Answer: Easily.
First, break your mouse. Both the grey squares and white triangles represent C57BL/6 mice on good old "high fat" D12451, so beloved of obesity researchers. They get a broken brain and gain weight. You can also feed chow CIAB to get the black diamonds:
Now let's do a little magic and render all of the adipocytes of the white triangle D12451 injured mice insulin resistant, in both brown and white adipose tissue. This is slightly tricky. Are you all standing in a circle holding hands? On a hill top in mid winter? OK, say the magic words while turning withershins. You have to chant:
Calories-in, calories out, turn this stupid mouse about! FIRKO-ISE...
OK, well done, you can all put your clothes back on now and stop dreaming of UCP-1.
I guess everyone realises by now we've been talking about the graph from this paper
with the classic use of ketosis to normalise the bodyweight of D12451 injured mice. Ketosis renders adipocytes insulin resistant, just like those of FIRKO mice. Of course, because ketogenic dieted C57BL/6 mice are functionally FIRKO, they don't cut calories. They eat as many calories as the D12451 injured mice. But they produce more heat:
"Thus, total heat output was 15% higher, averaged over 24 h, in KD animals (KD 0.538 ± 0.01 kcal/h vs. HF 480 ± 0.01 kcal/h, P < 0.05, n = 4). Oxygen consumption was increased by 34% averaged over 24 h (KD 4.370 ± 0.062 ml·kg–1·h–1 vs. HF 3.248 ± 0.052 ml·kg–1·h–1, P < 0.01, n = 4; Fig. 6C). Weight and CLAMS results were replicated in two additional independent cohorts using the same paradigm. CLAMS analysis also revealed that spontaneous dark-phase locomotor activity in KD animals was ∼30% lower than in HF animals."
[*Brownie point for spotting the typo in the quote. Hot mice indeed!]
They also avoid the gym. Heard that before?
We know that simply not eating for a while induces whole body physiological insulin resistance. We also know we can do exactly the same thing, without all the pesky death involved in sustained not-eating, by simply going in to deep ketosis without cutting calories.
Ketogenic dieting is slightly controversial. I've heard it said that the weight loss in these ketogenic fed mice is not real weight loss. I've even heard the change described as organ shrinkage. Interesting. The ketogenic mice become relatively hypoinsulinaemic and glycogen depleted. Do these affect lean bodyweight directly?
I had the full text of this paper sent to me by a friend and it has a nice summary of the effects of carbohydrate restriction on fluid balance (excuse the rather condescending tone, it's written by a leading obesity researcher):
"...energy is stored in the body as protein, fat, and glycogen, which is a form of carbohydrate. Any imbalance between the intake and use of these macronutrients will lead to an alteration of body composition since the stored protein, fat, or glycogen must change to compensate the imbalance. The energy stored per unit mass of carbohydrate, fat, and protein varies considerably, especially when accounting for the intracellular water associated with stored glycogen and protein.7 Furthermore, dietary carbohydrates have an effect on renal sodium excretion via insulin,60 which results in concomitant changes of extracellular fluid."
As far as I can make out losing liver glycogen, muscle glycogen, excess sodium and, in particular, the water associated with these body components shows up as lean body mass loss on a DEXA scan. Reducing your insulin-induced sodium retention may be good or bad depending on many factors (such as your starting blood pressure!), but it will show as a non adipose tissue body deficit in Fig 2, graph B, second column. There might even be a little muscle reduction, I can't say...
We know from the DEXA scans in Table 5 that ketogenic dieted, post-obese mice had a significant deficit (by mouse standards) of fat compared to the D12451 injured mice and most of it showed up in the whole body scans rather than the hind limb scans. This would suggest to me that they lost central, probably visceral, fat. I think we all pretty well agree that visceral fat is Bad Fat (maybe). It's usually the first to go on ketogenic dieting in humans. I don't see fluid loss or visceral fat loss as big worries.
There seem to be a whole stack of benefits to sticking D12451 injured mice on to an extreme ketogenic diet.
Real FIRKO mice live about 18% longer than CIAB fed mice.
What about these ketogenic fed, pseudo-FIRKO mice? Alas the sad story of their premature demise will have to be left for the next post...
Peter
68 comments:
480 instead of 0.480 :-D
"We also know we can do exactly the same thing, without all the pesky death involved in sustained not-eating, by simply going in to deep ketosis without cutting calories."
How do humans increase their heat output?
That KD (Kraft Dinner) must 'ave been mighty rewarding. Thanks Peter.
Thanks for always creating very informative posts. I could use your help understanding something, if you get a chance please consider : I have seen elsewhere too references to insulin resistance induced by 'not eating for a while' as well as some claims that it's induced with Very low carb diets but i don't know the mechanism. It seems contrary to the classic sequence: "hi glucose->hi insulin->down-regulation of insulin receptors (aka insulin resistance)". Could you describe how the opposite happens, low insulin l(from not eating) eading to insulin resistance? There must be some additional mechanism triggered in the Very low glucose case?
Thanks a lot :-)
"I've heard it said that the weight loss in these ketogenic fed mice is not real weight loss. I've even heard the change described as organ shrinkage."
Chris Masterjohn's post about oxaloacetate from carbs or protein being needed to burn fat was fun... but I mean, c'mon, it was a five percent protein diet. If these mice really did have a lower protein balance, it seems more likely it was just because protein intake was so low. Five percent protein in a mouse diet leads to lower lean mass, no?
Meant to say, in a high carb 5 percent protein diet, there's less protein in a mouse
donny,
I brought up a similar concern to Chris. The same thing [protein loss] happens to mice or humans on a low protein, high carb diet, even if overfed; where's the "protein sparing" action in that case? Unfortunately there aren't those measurements in higher protein ketogenic rodent studies, but there are in one of Volek's I think, and the ketogenic subjects had no problem maintaining muscle mass (and losing fat).
Peter,
Regarding type of fat, Lucas has an interesting post (http://www.lucastafur.com/2011/12/getting-fat-type-matters.html).
...Also, though I haven't seen much data on ketogenic diet and aging, Jacob Harney of Hartford University told me they're currently conducting research on ketogenic diets and aging, but the results will not be available for a while. I'm looking forward to the next post.
You just know what the answer is:
"Live fast, die young"
That is the outcome of a "unique metabolic state".
http://www.youtube.com/watch?v=ZocrHzjjwVU
I am interested in the results of ketosis research myself, because I use a ketogenic diet for therapeutic purposes. I don't think living in ketosis is an equivalent of leaving fast and dangerous lifestyle. I know that according to the evidence, Inuit women aged quite fast, but they lived a very different life. I think other details matter (for example - level of physical activity, level of physiological insulin resistance, A1c, amount of nutrients, stress). I doubt we will see an adequate data soon, I personally continue to relay on observation and common sense while making personal decisions. Right now I think that if my life style resulted in the improved resistance to infections and better autoimmune problems management, that the changes I made was beneficial for health. Is it possible that some changes may have a short-liven benefit for health but be detrimental for longevity on a long run? I once came across a remark that Vilhjalmur Stefansson died of a stroke and it was implied his diet contributed to that. However, his age at the time of death was not that bad - 83 years old. Younger that Ancel Keys, though.
Galina I think there is a dominant genetic component to longeivty,
for example if we get a group of people born at the same time but with different genetics, and we fed them all the EXACT same diet for thier whole lives, would they all die at the exact same time from the exact same cause?
Most likely not.
Have a look at this......
Uncoupling proteins, genetics, longevity.
@Nigel:
"How do humans increase their heat output?"
It is very simple. More blood is shunted to the extremities. More heat is radiated away. The body uses more energy to maintain the 37C core temperature.
"How do humans increase their heat output?"
Jump into a bath of cold water while doing the niacin flush?
On the "heat output" question, it seems elevated FFA levels can potentially raise it:
http://www.ncbi.nlm.nih.gov/pubmed/11244455
Not sure if there are other confounding factors involved, like whether adipose insulin resistance counteracts that or whatever.
In my low-carb/ketogenic dietary habits I've noticed the more butter I use, the warmer I feel (sweaty, even). I know Peter's blogged about Dr. Davis's link regarding butter raising FFA's before. And that not all oils/fats are created equal in that regard.
Very interesting, although I wonder if this holds true in humans.
Perhaps in mice ad lib ketosis results in body fat loss even with VMH injury but this might be true in people. Fat tissue regulation is not exactly identical; in mice leptin injections result in uncontrolled fat tissue emaciation, this never occurs in humans.
Given that human beings may be evolved and adapted to a ketogenic diet, uncontrolled body fat loss does not seem a likely outcome as this would not be adaptive; how would we prevent excessive energy use in low nutrient, ketogenic situations (this would -> death)? Mice do not naturally eat a ketogenic diet under any circumstance so perhaps in mice they lack the ability to modulate energy use if the diet is ketogenic (instead they develop perhaps total fat cell IR).
I suppose what I am saying is I do not think it is likely that in human beings a ketogenic diet would result in complete adipocyte IR as it does for a mouse.
The function of energy conservation is to preserve nutrition when nutrients from the environment are scarce;
A VMH injured animal/human always operates as if nutrients are scare as it cannot receive fat tissue feedback, which is the same as there being none;
Mice perhaps can totally circumvent VMH injury with ketosis as ketosis is totally novel to them but given ketosis/ketogenic diets have occasionally been known to humanity I would assume we have evolved some kind of ability to inhibit fat loss on ketogenic diets if the brain is also simultaneously perceiving signs of body fat atrophy & starvation (e.g. hypogleptinemia or a destroyed hypothalamus, logical or pathological, either or, both accomplish the same thing of throwing a switch in the body that says be uber thrifty with energy).
I don't see how humanity could have survived if CNS reads starvation but energy is used generously anyway if the diet is ketogenic. Fat tissue IR knockout is one thing - that's pathological. We are proposing here that ketogenic diets accomplish the same thing when I don't see how that can be evolutionarily logical, unless of course we are also saying that ketogenic diets are as pathological as a knock out of insulin receptors on fat tissue.
Of course I am just spouting off and may be entirely wrong.
The thing is though most fat people do not have a destroyed hypothalamus so all of this is a moot point.
The problem in obesity is excessive fat tissue insulin signalling for a myriad of reasons most commonly being abnormal glucose and fat oxidation (e.g. not oxidizing glucose fully at meal times; responding to dietary glucose with excessive insulin production therefore); ketogenic diets should work very well in most fat people as their hypothalamus and leptin levels are not deficient or damaged. Leptin feedback to hypothalamus would only be a problem after most body fat atrophy has occurred after a long time on an insulin suppressive low carb diet.
From my experience I can tell - the better adaptation to ketosis, fasting, exercising in a fasted state - the less weight loss caused by the ketogenic state. For me it all makes sense, but inconvenient.
I've noticed since going VLC that I am vastly more cold tolerant. My skins feels very warm bordering on hot most of the time.
Increased thermogenesis probably explains why HGs can easily tolerate being naked in very cool weather.
@blogblog
I experienced this as well, but only when taking leptin replacement to compensate my weight loss induced deficiency. It's been so long since I ate "normally" or weighed a heavy body weight I can't accurately state the comparison; I can, however, accurately state that while taking a very low dose basal leptin I felt MUCH warmer, even though my body fat was far less (lowest weight on leptin: 112 lbs and extremely little body fat... now I am ~120).
Leptin , being the major adipocyte feedback signal indicating non-starvation, controls UCP-1 and increases thermogenesis. Lack of a leptin signal leads to suppressed thermogenesis. Leptin pretty much controls every single energy waste or thrift mechanism in the body. Though I do not believe in set point theory, I do believe (and it is absolutely true) that our bodies modulate energy waste or thrift and this is primarily controlled by leptin signalling. Hypothalamus like swiss cheese is basically like being hypoleptinemic. Could be swimming in food and body fat and the brain thinks you're in the middle of a famine.
I don't see how it could be possible in an organism adapted to a ketogenic diet (human being), that is otherwise in tact and not diseased (e.g. normal IR on fat tissue), that energy processes would continue to operate at a high level even if fat tissue was atrophied and leptin level (leptin: major swtich to turn energy waste off / thrift on) was very low. This sounds like a recipe for those genes being erased from the face of the earth forever.
Hypoleptinemia at a thin body weight, with adequate nutrients, is only found in post obese individuals exposed to developmental hyperinsulinemia who have lost a lot of weight. It has no relationship to normal healthy people but it does explain why so many fat people lose a ton of weight on low carb and then pile it right back on; or alternatively, lose down to a semi-fat size and stay that way unless they start depriving themselves of dietary energy to unnaturally shrink fat tissue.
Not to dominate this dicussion with LEPTIN!! rants ... I just find it hard to reconcile the idea that a destroyed hypothalamus + ad lib ketogenic diet = same thing as FIRKO, at least in human beings. Doesn't seem likely given evolutionary pressure to stay alive in starvation.
Peter, great post. Nice connection between FIRKO and KD.
Galina, I couldn't find an equivalent for Stefansson, but these pics were interesting:
http://www.proteinpower.com/drmike/low-carb-diets/jack-lalanne-vs-ancel-keys/
@Bill
Awww look at ancel keys at 100. That's a nursing home resident for sure.
He looks parkinsonian. Very rigid. Or maybe it's just the multiple CVAs giving him that look (I see right sided facial parlysis + cane).
Poor thing, he looks less able bodied than many of my LTC residents. I wonder if he had all of his faculties?
Anecdotal evidence, I'm now 29 and I have been eating very low carb since 20. No one guesses my age correctly, I've been about 5 years younger than my real age forever. When I tell people I am near 30 they usually follow that with "wow" and shock.
My skin shows very few signs of aging and I have tons of energy for knocking on 30. People generally assume I"m mid 20s.
@Woo,
the body has no trouble distinguishing between an adequate ketogenic diet and starvation.
I did a military survival course 30 years ago involving three days of complete starvation (a very unpleasant experience). The activity levels of all the participants immediately dropped to almost zero.
@Woo,
Stefansson noted that 80yo Inuits were as healthy as 20yo American college students (way back when 20yo Americans were still healthy).
There was a documentary a few years ago about a an elderly (late 60s) Australian Aborigine recreating his traditional "walkabout" (annual migration). He walked 1200km in seven days (170km/day) in some of the toughest terrain in Australia. He lived entirely off the land and was only equipped with basic clothing, a pocket knife and some matches. He didn't lose any weight and didn't even get a blister.
I agree with Woo (faints!) :-D
There's a big difference between small animals like rodents (also baby humans) and adult humans.
Small animals have a high surface area to mass ratio and therefore have a high heat loss per unit mass. Their biggest problem is to stay warm - or die. This is why they have loads of BAT to generate heat.
Adult humans don't have this problem, hence we have minimal BAT. Shivering is enough to keep our bodies warm in the cold.
Therefore, comparing the effects of a ketogenic diet in rodents with adult humans is pointless.
Adult humans who don't wear clothes (e.g. HG's) or who work in cold environments (e.g. lumberjacks) have more BAT activity than people who wear clothes and live in heated buildings.
"Brown-adipose-tissue activity was observed in 23 of the 24 subjects (96%) during cold exposure but not under thermoneutral conditions. The activity was significantly lower in the overweight or obese subjects than in the lean subjects (P=0.007)." Oh dear!
While I agree that extrapolation from rodent studies to humans is kind of pointless, I want only to point our that it's Stephan and his ilks that do so. From the long reading of Peter's blog I am quite sure that he does know the difference. As a vet, I think he has an advantage here over most MD and PhD in that he sees first hand that the metabolism of animals differ in subtle but fundamental ways. But Nigel and Woo are right to point it out, people don't always know the whole context.
Peter,
The following post and piece of research from That Paleo Guy's Blog has received remarkably little discussion. (I'm not surprised.)I've waited to see if there would be discussion popping up anywhere and there has not been. You're just the fellow to get it going! ;) And, i am very interested in your take on it.
"A high protein intake is known to increase satiety and thereby to reduce energy intake. Thus, in order to exclude the possibility that reduced adipose tissue mass in mice fed corn oil and protein ad libitum was simply due to reduced caloric intake, a third set of mice was pair-fed the same diets for 56 days. The mice fed corn oil in combination with sucrose gained an average of 11.3 g of body weight and became visibly obese.The mice fed corn oil in combination with protein gained on average less than 1.8 g of body weight during the 56 days of feeding and had small amounts of white adipose tissue. In fact, the weight gain and amount of body fat in mice fed a high corn oil diet supplemented with protein was comparable with the body weight gain and adipose tissue mass in mice fed an energy-restricted low-fat chow diet."
"So, the mice on the high-corn oil/high-sugar diet were not protein deficient. In fact, at 20% protein, they were probably consuming more protein than most New Zealanders (The 2008/09 NZ Adult Nutrition Survey found we are averaging just 16.5% energy from protein). This was also an ad libitum feeding study, meaning the mice get to eat when and where they like, similar to free-living humans. Whilst the fat+sugar mice became noticeably obese, the fat+protein mice gained relatively little body fat and tended to metabolise more fat and protein for energy. They also tended to be more satisfied by less food than those eating the fat+sugar and had comparable body compositions to the mice fed Jenny Craig their energy-restricted, low-fat chow diet."
"The authors make the following statement that seems to make a mockery of the calories-in, calories-out meme that is typically floated by conventional wisdom… you know the one – “as long as you balance your calories in and out, then what you eat doesn’t really matter…”
Our in vitro results and feeding experiments suggest that the adipogenic potential of n-6 PUFAs can be determined by the hormonal status of the animals.
So it becomes less a case of the number of calories consumed when it comes to body fat, and more a case of what hormonal response will be triggered by the foods that those calories are sourced from… quality trumps quantity. This is highlighted further by the following comment from the authors;"
"We observed a remarkable difference in feed efficiency between mice fed the protein-enriched versus the carbohydrate-enriched diet. In the high protein group, 467.8 kcal were needed to produce a weight gain of 1 g, whereas the high carbohydrate group only needed 67.8 kcal to produce the same weight gain, which almost exclusively represented an increase in adipose tissues."
"The mice eating the high-protein diet were able to consume 400 more calories than those in the high-carbohydrate group before gaining an additional gram of weight. Might this phenomenon explain the observation that those eating a paleo-type diet can appear to be over-eating by conventional standards yet still remain relatively lean?"
http://thatpaleoguy.com/2012/01/22/the-adipogenic-effect-of-omega-6-polyunsaturated-fats/
I'm very interested in your take. As I wrote in comments on the blog, though CICO is certainly a factor, it is not in my experience, the inviolable deity that it is touted as being. Not by a long shot.
mem
Peter,
I left a comment early this evening and it seems to have disappeared. Did you get it?
mem
@blogblog
Well yes a low calorie intake is obviously starvation and will lead to energy conservation, but I mean adipocyte feedback such as leptin/hypothalamus signalling... I don't see how, in human beings, one can be leptin deficient (or have hypothalamic damage), eat a high cal ketogenic diet, and have fully restored/improved metabolic functioning. I would believe that it might circumvent or blunt the drive to grow fat but I don't see it being true that a person would lose a lot of weight and be thinner/healthier, as is the case with mice.
The leptin signal is EXTREMELY important in human survival, particularly females (inhibiting reproduction during low body fat). It is the major signal of body fat / nutrition history. As humans are adapted to ketogenic diets, if the leptin switch is off (or your hypothalamus is lanced) I would assume a low leptin feedback would still result in thrifty use of energy, and I would imagine adding calories to a ketogenic diet would just contribute to more weight gain as opposed to liberal use of energy in such a case.
Even if this is only true in mice it is still extremely interesting.
I suspect the effect is also true in humans, in that I am quite sure very low carb / ketogenic diets circumvent hypoleptinemia and hypothalamic damage... I am only arguing splitting hairs, in that I don't think we would see a total improvement better than non-diseased state.
I have argued for a long time that very low carb diet is the only way I am able to stay this thin even with basal hypoleptinemia. If I tried to eat carbs I would be as fat as carbsane. It would be physically impossible. My glucose tolerance and sensitivity to insulin mediated fattening is horrible now after losing 160 pounds... but with very low carb diet? It doesn't matter that much.
I also think the reason so many people regain weight after LC diets is because they do not know how to handle/respond to the normal dropping leptin-mediated increased hunger and food desire they feel after massive weight loss. They end up eating more carbs from this increased hunger, and promptly regain weight at lighting fast speed. They then start saying stuff like "insulin doesn't cause obesity" and writing blogs about it, lol.
The reaosn IR knockout and ketogenic diets work in these obese animal models is because the CNS only gets us to grow fat by giving a helping hand to insulin. If you refuse to put glucose in your mouth, any leptin or hypothalamic issue is circumvented. Sort of like, unplugging a broken appliance. Leptin leads to fattening by ruining glucose processing and fat cell insulin hypersensitivity and more insulin production and lower dopamine and so fourth. If you don't put much glucose in your body, none of those really matter that much you will stay thin and not have unmangable hunger. I R LIVING PROOF.
After quitting leptin, I naturally and intuitively began eating a much lower carb intake again. First I went down to 60s, now I am down to 40s, and 30s and 20s sometimes. Every time I go lower I feel better, less hungry, easier body fat control.
While taking adequate leptin none of it matters, I can eat a decent amount of carbs and preserve a thin body mass because my body is no longer constitutionally driven to fatten from adipocyte hypotrophy. Off leptin? Yea, insulin mediated damage to fat tissue sort of necessitates either life long leptin replacement or life long ketosis, or life long fatness. Take your pick. Most choose fatness, it's the easiest option.
mem, it went in to spam for some reason best known to blogger software, it's up now.
Peter
In the addendum of this post, Michael Eades talks about how high fat diets will cause us to increase futile cycling of protons across the mitochondrial membrane, creating waste heat:
http://proteinpower.com/drmike/metabolic-advantage/thermodynamics-and-the-metabolic-advantage/
@Nigel;
"Therefore, comparing the effects of a ketogenic diet in rodents with adult humans is pointless."
I agree completely.
Natural rat or mouse approximate diet ratios:
80-85% complex carbohydrate
10-15% protein
2-5% fat
Wild rats and mice eat mostly seeds and starchy tubers. They use gut bacteria to convert starch and fibre into fat and protein in the caecum. They don't eat fatty diets by choice.
mem wrote: "The authors make the following statement that seems to make a mockery of the calories-in, calories-out meme that is typically floated by conventional wisdom… you know the one – “as long as you balance your calories in and out, then what you eat doesn’t really matter…”
That's a straw man. CICO only affects body weight. Body composition is affected by loads of things.
Adipogenicity is merely a shift in nutrient partitioning towards fat mass and away from muscle mass. This can occur with no change in body weight.
Body-builders can shift nutrient partitioning towards muscle mass and away from fat mass by doing resistance exercises. This can occur with no change in body weight. They call it "lean bulking".
TB, I think what happens is Ketogenic diets increase uncoupling proteins, which is basically energy wasteing.
"protons can leak across the mitochondrial inner membrane independently of ATP production. This unregulated, futile proton conductance is of considerable physiological relevance, as it can account for as much as 20-70% of cellular metabolic rate depending on cell type. A majority of proton leak can be strictly attributed to the abundance, but not activity, of mitochondrial carrier proteins such as the adenine nucleotide translocase (ANT) and, in brown adipose tissue (BAT), uncoupling protein 1 (UCP1)."
"UCP1, is best known for its role in adaptive non-shivering thermogenesis and control of body weight, whereby a cold stimulus or over-feeding results in sympathomimetic stimulation of β3-adrenergic receptors in BAT. This leads to upregulation of Ucp1 mRNA expression via a BAT-specific enhancer box, activation of UCP1 by fatty acids produced from lipolysis, and the transduction of the mitochondrial protonmotive force into heat. Indeed Ucp1 knockout results in the absence of non-shivering thermogenesis, loss of cold tolerance and appearance of obesity at thermoneutrality.
@mem: Studies that measure Calories In but not Calories Out produce meaningless results.
See The Energy Balance Equation.
@Kindke: Adult humans have a much lower surface area to mass ratio than rodents, so we can overheat much more easily.
DNP increases energy wastage. People have died from the complications of hyperthermia by taking too much DNP.
mem,
I would just look at it from the point of view that sucrose fed rats lost calories to adipose tissue and never let them out again because they were chronically hyperinsulinaemic (that's the usual effect of sucrose, I'm assuming it happened here). The high protein mice also stored their corn oil as adipose tissue after eating (big post prandial insulin spike with high protein) but had easy access to it during period between meals. I'd expect the sucrose fed rats to move less and probably do their damnedest to keep warm. Calories in ALWAYs equal calories out, but I would include loss to adipocytes as calories out as well as metabolic inefficiency loss (heat) and straight UCP facilitated mega heat loss, especially if you own BAT. Suggesting calories consumed = weight gained is stupidity at the ultimate dietitian level.
blog blog, I'd not suggest people enjoy fasting or are not hungry. But they ARE insulin resistant. The aesthetic experience of insulin resistance due to starvation and insulin resistance due to carbohydrate restriction are very different, but both are insulin resistance. No one is suggesting that all humans are mice and could maintain caloric intake while using BAT UCP-1 and muscle UCP-3 to waste heat and so lose weight, although undoubtedly some people can. It probably depends on how much BAT you have and how good you are at using UCP-3. These are both currently major targets for drug development to allow people to eat crap and still lose weight. With adequate adipose tissue to provide calories most people in carb restricted ketosis, as you well know, just say no to that last slice of bacon or six. We're not mice.
john, there's a lot to think about in VAT vs SAT about the hows and whys despite the end result that VAT is Bad Fat. The fascinating question is why is it doing what it is doing.
Leon, live fast, die young, breed early = insulin. Or rather, the equation reversed. The mice are undoubtedly hypo insulinaemic. Nice track though!
TB and kindke, UCPs = Good, PSS's conclusion. In physiology, ignoring DNP, proton leakage is neither unregulated nor futile. Amongst multiple effects uncoupling allows free flow of electrons down the electron transport chain so reduces free radical generation, especially at complex 1. More uncoupling = less free radicals, less need for SOD, less damage, possibly less aging. Ketosis generally gets us there. There are other approaches to minimising free radical generation mentioned in PSS and resistance training comes out rather well.
Peter
Nigel, plus one Brownie point
Thanks, Peter. Much appreciated.
Nigel, there was a 400 cal difference in what it took for the rats to gain a gram of weight. I get the whole CICO gig. I simply think it's much more complex than it is ever thrown around as being. I certainly get that weight is different from body comp.I also think that if the sucrose+corn oil rodent's activity rate had been noticeably different, that would have been noted in the study. I don't think they were all flopped on each other in the bottom of the cage. Yes, it would have been optimum if they had been paired on rat wheels, etc.
mem, sorry for a typo:
"Suggesting calories consumed = weight gained is stupidity at the ultimate dietitian level."
should say
"Suggesting EXCESS calories consumed = weight gained is stupidity at the ultimate dietitian level."
Oops
Peter
Marie, not eating = no glucose bar gluconeogenesis = death from hypoglycaemia unless muscles etc stop using glucose and switch to ketone bodies and FFAs. They do this because FFAs rise and cause insulin resistance, particularly palmitic acid.
The problems come when you have adipocyte distension induced elevated FFAs and so have FFAs in abundance then eat a ton of carbs. This is the classic recipe for hyperglycaemia and is utterly pathological.
Not eating gives a physiological insulin resistance which keeps you alive when glucose is in short supply.
Peter
"Given that human beings may be evolved and adapted to a ketogenic diet, uncontrolled body fat loss does not seem a likely outcome as this would not be adaptive."
Well, that´s something most of us who have tried Ketogenic diets can attest to...
Still, that might be why CKD:s are a popular option for body fat loss.
Report from the Swedish front. Ketogenic high-fat dieting popped onto the radar in these parts in 2007 or so.
Here is a choice stat: The sale of low-fat ("Cholesterol lowering!") margarine har "more than halved" in four years...
http://www.dn.se/ekonomi/nyckelhalet-lockar-farre
Also, always remember this kids:
- Decreased water retention from lowering salt intake: DoubleplusGood (TM). Everyone should do it, even if no direct benefit can be shown.
- Decreased water retention from lowering carbohydrate intake: Dangerous experimentation / obfuscating factor / (insert scare story here).
mem said: "I also think that if the sucrose+corn oil rodent's activity rate had been noticeably different, that would have been noted in the study."
Rodents have a tiny mass, so physical activity results in tiny energy expenditure. The vast majority of a rodent's energy expenditure is heat, due to the high surface area to volume ratio. This expenditure can vary a lot without having a significant effect on the rodent's body temperature.
I've been reading about brown fat recently, that mice and human babies have the most of those studied; and that being chilly creates more in adult men (women weren't in study). Both my spouse and I have been on ketogenic diet most of the time for about two years, & did Atkins for about six years before. What I wonder is what makes my husband always cold while I easily get overly warm? He is a lot more active than I, too. I am IR, we're in early 60s, generally fit and both look younger than our peers--it's often commented upon, so I'm not meaning to boast. Seems like I should feel colder than he does.
Oh and in something totally and completely unrelated..
At carbsane's blog she discusses this blog post. Ignoring her analysis for a moment (which is of course horrible/pointless/wrong), I would like to focus on her strange criticism that Peter coined the term "physiologic insulin resistance". I don't know why anyone would offer criticism of developing such an obviously useful and correct term.
The term physiologic insulin resistance is perfect. Brilliant. It demystifies why the body does not prefer to use glucose in states of starvation or glucose deprivation, which otherwise might lead to the irrational conclusion that eating fat or being in a very low calorie intake causes similar metabolic defects as having a metabolic disorder, mitochondrial insufficiency, which is the cause of pathological insulin resistance.
The term physiologic is appropriate, because it is a normal function of the body that is rapidly reversed upon termination of the condition inducing it (lack of food, lack of glucose). It is also appropriate because it helps the body to adapt to environmental conditions and does not harm the body, like pathological insulin resistance.
Criticizing someone for having such amazing insight and coining such a useful label is like laughing at an artist for creating a masterpiece simply because the in crowd doesn't recognize it as being that.
But I guess when you lack the ability to think, have unique interesting insights, and are pretty much a lobotomized robot, you would expect that the barometer of usefulness/correctness of a term would be the number of (failed) obesity researchers who said it before you.
donny, never replied, the mice on 5% protein are on very low intakes (low methionine too I guess), I agree. They seem to have reasonable muscle mass on DEXA once you take the fluid shifts in to account. They may not look like Schwarzenegger in his peak years but they're not emaciated vegans either...
nancan, there are an awful lot of variables to think about in terms of human cold tolerance. It's certainly not as simple as "eat high fat, improve cold tolerance" but it's a reasonable start. As you realise, there's a lot on the go about UCPs and BAT in humans. We all have some, even in adulthood.
It's, teehee, I see you've been overdoing the ondansetron recently! There are limits to what I have time to read and stuff requiring antiemetics is not high on my priority list.
Peter
"as having a metabolic disorder, mitochondrial insufficiency, which is the cause of pathological insulin resistance."
Has Peter ever made a combo-all-in-one post about the entire causality chain "cause -> mitochondrial insufficiency -> bad stuff", etc.
If not, it would be a service to humanity, etc. etc.
"Thus, total heat output was 15% higher, averaged over 24 h, in KD animals (KD 0.538 ± 0.01 kcal/h vs. HF 480 ± 0.01 kcal/h, P < 0.05, n = 4)."
Now, such an increase in humans may hardly show on the thermometer, because the heat is being regulated by its loss to the outside through heatpumps like skin, sweat, urine.
Exposure to cold ought to increase heat output, drinking water, perhaps breathing exercises.
Chillie raises body temp 1 degree while it lasts; presumably normalizing this increases heat output.
This is where the metabolic advantage goes, I guess.
Steffanson only followed the all-meat diet for 3 periods; on the ice with the Inuit, in the Bellevue experiment, then towards the end of his life. I don't know if he smoked or drank either. When he stated again late in life he had health problems - overweight, arthritis - that the diet reversed. And that you would expect to be life-shortening.
It's often the case that low-carbers are trying to reverse years of damage from bad habits. And may backslide like anyone else, though perhaps less often. So it's hard to draw conclusions from anything but controlled interventions.
Epidemiologically, it seems like a high SFA intake is not associated with CHD even on a normal diet, and is somewhat negatively associated with stroke, cancer and suicide.
Mem, thanks for the link on n=6 EFA
I have been looking for the mechanism; it seems to me self-evident that food cooked in vege oil is more fattening than the same food cooked in tallow.
My theory is that excess PUFA competes with MUFA for the saturase enzymes that convert all unsaturated fats to SFA before beta-oxidation.
Evidence of this is the elevated MUFA: SFA ratio seen in fatty liver diseases.
The antiemetic reference is particularly apt.
Looking for good ideas on carbsane's blog is like looking for gold coins in a pool of vomit.
George Henderson said...
""Thus, total heat output was 15% higher, averaged over 24 h, in KD animals (KD 0.538 ± 0.01 kcal/h vs. HF 480 ± 0.01 kcal/h, P < 0.05, n = 4)."
Now, such an increase in humans may hardly show on the thermometer, because the heat is being regulated by its loss to the outside through heatpumps like skin, sweat, urine."
An increase in BMR of 15% will result in an increase in human body temperature of ~1.5°C, or ~2.7°F. This would definitely be noticeable!
Another thing that occurs to me with the ketogenic mice and lean mass. If you feed rats or pigs, I assume mice, a diet crazy high in resistant starch or fiber, there's a pretty good increase in colon length. A ketogenic diet might make for the opposite (not so much fermentation).
@Makro I don't think peter would attempt this because odds are better than not there will never be one unanimous universal cause for metabolic disorders and abnormal mitochondrial functioning, deficiency, or insufficiency. Some are functional/physiological, such as low dopamine signalling (seasonal switch to metabolic conservation/hibernation) or being a lower body weight with low leptin signalling. The mitochondria are still normal they are just altering function and not using glucose for energy due to dopamine signal being deficient. And in the case of leptin deficiency, not using fat for energy either.
Some are pathological, like the mitochondria of diabetics which are few in number and damaged. There are tons of ways to get damaged mitochondria. Toxins, prenatal damage, pathogens, genetics, and of course the most well cited reason by obesity researchers: overnutrition, energy in excess of what can be used or coped with, is very toxic to mitochondria;
Insulin resistance in lean tissue with relatively more in fat tissue and symptomatic fat gain (the pre-type II DM phenotype) is a method of preserving mitochondria when confronted with energy that cannot be utilized (mitochondria defect/damage). This is effectively shunting energy away from energy use (which sucks) toward adipocyte storage (first).
Later when eventually that method is exhausted via maximal obesity (this is genetically determined) you decompensate with insulin resistant fat tissue and hyperglycemia and congrats you are now diabetic... here is your dialysis schedule and your revolving door admission to hospitals for infections and I hope you don't mind feeling nothing in your feet/having them rot off.
Regarding conversion to type II diabetes, there is also an element of other endocrine disturbances leading to loss of insulin-producing capacity in the pancreas due to toxic amyloidosis (related to abnormalities in amylin processing), as well as lack of GLP-1. These are also part of the pathophysiology of type II DM.
So when one converts to diabetes from being an IR fatso, it might not be true that their fat tissue is maximally resistant; it might also be true that their pancreas is broken down like a 1985 ford.
http://age.bjmu.edu.cn/old/progress/pbl/08.pdf <--- not a bad, basic description of how toxicity to mitochondria (this is focusing on lipotoxicity in particular) lead to insulin resistance and diabetes. An inability to oxidize LCFA (which is, BTW, not exclusively a function of abnormal fat metabolism, it is also related to excessive glucose intakes in people who have poor glucose metabolisms - Hi there inhibited CPT-1 nice to see you) leads to lipid accumulation, toxicity, mitochondrial loss/damage.
@George,
Stefansson spent most of his adult life on an all meat diet. He lived 10 years on the ice (1904-1914). He returned to the all meat diet in 1927 (Bellevue experiment) at age 48. He remained on the diet until is death in 1962 (aged 82).
@Donny,
all raw starch is highly resistant. Raw potatoes have a GI of around 6.
Forgive the way off topic nature of this comment, I like to read the comments associated with the articles that Peter posts, thanks to the helpful and knowledgable posters. When there are a lot of comments combined with returning every day or 2 - the timestamp on the comment, "11.47 AM" is no help at all as an aid to figure out where I left off.
The timestamp is, frankly, useless.
A date, time, timezone can't be that hard?
Hi Peter, I found your blog researching a question for my translators FB group: a colleague has encountered the sentence "the room reeked of hot mice and TCP," and we have no idea what "hot mice" are. Do you think you could help us poor language specialists?
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