/50 g, which is all I need in a 24 hour period to keep hunger away and to stay in ketosis for that entire period). And, 100 g of cream provides only 2.9 and 2.4 g carb and protein, respectively, so not enough to knock me out of ketosis (which is also beneficial on top of the autophagy).
I downloaded this article yesterday, which you might find interesting regarding autophagy. Plus, if I remember correctly, Paul has a lot of good things to say about glucosamine in the book.
http://www.ncbi.nlm.nih.gov/pubmed/20045674
Nice Paul,
No one fully understands the fat gain riddle, which is why it’s so important to discuss it in the manner you are here – trying to figure it out, instead of telling everyone how you figured out (a very common error in the health/nutrition field, OBVIOUSLY!)
In my experience, the macronutrient war is futile, and one that simply can’t be won. But from that vantage point many new intriguing possibilities emerge.
When you start to delve into leptin, it becomes abundantly clear that leptin is the head honcho of weight regulation. However, it obviously can be trumped by other forces if everyone is developing resistance to the hormone leptin, which I believe is a mechanism that the body employs to raise the body fat set point. Muscle insulin resistance obviously helps out with this too, keeping energy out of muscle for metabolism suppression (I think it’s much more likely to be the activity of thyroid hormones that controls whether one is going to be in positive or negative fat balance eating to appetite of a mixed diet).
I’ve been increasingly led to believe that the most common factor that trumps leptin is the brain’s pleasure center. In other words, addiction trumps leptin. If that’s the case, then chemical flavor enhancers, refined carbohydrates, artificial sweeteners, refined sugar, liquid calories, HFCS and other modern food factors would be responsible for the body’s tendency to maintain a higher weight set point, which would make more sense.
Stress hormones can do it too, no doubt about that – which puts the obesity blame on dieting, stress, overexercising, chronic nutrient deficiency, and inflammation primarily. This actually makes sense in terms of why the body would increase its fat stores – this seems to be the smart adaptation to chronic elevation of stress hormones like one would see in a famine, and one of the strongest links to obesity is having your parents go through famine or your mom diet while you’re in the womb!
Anyway, like you said. We learn something new every day that we delve into this stuff. Keep up the good work. Look forward to checking out your book.
I agree with Matt Stone that stress hormones and the palatability of foods with its addiction aspect are important too and are seldom mentioned.
I noticed that stress (worries, fear) increases my appetite and I tend to look for sweeter/fatty things almost immediately even if I know I shouldn’t (a little bit is OK leads to binge days, in my case there should be no cheat days or holidays at all, there are cues for my brain that I should avoid). All this is compounded by a low T3 which means the metabolism is on storage mode due maybe to protein sparing after low carb so rapid fat gain ensues. I have to be careful not to let a vicious circle develop and focus on the positive, while moving on.
Hi Matt,
Much to learn as you say. I’m still undecided how much of the problem is in the brain and how much in the liver/adipose cells/muscle. Perhaps everything gets better or worse together.
Hi simona,
I definitely think there is a protein sparing program which, if it became epigenetically entrenched, could contribute to weight problems. Hopefully your thyroid issues will come around and maybe things will get better. Stay positive!
Best, Paul
There’s so many big questions out there Paul, like why is being white so protective against obesity? In the Pacific in places like Nauru, the greatest single determinant of future bodyweight is the amount of European ancestry one has – the more you have the less you weigh.
And it’s known that people like the Pima Indians, Pacific Islanders, etc. have much higher rates of alcoholism – which everyone knows is highly hereditary (and speaks to the possibility of addiction proneness as a potential determinant of how one responds to a western diet).
Of course, to have NAFLD and hepatic insulin resistance, it probably requires eating an excess of overall calories to the point where de novo lipogenesis starts to occur in the first place. But why would someone eat too many calories? In just about all animal models overeating only occurs when there is a flaw with the leptin system/hypothalamus. But interestingly, aspartame, saccharin, and sucralose all raise the weight set point and stimulate more eating than sugar. Sugar in liquid form causes more overeating than sugar in crystalline form. However, if you give a rat an all-liquid diet it doesn’t matter how much sugar is in there, it loses weight because monotony reduces calorie intake!
A lot to think about. But I think one common theme repeated is that if your parents ate a sparse, low-calorie, whole foods diet with low-calorie density (traditional diet), you are more likely to be born into the world with more highly attuned reward centers to help you better secure calorie-dense and pleasureful foods, which would explain why populations that had the most sudden transition to Western Diet fared the most poorly.
Interestingly, one difference between normal weight and obese people that’s been discovered is that obese people produce less dopamine in response to food – and need to eat more of it to get the same feeling of satisfaction/pleasure/gratification that a lean person does.
http://180degreehealth.blogspot.com/2010/08/dopamine-and-weight-loss.html
Hi Matt,
The first question I think is fairly easy. There’s been some adaptation to grains, so those with an 8,000 year ancestry as farmers, like Europeans, are somewhat adapted to them, but those with zero history of grain farming, like Polynesians, or a short history like Pima Indians are very vulnerable to toxic diets.
Also with alcohol we know that in ancient times the Romans were adapted to alcohol but the Germans weren’t, and alcoholism was a major problem among them. Alcohol was Rome’s most valuable export for a time.
One interesting aspect of this is how much variability there may be between persons. Perhaps obesity is really many different conditions, or a highly heterogeneous condition.
Seth Roberts’s experiments are certainly intriguing. I hope to learn more about these dopamine/hypothalamus/appetite/setpoint issues this year. Thanks for the link!
Speaking of animals Matt, I was checking out the pigeons poking around a parking lot of the grocery I frequent. They are FAT. Someone feeds them routinely as they tend to congregate and appear to be chowing down most times in a place in the lot a bit remote from any store, dumpster, etc. Dr. Eades noted on his blog a while back how the “pastured” pigs at a farm preferred to congregate by the austere concrete feed structure rather than frolic around in the presumably more pleasing pasture environment rooting away for acorns. I do believe that we overlook the obvious sometimes that for a goodly portion of us, we get obese because we eat a bit too much when everything is prepped for us, hot in 30 sec in the microwave, etc.
i found these two reads just intriguing and it deals with the leptin and brain sense yall are talking about but leaves me thinkin Glutamine is the next alli or something:
http://naivenutrition.blogspot.com/2010/03/this-is-getting-little-silly.html
http://naivenutrition.blogspot.com/2010/03/amylin-pyruvic-acid-regulator.html
Nice post!
One more mechanism that I think is relevant is the PPAR’s, particularly alpha and gamma, which facilitate peroxisomal beta oxidation. Basically, if those are downregulated free fatty acids aren’t oxidized as efficiently and that contributes to lipotoxicity.
This paper makes the point http://diabetes.diabetesjournals.org/content/56/4/1034.long, although I’m not sure how relevant the experiment is because it’s an extremely high fish oil diet, but basically omega-3 fatty acids are PPAR-a and g ligands and when you supplement rats with fish oil from day one (as opposed to trying to slide it in once they already have diabetes which doesn’t work so well)you prevent insulin resistance. That’s also supported by a few studies where they gave them omega-3 on a high fat diet from the start and it prevented metabolic syndrome. Gamma too. It could also be the anti-inflammatory aspect http://www.ncbi.nlm.nih.gov/pubmed/9256257 And probably preventing leptin resistance.
Links:
http://www.wellnessresources.com/health/articles/dha_vs._diabetes_drugs_did_you_balance_your_ppar_gamma_today/
http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030064
http://www.ncbi.nlm.nih.gov/pubmed/3303333
Yeah! So keeping omega-6 low and getting a modest amount of omega-3 could reduce lipotoxicity and lipid overload many ways. I think. Let me know what you think.
Cheers.