July 18, 2013

Nutritional Biochemistry

How to make a fat cell less not thin: the lessons of fat flux

Does being in ketosis automatically translate to fat loss?

Read Time 16 minutes

One of the questions I most often receive: Does being in ketosis automatically translate to fat loss?

For those too busy to read ahead, let me give you the punch line: No. For those who want to understand why, keep reading (hopefully this is still everyone). This topic is — surprise, surprise — very nuanced, and almost always bastardized when oversimplified, which I’m about to do, though hopefully less than most.  Without oversimplifying, though, this will turn into a textbook of 1,000 pages.

From the ketosis series, or at least the first and second part, along with the video in this previous post, you should have taken away that ketosis is not some ‘magical state of mystery.’  It’s simply a state of physiology where our liver turns fatty acid (both ingested and stored) into ketones.

There seems to be great confusion around ‘nutritional’ ketosis (a term we use to distinguish ‘dietary-induced’ ketosis from the other 2 forms of ketosis: starvation ketosis and ketoacidosis, the latter a serious complication of type I diabetes). But, before I try to dispel any of the confusion, we need to go through a little primer on what I like to call “fat flux.”

One point before diving in, please do not assume because I’m writing this post that I think adiposity (the technical term for relative amount of fat in the body) is the most important thing to worry about.  On the contrary, I think the metabolic state of the cell is far more important. While there is a correlation between high adiposity (excessive fat) and metabolic dysfunction, that correlation is far from perfect, and, as I’ve discussed elsewhere, I think the arrow of causation goes from metabolic dysfunction to adiposity, not the reverse.  But, everyone wants to lose fat, it seems, so let’s at least get the facts straight.

Let’s start with an assertion: Barring the presence of scientific evidence I’m unaware of, and barring surgical intervention (e.g., liposuction), reducing the adiposity of a person is achieved by reducing the adiposity of individual adipose cells, collectively. In other words, the number of adipocytes (fat cells) we have as an adult does not change nearly as much as their size and fat content.  So, for people to reduce their fat mass, their fat cells must collectively lose fat mass. 

Fat flux 101

According to “An Etymological Dictionary of Modern English,” the word flux comes from the Latin word fluxus and fluere, which mean “flow” and “to flow,” respectively. While the term has a clear mathematical meaning in physics, defined by a dot product I promise I won’t speak of, you can think of flux as the net throughput which takes into account positive and negative accumulation.

If we start with a bucket of water and put a hole in the bottom, the result, needless to say, is an efflux of water, or negative water flux.  Conversely, if we start with a bucket – no hole – and we pour water in, that’s an influx of water, or positive water flux.

If that makes sense, then the idea of fat flux is pretty straight forward.  If more fat enters a fat cell (called an adipocyte) than leaves it, the fat cell is experiencing a net influx – i.e., positive fat flux.  And, if more fat leaves a fat cell than enters, the reverse is true: it is experiencing a net efflux, or negative fat flux.

Not surprisingly, a fat cell is more complicated than a bucket.  Basically, though, there are two “inputs” and one “output.” The figure below shows this in some detail. (TAG stands for triacylglycerol, which is another word for triglyceride, which is the storage form of fat.)  The first thing you may appreciate, especially since I’ve highlighted it, is the role insulin plays in regulating the process of fat flux.  Insulin does the following:

  1. Upregulates lipoprotein lipase (LPL), an enzyme that breaks down TAG so they can be transported across cell membranes. Since TAG are too big to bring across cell membranes, they need to be “hydrolyzed” first into free fatty acids, then re-assembled (re-esterified) back into TAG.
  2. Translocates GLUT4 transporters to the plasma membrane from endosomes within the cell.  In other words, insulin moves the GLUT4 transporter to the cell surface to bring glucose into the cell.
  3. Facilitates lipogenesis, that is, facilitates the conversion of glucose into acetyl CoA which gets assembled into fatty acids along with glycerol.
  4. Facilitates esterification, that is, facilitates the process of assembling fatty acids into TAG (3 fatty acids per TAG).
  5. Inhibits hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), two important enzymes that breaks down TAG into fatty acids and glycerol such that the fatty acids can be released from the fat cell. Once bound to albumin the free fatty acids are free to travel elsewhere in the body for use (e.g., to the liver for conversion to ketones, to the heart muscle or skeletal muscles for conversion to ATP).
  6. Though not shown in this figure, insulin appears to indirectly act on malonyl-CoA, a potent inhibitor of CPT I, one of the most important mitochondrial enzymes that facilitates the oxidation of fatty acids. (CPT I is what enables fatty acids to be shuttled into the mitochondria for oxidation, the process which releases or liberates their energy through electron transport.)

Other hormones and enzymes in the body also play a role.  For example, under a sympathetic response, the so-called “fight or flight” response, adrenaline and noradrenaline (i.e., epinephrine and norepinephrine) activate HSL and ATGL to combat the effect of insulin as an inhibitor of lipolysis, thereby increasing lipolysis, or liberating stored energy from the fat cell.  Glucagon may also play a role in this process, though the exact role is not as well understood, at least not in humans.

So in summary, insulin is indeed the master hormone that regulates the flow of fat (and glucose) into and out of a fat cell.  There are other players in this game, to be sure, but insulin is The General. High levels of insulin promote fat storage and inhibit fat oxidation, and low levels of insulin promote fat mobilization or release along with fat oxidation.

If this sounds crazy – the notion that insulin plays such a crucial role in fat tissue — consider the following two clinical extremes: type 1 diabetes (T1D) and insulinoma. In the former, the immune system destroys beta-cells (the pancreatic cells that make insulin) – this is an extreme case of low insulin.  In the case of the latter, a tumor of the beta-cell leads to hypersecretion of insulin – this is an extreme case of high insulin.  Prior to the discovery of insulin as the only treatment, patients who developed T1D would become emaciated, if the other complications of glycosuria and dehydration didn’t harm them first. They literally lost all fat and muscle.  Conversely, patients with insulinoma often present looking not just obese, but almost disfigured in their adiposity.  Because Johns Hopkins is a high-volume referral center for pancreatic surgery, it was not uncommon to see patients with insulinoma when I was there.  As quickly as we would remove these tumors, the patients would begin to return to their previous state and the adipose tissue would melt away.

For the purpose of our discussion, I’ve simplified the more detailed figure above into this simplified figure, below. I’ve tried to size the arrows accordingly to match their relative contributions of each input and output.

The first figure, below, shows a state of fat balance, or zero net fat flux.

Input #1: De novo lipogenesis, or “DNL” – Until the early 1990’s there was no way to measure this directly, and so no one really had any idea how much this process (i.e., the conversion of glucose to fat) contributed to overall fat balance.  Without going into great technical detail, , arguably one of the world’s foremost authorities on metabolomics and DNL, developed a tracer technique to directly measure this process. If I recall correctly, the original report was in 1991, but this paper is a great summary.  Published in 1995 in the Journal of Clinical Investigationthis paper would go on to become the “citation classic.” This study demonstrated that under eucaloric feeding conditions, with about 50% of energy coming from CHO, DNL did not represent a significant contribution to fat flux. It was about 5%, hence the tiny red arrow under a state of fat balance (i.e., a state where fat entering the fat cell is equal to fat leaving the fat cell). A very important point to be mindful of, however, is this: this represents an average throughout the body and does not differentiate specifically between, say, DNL in the liver and DNL in the periphery (i.e., fat cells). This limitation is not trivial, but rather than focus on the very specific details of this paper, I’d rather use it as a framework for this discussion. (This paper is really interesting, and were it not for the fact that this post is going to be long enough, I would say much more about it.  As such, I will probably do a full post on this paper and related topic in the future. The 1995 paper also examined what happened to DNL during periods of over- and under-feeding CHO and fat.)

Input #2: Re-esterification, or “RE” – In a state of fat balance, RE is largely composed of dietary fat sources that are not immediately used, but rather stored for later use.  (Nuanced point: RE also includes fatty acids that were previously liberated from adipocytes, not oxidized, and are now being recycled back into TAG.  This is a normal consequence of fat liberation.  The fat cell probably ‘deliberately overdoes it’ by liberating more fatty acid from TAG just to be safe; that which is not oxidized is re-esterified.  The exact balance of RE composed from dietary sources versus recycled fatty acids will depend on fat consumption and energy demands of the person. For the purpose of simplicity, this diagram does not show some portion of the L fraction returning to the RE fraction, though this is exactly what is happening in ‘real life.’)

Obviously, though, the relative size of the blue arrow depends on how much fat one is consuming and how many metabolic demands are in place for fatty acids.  The latter is highly determined by dietary composition (see the discussion on RQ, or respiratory quotient, at about minute 31 in this video).

For the real aficionado, there is another wee bit of nuance here. This study, published in 1991 in the Journal of Lipid Research, suggested that the RE process is a bit more complicated than simply re-assembling fatty acids on a glycerol backbone inside an adipocyte.  Based on these experiments, which used a similar* tracer method to the one used by Hellerstein et al. to evaluate DNL, the authors (which included Rudy Leibel, the co-discoverer of leptin) suggested that RE requires an intermediate step outside of the adipocyte in the interstitial and capillary space (figure 8 of the paper demonstrates this very well schematically).

(*) Technically, Hellerstein et al. used a heavy isotope; Leibel et al. used radioactive isotopes.

Output: Lipolysis, or “L” – Finally, in a state of fat balance, lipolysis must be equal to the sum of DNL and RE.  This is true if we are talking about tiny little fat cells or giant ones.  Remember, it’s the balance that matters.

I hope it’s clear from this summary that there are an infinite number of physiologic states that can satisfy the equation of fat balance: DNL + RE = L. For example, someone like me who is in fat balance (i.e., I’m neither gaining nor losing fat mass at this point) on a ketogenic diet with daily fat intake often exceeding 400 grams, has virtually zero DNL, but quite high RE, especially after meals.  Consequently, I have very high L.  If you took a person on a very low-fat diet (e.g., 20% fat, but 65% CHO), they would have modest DNL and low RE, but they would have low L.  We would both be in fat balance, but we satisfy the equation DNL + RE = L by very different means.

OK, so let’s turn our attention to the non-equilibrium states: Net fat influx and net fat efflux.

Fat influx

In a state of net fat influx – accumulation of fat within a fat cell – the following condition must be met (on average): DNL + RE > L.  (I say “on average” because, of course, a fat cell is a dynamic system with constant changes in these parameters.  So, at any moment in time the balance can shift, but over a period of time the equation is correct.)

The next (overly simplistic) figure below gives you a representative state of what fat influx or ‘positive fat flux’ probably looks like.  DNL is higher, but still relatively small, unless overfeeding CHO.  RE is larger than it was in a balanced state, but not necessarily ‘huge.’  Most cases of net fat influx are probably governed by low L.  In other words, fat accumulation is probably more governed by a failure to mobilize (breakdown TG into fatty acids for export and use) TAG than anything else.

Have you ever spoken with someone who is trying desperately to lose weight (fat) who says, “I don’t understand what’s happening…I hardly eat any fat, and yet I can’t lose a pound (of fat)!”  The skinny people in the group scoff, right? Well, not so fast.  It’s quite possible, if the hormones that regulate fat tissue are not working in your favor, to do such a poor job mobilizing fat from fat cells, and oxidizing that fat (see below), that you can be in fat balance, or even fat imbalance with accumulation, despite small DNL and small RE.

If you think about it, lipolysis (L), or liberating fat from a fat cell is a necessary, but not sufficient condition to actually generate the free energy inherent or stored within it.  One more major step is necessary – oxidizing the fatty acid via the process of beta-oxidation. This is where one actually gets the energy (ATP) from fatty acids. The same hormones and enzymes that promote L, directly or indirectly act on other intermediaries that promote oxidation, more or less. The converse is also largely true.

Brief digression: I’m always troubled by folks who have never tried to take care of someone who is struggling to lose weight (fat), and who themselves have never been overweight, but who insist obesity is ‘simply’ an energy balance problem – people eat too many calories.  When eternally lean people preach about the virtues of their ‘obvious’ solutions to obesity – just eat less and exercise more – I’m reminded of a quote (source unknown to me), “He was born on the finish line, so he thinks he won the race.”  You only need to meet one woman with PCOS, or one person with hypothyroidism, or one child with Cushing’s disease to know that adiposity can – and is – largely regulated by hormones.  The fact that such patients need to create a positive energy balance (i.e., eat more calories than they expend) to allow it does not seem to provide a meaningful insight into the mechanism of why.

Fat efflux

In a state of net fat efflux – reduction of fat within a fat cell – the following condition must be met (on average): DNL + RE < L (same caveat as above on the idea of “on average”). Again, looking at the figure, you can see one physiologically common way this occurs, the setting of carbohydrate restriction.  DNL is reduced (probably even to immeasurable levels, depending on the extent of restriction), but RE actually goes up.  The net efflux, however, results from the greater increase in L.

A person in nutritional ketosis, if experiencing fat loss, probably looks like this. (Don’t worry, I have not forgot the opening questions: Does being in nutritional ketosis automatically put you in this state?).  Certainly another state of net fat efflux is starvation.  DNL and RE are both very small, especially DNL, and lipolysis is quite large. This is probably the most rapid state of negative fat flux a human can experience.

So what we do about it?

I do not believe there is only one state, shy of total starvation, which will assuredly put you in state of negative fat flux.  Of course, starvation is not sustainable, and therefore should be taken off the table as a viable long term eating strategy.

What about profound caloric restriction? Yup, this is probably (though not necessarily) going to work, depending on how “profound” is defined.  If defined as a 40% reduction of energy stable intake, it’s probably going to work.  If defined as a 10% reduction, it would be difficult to know without knowing at least two other things:

  1. Baseline level of insulin resistance;
  2. RQ of pre- and post-diet.

What about dramatic alterations in macronutrient composition? This is where the discussion gets really interesting.  Many people, myself included, advocate a diet that overall reduces insulin secretion. The rationale, of course, is provided by the first figure above (from the textbook) and a slew of clinical studies which I will not review here (see Gardner JAMA 2007, Ludwig JAMA 2012, and Shai NEJM 2008 to name a few).

But, the bigger question is why? Why do most (but not all, by the way) people with excess fat to spare who are on well-formulated carbohydrate-reduced diets lose fat? (Notice, I did not say weight, because the initial – and often rapid — weight loss achieved by many is actually water loss.)

Is it because of a physiologic change that leads them to reduce overall intake?

Is it because of a physiologic change that, despite the same intake in overall calories, increases their energy expenditure?

Is it some combination of these?

I wish I knew the answer, but I don’t (universally).  I believe we will know the answer to this question in a few years, but until then, I’m left to offer the best my limited intuition can offer.  In other words, what I suggest below is my best interpretation of the literature, my personal experience that I’ve had with hundreds of other people, and my discussions with some of the most thoughtful scientists in the world on this topic:

Thought #1: I suspect that many people who reduce simple carbohydrates and sugars end up eating fewer calories.  This observation, however, may confound our understanding of why they lose weight.  Do they lose weight because they eat less? Or, do they eat less because they are losing weight? I suspect the later.  In this state, lipolysis — and by extension, given the hormonal milieu, oxidation — are very high, certainly relative to their previous state.  By definition, L > DNL + RE, so there is ample ATP generated by oxidation of the fatty acid.  If you believe (as I do*) that the liver is the master organ of appetite regulation, increases in ‘available energy’ (i.e., ATP) would naturally reduce appetite (though I don’t think we know if ATP per se is the driver of this feedback loop).  But don’t confuse what’s happening. They are not giving up fat from their fat cells because they are eating less.  They are eating less because they are giving up fat from their fat cells.  Big difference.

(*) The especially astute reader will note that this is the first time I have made reference to this point.  I have been heavily influenced recently by the work of Mark Friedman, and a discussion of this point is worth an entire post, which I promise to deliver at some point in the future. If you can’t wait, which I can understand, I highly encourage you to start scouring the literature for Mark’s work.  It’s simply remarkable.

Thought #2: I also suspect that some fraction of people who follow this eating strategy lose fat without any appreciable reduction in their total caloric intake, at least initially. What?, you say, doesn’t this violate the First Law of Thermodynamics? Not at all.  If L > DNL + RE, and the increase in lipolysis (i.e., fatty acid flux out of the fat cell) results in increased oxidation of fatty acids, energy expenditure (EE) would be expected to rise.  A rise in EE, in the face of constant input, is a sign of fat loss. What differentiates those in this camp (I was in this camp) from those above (point #1), is unclear to me.  It may have to do with concomitant exercise.  I have seen unpublished data, which I can’t share, suggesting non-deliberate EE rises more in a low RQ (high fat, low carb) environment when a person is exercising significantly. I’m not stating the obvious – that the deliberate EE is higher – that is clearly true. I’m suggesting resting EE is for some reason more likely to rise in this setting.  Since I’m taking the liberty of hypothesizing, I would guess this effect (if real) is a result of the body trying to keep up with a higher energy demand and making one trade-off (generating more free ATP via more lipolysis) for another (ensuring a constant supply of available energy to meet frequent demands). It is also possible that this increase in free/available energy results in an increase in deliberate EE (i.e., the person who suddenly, in the presence of a cleaned up diet feels the desire to walk up the stairs when they previously took the elevator).  Finally, and perhaps most importantly, whether or not this up-regulation of energy takes place may be dependent on the other hormones in the body that also play a role in fat regulation, including cortisol, testosterone, and estrogen. They could be partly or mostly responsible for this. The literature is quite dilute with respect to this question, but in my experience (feel free to dismiss), it is not uncommon to see a reduction in cortisol and an increase in testosterone (I experienced about 50% in free and total testosterone) with a dietary shift that improves food quality.  The same may be true of estrogen in women, by the way, though I have less clinical experience with estrogen.

Thought #3: As a subset to the point above (point #2), in an ‘extreme’ state of carbohydrate restriction, i.e., — nutritional ketosis — there is an energy cost of making the ketones from fatty acids.  I referred to this as the “Hall Paradox” after Kevin Hall, who first alerted me to this, in this post (near the bottom of the post).  What is not clear (to me, at least) is if this effect is transient and if so, how significant it is.  I recall that during the first three months of my foray into nutritional ketosis, I was eating between 4,000 and 4,500 kcal/day for a 12-week period, yet my weight reduced from 176 lb (about 9.5% bf by DEXA) to 171 lb (about 7.5% bf by DEXA), which means that of the 5 pounds I lost in 12 weeks, 4 were fat tissue. Today, however, I don’t consume this much, closer to 3,800 kcal/day, and one reason may be that two years later my body is more efficient at making ketones and this so-called “metabolic advantage” is no longer present.

(I have always found the term “metabolic advantage” to be misleading, though I’m guilty of using it periodically.  It’s really a metabolic disadvantage if your body requires more energy to do the same work, but nevertheless, people refer to – and argue vehemently about – this phenomenon. The question is not, does it exist?  One look at individual summary data from David Ludwig’s JAMA paper on this topic makes that clear. The questions are, why does it only exist in some people, what relevance does it have to fat loss – is it cause or effect? – and, for how long does it persist?)

Thought #4: For reasons I have yet to fully understand, some people can only lose fat on a diet that restricts fat (and by extension a diet that is still high in carbohydrate, since I’m excluding starvation and profound caloric restriction from this discussion). In my experience (and Gardner’s A TO Z trial seems to validate this, at least in pre-menopausal women), about 20% of people aspiring to reduce adiposity seem to do it better in a higher RQ environment. Using the Ornish diet as the example from this paper, I suspect the reason is multifactorial.  For example, the Ornish diet restricts many things, besides fat. It restricts sugar, flour, and processed carbohydrates.  Much of the carbohydrate in this diet is very low in glycemic index and comes primarily from vegetables. So, I don’t really know how likely it is to lose weight on a eucaloric diet that is 60% CHO and 20% fat, if the quality of the carbohydrates is very poor (e.g., cookies, potato chips).  The big confounder in these observations is that most low-fat diets, though still modestly high in RQ relative to a low-carb diet, reduce greatly the glycemic index and glycemic load, as well as the fructose.

Which brings us to the point…

Does being in nutritional ketosis ensure negative fat flux (i.e., fat loss, or L > DNL + RE)?

Being in ketosis tells us nothing about this equation!  Let me repeat this: It is metaphysically impossible to infer from a measurement of B-OHB in the blood if this equation is being satisfied.  It just tells us that our body is using some fraction of our dietary fat and stored fat (once it undergoes lipolysis) to make ketones, given that glucose intake is very low and protein intake is modest (net effect = minimal insulin secretion).

If you look at the figure below, you see this point (It’s simplified, obviously, and for example, does not show that fat from fat cells can be used directly by skeletal muscles).  Nothing in this figure implies a reduction in the size of the cells at the bottom right of the figure. It’s quite possible, of course, since ketosis results in a large L and implies a very small DNL.  But, if (small) DNL + (very large) RE is greater than (large) L, guess what? Fat flux is net positive.  Fat is gained, not lost. Still in ketosis, by the way (quantified loosely by fasting levels of B-OHB greater than about 0.5 to 1 mM), but not losing fat. (I hope the first attempt at a solution in this setting is obvious by now, notwithstanding the fact that I’ve seen this situation dozens of times with more than one solution, including the ‘obvious’ one — reducing fat intake.)

The other myth worth addressing is that the higher the level of B-OHB, the more “fat burning” that is going on.  This is not necessarily true at all.  As you can tell, I love equations, so consider this one:

B-OHB (measured in blood) = B-OHB produced (from dietary fat) plus B-OHB produced (from lipolysis of TAG) less B-OHB consumed by working muscles, heart, brain.

How does knowing one of these numbers (B-OHB measured in blood) give definitive answers to another (B-OHB produced from lipolysis of TAG)? It can’t. That’s the problem with multivariate algebra (and physiology).

Many people who enter nutritional ketosis do so, I worry, because they believe it “guarantees” fat loss. I hope I have convinced you that this is not true.  Nutritional ketosis is one eating strategy to facilitate negative fat flux, and it works very well if done correctly. It comes with some advantages and some disadvantages, just like other eating strategies.  When I get back to the series on ketosis, I will address these, but for now I felt it was very important to put things in perspective a bit.  Furthermore, I am convinced that it is not the ideal eating strategy for everyone.

Delorean by Marci Maleski is licensed under CC by 2.0

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417 Comments

  1. Hi Peter,

    First of all many congratulations and thanks for all your contribution to make people’s life.

    Before posting my questions I would like to briefly explain the context please. I’m 6ft, 32 years old male. The lightest ive been was 95KG that was 10 years ago. The average ive been is around. 110 KG. The heaviest ive been is 119KG that was a year ago when I started to count and restrict my calories to 1600 a day to lose weight. I did not restrict carbs or sugar (i had a sweet tooth). With this I managed to lose about 14KG during 5 months wit moderate exercise 3/4 times a week but during this I had been constatntly fighting with craving and hunger. I stalled at 105KG and started to gain weight upto 111KG. So I lost hope with calorie deficit approach. Four months ago I discovered low carb which lead me to read up on it including ofcourse Gary Taubes. Having been on low carb since then about 70gm per day I weigh 98 KG. A few weeks ago I dropped carbs to under 50gm per day. My calorie intake on low carb has been around 1800 a day that is without restricting them, ive to force myself to go over 2000 a day. Before starting low carb my TGHDL ratio was under one and my fasting blood glucose was 4.2 which makes me think probably im not insulin resistant.

    My Questions:

    1.Could it be that the weigh Ive lost on low carb is in fact due to eating less calories?

    2. If Im not insulin rgsistant, why have I been gaining weight?

    3. On low carb is it ok to have around 1800 calories a day that is without consciously restricting cals?

    4. My hunger has really gone down? Is it because of being in ketosis?

    Thanks

    • Thank you, Norm, for your kind words. I’ll try to address.
      1. Certainly. Caloric restriction often results in shift of dietary nutrients (and often reductions in all F/C/P), so could be multiple things explaining effect.
      2. Hard to answer without knowing more, but certainly as many as 30% of those overweight are NOT insulin resistant.
      3. Not sure I understand question. The calories are what they are.
      4. Possibly, or possibly because your liver is sensing no need to eat as much if you’re mobilizing so many internal stores of fat.

  2. Hi, great article, really helped me understand the fat flux biochemical fundamentals better.

    Sorry if this question is off-topic and a bit obvious but how does a high fat diet facilitate fat loss? i.e. why doesn’t the body use dietary fat preferentially over activating lipolysis? In other words, why would lipolysis be activated at all if dietary fat is ample. Sorry if this question is amateur hour but it’s been bugging me a while as something that sounds so simple but I can’t seem to find an answer to.

    thanks
    Alex

  3. Hi Peter,
    I was wondering a couple things. Have you tested testosterone levels pre and post ketosis and have you noticed any increase or decrease in sex drive pre and post ketosis?
    Thanks for your time,
    Dave

    • Yes, my testosterone rose quite a bit (about 250 to 450), BUT there is a huge confoudner, so I have no idea if it was ketosis per se, or the the reduction in my training volume. I’ve been very low my whole adult life, and looking back assume it was due to a combination of excessive exercise and poor diet.

  4. Thanks Peter for a prompt response to my previous post. If you could kindly shed some light on the following please :

    If Insulin is the FAT regulator, why some overweight people are NOT insulin resistant?

    On low carb, am I under eating by taking around 1800 calories per day as Ive to force myself to go over it? ( im 6ft tall, male, 32 years and trying to lose weight).

    Many thanks

    • Any number of factors, including genetic of course, that prevent negative fat flux. Other hormones are often part of the problem, such as androgens, glucocorticoids, and thyroid. Basically, if the HPA axis is off, fat accumulation can and often occurs.

  5. Peter,
    With a few weeks between major cycling events I decided to experiment with going from low carb (approx 100g/day) to VLC <20g/day also keeping an eye on protein 100g day.

    After 12 days I've noticed a drop in peak power.

    After the first few days intervals 2×20@80-85% FTP (275 watts) felt normal, the second day of intervals 2×20 same watts felt difficult but I suffered through, the third day of intervals (day 9 VLC) I was unable to complete the interval session. Endurance power was unchanged at 200-230 watts for 2 to 3 hours.

    Yesterday after a recovery day I had a lot of difficulty with a harder session 5min@285watts/30sec VO2Max/5min@285watts two sets, the first set was hard between sets I drank approx 8oz UCan 15min between sets. The second set I was unable to finish the second 5min.

    Do you have any insight into performance at the beginning of keto phase and performance, I'd like to gain the metabolic flexibility you describe. Can I supplement with more carbs on days with difficult workouts or races and still reach ketosis or do I need a sustained 2 to 4 weeks VLC. Will the peak power come back once I reach full ketosis.

    As a track racer and TT/Individual Pursuit specialist I will need that peak power as well as being able to stay at FTP for up to an hour at a time.

    Should the Ucan supply me with enough glucose to complete difficult workouts like I described? or will I need more carbs than UCan alone can supply.

    What would be a strategy for "carbing up" prior to a diffiult training or race day if that is even possible and still reach ketosis

    FYI on the test strips I still only show trace amounts of ketones, after approx 12 days I've noticed no change in weight or %BF always between 155-160 lbs, 5ft 9in.

    Cheers

    • Jeff, I experienced this exactly. Similar numbers, too. In 12 weeks I can fully adapted aerobically (and actually made huge gains), but — and I hope you’re sitting down — it took me probably 18 months to exceed the anaerobic performance I had prior to ketosis. UCAN will definitely help, but I still think the cells need to re-learn how to access which fuels, and when to do it. Of course, my experience says nothing of what yours might look like. You may adapt quicker.
      BTW – based on your last comment you may have a different issue. That is, you may not be in ketosis at all. You may be in “no man’s land” — too little glucose and too little BHB. First step is counting your protein intake. That’s usually the issue.

  6. I’ve had my brain in your blog for 3 days now. We threw away 3 lbs of sweets from our cupboards this evening. We – my husband and I. The last 7 months, I have done nothing else but try to find out why I am broken. Because I’m ill. I have always been ill.

    I’m fat (obviously). My mum is fat, my grandmother was fat, my brother is fat. They are not American and neither did any of us grow up with processed food, fizzy drinks or any of the “sins” that should’ve caused our bodily mishaps. Faremers, hardworking, traditional, poor. ALl that jazz. Brother, mother, maternal grandmother all have Type 2 diabetes. I don’t. Not yet. But I have been a zealot with my diet since January 2009. I lost over 50 kilo (How much exactly, I don’t know, ‘cos my scales couldn’t weigh me to begin with) and landed on 64 kilo. Haven’t been 64 kilo since I was in 3rd grade! Anyway, I say “landed” because no matter what I did – HA! – yes, I know now I that I didn’t do the right thing – but I did as I had been told would solve ALL my problems in life – and suddenly, the weight would not budge. Not a gram. I ate and eat 1200-1400 calories a day and was as active as I could be with my fibromyalgia, PMDD, and the masses of other pathetic health issues I was SURE would go once the fat had gone. Needless to say, they did not. In fact and to my surprise, it got worse. I got worse! Then I fell pg. And BAM! Still on a 1200-1400 calories diet, I gained 40 kilo! That’s not possible. It’s impossible. That’s NOT how the body work. Calories in, calories out. You must be lying. You are eating on the sly. You’re not “doing it right.”

    During my other two pregnancies and on an unrestricted diet (whilst morbidly obese) I gained about 7 kilo. That’s not even the weight of the pregnancy itself! So WTF? (Pardon my language).

    My math had broken! My math IS broken!. Since giving birth and still, I remain stuck at 86 kilo. And not just that – I am now so ill I can barely lift my baby to change him.

    My NHS doctor… well, he suggested a thyroid problem. Tested my THS and as that came back normal, sent me away with a prescription for morphine and antidepressants. I declined. I paid for private doctor. He also tested my thyroid and found my T3/reverse T3 shockingly low. But he didn’t know what to do with this information – was scared of the Standard Practise, which looks at THS, T4 and T3 only and suggested I diet and exercise to get better. He actually said that as a doctor, his must important mantra was “do no harm”. So, I guess, in my case, it prevented him from doing good. I’m still looking for a doctor. Maybe. Or maybe I can go it alone like I did with my first (but flawed) weight loss.

    But it’s my hormones. And I fear I’m born with a vulnerability. And that environmental factors and “good” but oh so wrong diet have exacerbated my situation. And I feel like I’m staring into the abyss. It feels insurmountable. For several reasons, but mainly because I have never – and I mean never – had support from any health care professionals I have been in contact with. If you’re fat, you’re fair game. Dysmenorrhea and menorrhagia? It’s ‘cos you’re fat. Feeling blue? It’s ‘cos you’re fat. Aches and pains? It’s ‘cos you’re fat. Lose weight, and you’ll see – all will be good. Never even once did anyone suggest that the reasons I’m fat might be the same reason as is causing the other problems. I didn’t even realise fat could be a symptom. I believed it was My Fault. And I have spent the 33 years Hating Myself. What a waste! What a sad, sad waste.

    And now that I know better, I feel more alone than ever, because I realise that now, the support from the medical professionals is further away than it ever was. Now, I’m one of the Crazy People, who believe in Crazy Theories that go against Recognised Science. I’m on my own. Well, I’m not. I have you and the other crazy people on the internet to back me up. And of course my never faltering and lean and eats what he likes husband, who supports me so much.

    He’s a good man. He was always confused by my size. “But you hardly eat anything.” he’d say even when we first met. “You can’t be big because of your diet. There must be something else going on.” He likened it to dark matter. Scientist knew it was there long before they could prove it because of the way other elements of the universe were acting. Dark matter had to exist. And I guess all these years, we’ve been looking for My Dark Matter. The thing that was “breaking my body-math”.

    Being fat sucks. Not because of the health implications. Nope. It’s because of the social implications. I can’t eat an ice cream in public or I will get comments and *tut-tut*. I can’t go shopping without ppl peering at my shopping choices. What they’re trying to glean from them, I’m not sure. They’ll see nothing but organic-fairtrade-food pyramid-compliance. In fact, bar a few years of student life, they would have never seen anything but organic-fairtrade-food-pyramid-compliance.

    I feel a little betrayed. Lied to. But my eyes are being opened. It hurts a little, all this light suddenly coming in. It’s pretty hardcore stuff. I’m struggling to compute it all. I’m sure I’ll be struggling even more to implement it. But I’m pretty fierce and I’m also immensely angry, and there’s nothing quite like anger that can make people do what they didn’t think they could!

    But actually, what I came here to say was thank you. You are saving lives of that I am certain. I’m hoping mine will be next.

  7. Sorry for all the spelling mistakes. My brain, being part of my body – just doesn’t work very well any more. I used to be an accomplished academic. Now I can barely manage a comment on a brilliant blog. My apologies. Hope it doesn’t detract from the dishevelled ramblings too much. I started my period today. Does that count? You know what they’re like, those hormonal women! 😉

  8. Peter,
    Thanks for the respomse, i have tried to keep protein under 100g, i did read both Phinney/volek books, trying to get my fat from butter, cream, avacados, olive oil. I haven’t been eating excessive amounts of meat usually one serving per meal, 2 or 3 eggs for breakfast, yogurt once a day.

    I seemd to have most of the other classic symptoms of ketosis, lots of trips to the bathroom,appetite supression. I also have some muscle ache that i dont attribute to my current training load.

    My experiment my have to wait for the winter off season but even that is very short for me usually only 4 weeks between cyclocross nationals and beginning training again.

    In your opinion can an athlete better utilize fat as a fuel source without reaching ketosis?

    Also you said over a year ago if you were training for the TDF this wouldn’t be your nutritional plan, would you change your mind about that now? Do you think something like that could be done? Bicycle racing is such a different animal than triathlon or ultra endurance running.

    • In the end, unless plasma levels of BHB are elevated (0.5 mM is the bar minimum, but the real benefits don’t really kick in, especially for exercise until you’re in the 1 to 3 mM range), nothing else matters. As far as TDF, complicated question I can’t address at this time.

    • Peter, sorry for the stupid question, how are you measureing BHB, with a blood glucose meter? Any recommendations for what kind you like?

  9. Peter,

    I saw your you-tube “Peter Attia: What if we’re wrong about diabetes?” I have T2D and am holding my blood sugar in check with diet and exercise (no drugs). If there is any way I can help in your efforts, please let me know.

    Thanks

  10. I’ve seen you mention that too much protein can prevent you to be in ketosis. I weigh 210lb and have been at ~60-80g protein/day and <30g carbs and 140-170g fat for two weeks and am in no mans land. Blood ketones were .2mmol/L post prandial today. Is that really still too much protein? It's spread over 2-3 meals during the day.

    • Carbs can be hidden in many, many places. They often are not on labels. Some spice mixes are really high in carbs. Even sweetener packets have about a gram of carbohydrate each in them.

  11. I’m not sure if that makes me feel better or worse. I can’t really find much research as to why that would happen. Are you able to consult hypothetically? No meds or conditions. I can’t think of a single reason why I’m such an outlier.

    • I hear you. Without doing a detailed assessment of everything you’re eating, including a measured assessment of what you’re eating and what kind of activity you’re undertaking, I can’t really speculate.

  12. Love this site and the work you do. I’m very excited to see what you (and Taubes) come up with in the next few years. My question is about insulin resistance: It seems to me that being resistant to insulin is a good thing–your body is less willing to respond to the signals from insulin to store fat. Am I just interpreting this wrong?

    • Todd,

      Here’s what I know (or think I know) on this topic:

      In this video, Dr. Tara Dall explains the problem of being insulin resistant: https://www.youtube.com/watch?v=qL6aXRwuMgg .

      In other words, after eating carbs your body HAS to bring your blood sugar down (or you’re in deep trouble). So your body will keep producing insulin until your blood sugar drops (that is, unless one is diabetic and cannot produce enough insulin anymore, in which case one needs to get it externally). In the insulin-resistant person, their blood sugar often drops too far and the body’s self-defense mechanism kicks-in to bring blood sugar back up to normal. It does that by making us hungry — especially for carbs.

      (In my case, most days I could go until supper without being hungry and without eating. But after supper I would have all the symptoms Dr. Tall talks about — I’d feel tired, light-headed, and have cravings, especially for carbs. That would start just an hour or so after eating. Why? My body was producing too much insulin after the meal and dropping my blood sugar too low.)

      How did some of us get this way? Most people think genetics has a lot to do with it. Many of us also think a lifetime of over-exposure to carbs is a primary cause of insulin resistance. (Our bodies are trying to defend themselves again, in this case from all the carbs.) I’ve started to call it “carbohydrate poisoning,” though a better term might be acquired carbohydrate intolerance.

      How do you cure it? Cut out the carbs as much as you can. (Dietary fat alone creates no insulin response, and protein creates a little, though it is different for other reasons.) Without the carbs, one can finally get off the insulin rollercoaster. And over time, it seems that some of us can recover and be less insulin resistant.

      At least, that’s what I understand now. I hope that helps!

  13. Fascinating article Peter. Thanks for the in depth explanation.

    I’m particularly interested in exercise and it’s effect in regulating insulin. Particularly it’s role in making cells more responsive to insulin reducing the amount of insulin required to trigger the required responses of sugar transport. In turn this requires a smaller insulin response by the body to achieve the same result. I explain it more at https://cellyoursole.blogspot.co.uk/2013/05/heart-disease-and-diabetes-move-out-of.html. That’s my understanding so far. I was focusing on regulation of sugar. Not fat. I had forgotten this role.

    Promoting activity is important to me because the food and activity situation has been turned on its head in the last century. Activity used to be normal and food used to be scarce. Now it’s food that’s everywhere and activity is scarce. The effect is more complicated than is generally realised. Obviously more calories being consumed than burnt is a result but it also seems to me that we’re less able to recover from the challenges of the day. Activity forces our body to maintain itself and thus recover properly each day. Hence activity forces cells to listen to insulin by creating a need to regulate energy properly.

    That’s a quick overview of where my research is leading me. I’m wondering if you know much about exercise and insulin and it’s wider role in fat regulation. It’s mainly viewed simply as a process to burn calories. I feel that’s simplistic. Few seem aware that it can directly affect a cells ability to respond to insulin when present. There are many other effects but that seems most relevant to this post.

    I like your style and thoroughness. Activity doesn’t seem to get due attention in medical circles, nutrition seems to take priority. So I’m interested to hear your views. Am I misinterpreting the evidence? Maybe you’ve got a good understanding on exercise and it’s effects. Maybe I’ve added another angle you can look at. Particularly something people can do for themselves without popping pills.

    Colin

    • Exercise, certainly if strenuous, blunts the insulin response somewhat, but the real drawback of hyperinsulinemia during exercise is the inhibition of lipolysis.

  14. Nice article as usual!

    I was reading about the resveratrol researches in past years after watching a David Sinclair talk this week. He was explaining how resveratrol mimics caloric restriction impact on longevity by activating the sirtuin gene and I wondered if this was recurrent with Ketosis? It seems they are developping analog drugs that would be more powerful than revesratrol and it seems a big deal. From what I understand, this gene is implicated in the signal to produce ketone? I’ve found those 3 papers explaining it a bit, but I thought you might have an interesting opinion on that subject:

    “Sirtuins: a conserved key unlocking AceCS activity”
    “SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production.”
    “Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle”

    In the last paper, they conclude in the abstract: “Our data indicate that a relative deficiency in carbohydrate intake or, albeit less likely, a relative excess of fat intake even in the absence of caloric deprivation is sufficient to activate the AMPK-SIRT 1-PGC1? energy-sensing cellular network in human skeletal muscle.”

    Do you know if there was any animal longevity experiments on ketogenic diet similar to those who study caloric restriction?

  15. Not losing weight on a strict ketogenic diet?

    Could the actual problem be a lack of patience?
    My own weight loss was not without many plateaus, and some necessary adjustments (hidden carbs and sugars, longer breaks over night, etc.). Sometimes nothing happened for months, no weight loss at all, and I thought I had reached my set-point. But, as I felt so much better overall, i continued eating ketogenic. Suddenly, I would enter another brief weight loss phase, and so on, until I stayed around 120 lbs for the last couple of years, less than I weighed as a teen.
    ( I am also watching my omega 6 intake, as this seems to have some effect on my well-being.)

    Could it be, that the body, at least the bodies of some people need more time to regenerate and adjust? Are the studies too short? Do people give up prematurely, and do we come to the wrong conclusions because of this?

    The situation reminds me of a paper by Chris Masterjohn, where he discussed the effects of omega six laden vegetable oils, and that they increase the incidence of cancer. This fact was missed, because the effect starts to show up after about 7 years, and even the long-term studies only went for about 5 years.

    Would the effectiveness of a ketogenic diet (without cheating or inadvertent mistakes) be universal for humans, IF they would stick with it long enough?

    • Sabine, I thoroughly agree with you. Patience and persistence are the appropriate response. It may take over a year to thoroughly normalize bodily homeostasis after beginning a ketogenic diet. It certainly took that long for me. And there are clear oscillations – both up and down – in weight that tend to come and go for weeks at a time. People do not become obese overnight and it is a little hard to expect they will become lean within the same timespan. Most overweight/obesity is a gradual process spanning years.

  16. Such a great read and very easy to understand thank you. I just have one question that may or may not be able to be answered in a simple response. I have recently been consuming less than 30g carbs, about 1.5g/kg of protein, and 75% of total calories from fat a day. I am much leaner for sure. I understand that by lowering my carbs I am lowering my DNL, although I am still a little confused as to how consuming a high % of calories from fat (about 250-300gm/fat/day) is “helping” (if at all) with my fat efflux? (sorry if you already answered this in a previous post or in this post)

    • If you kept protein and carb constant, and lowered fat intake, you would likely get leaner. The question is, could you do that without increasing your appetite significantly?

  17. Hi Peter,

    I would really like to know your take on gynechomastia? Is going under the knife only option? Would appreciate your guidance in this regard.

    Thanks

    • Not until you have your estradiol checked! You have this because you’re shunting too much testosterone into estrogen. Surgery is not the treatment for that.

  18. Ok, thanks. What do I exactly ask my GP to do then please? Would really appreciate your guide on going about fixing it please.

    Many thanks

  19. Is there some reason the blog post is blank other than the comments and discussion?

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