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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  1. Sorry for the confusion – I was trying to understand if it was indeed possible for someone who is in nutritional ketosis (say approx. 1mM) to also be in a state of net fat influx.

    It seems to me that the insulin levels necessary to maintain this level of nutritional ketosis would be sufficiently low to prohibit net cellular fat influx – is that not the case?


  2. Thank you, thank you, thank you for taking the time to educate us!!!! I am not a scientist so I have to read and reread your articles, but I learn so much more from your blog than anywhere else on the internet.

    I have been on a very low carb (10-15 carbs/day) and high fat diet for about 18 months. I keep my protein around 60-70g/ day and never more 25-30g/ protein per meal. Almost all my carbs come from the heavy cream in my coffee. I play singles tennis (3 days/week), ride my bike (~30 miles/week) and walk (~25 miles/week). I am 5″ 4″ tall and weigh 128. There is an extra 5-8 pounds on my back, stomach, and upper arms that I would like to lose.

    Am I reading this article correctly? If the only switch I make to my diet is replacing my heavy cream with half and half, could that possibly help me lose those few extra pounds? Would it be worth it to add the extra 2-3 grams of carbs in exchange for the lower the fat content? (1/2 cup of heavy cream has44g/ fat & 3.5g/ carbs. Half/ half has 14g/ fat & 5 carbs)

    I do not want to give up the coffee, and I can’t drink it black. This way of eating has not only helped me lose weight and be able to play sports in the hot, humid southwest FL sun, but the most amazing part has been the freedom I have gained from not obsessing about food all the time. My meals are simple: grill a piece of fish or meat and treat myself with coffee and cream a few times a day. I have tried giving up the coffee and substituting a small side of vegetables at each meal. The side effect is I start thinking about food again. Variety seems to be a downfall for me.

    Any thoughts would be greatly appreciated. And again, thank you so much for giving so much of your time to education.

    • Tiffany,

      I am not a woman and hormones have a say in these matters. But I was myself in ketosis for a few months and reached homeostasis at a point where I was not too satisfied. What I did (and was not something I planned but was the result of the ketosis) was to skip breakfast and then luncnh entirely. I work out fasted and make sure I get enough “healthy” carbs (à la Primal Blueprint) when I know I will have high intensity workouts. So my fat intake varies wildly from day to day because I no longer track carb or fat limit. What works for me is to work out fasted. I do have coffee in the morning but I like it black. However, heavy cream in it will not screw up the fasted state. But I do not have coffee after early morning because I don’t see the point of kicking the adrenals late in the day … Having reprogrammed my meal timing is the best thing I did after switching to a so-called primal diet (which I follow loosely since I eat chocolate, and a bit of dairy here and there). But reducing the fat and upping the carb has been a good idea as well 🙂 Since I eat in the evening, I have no problem dealing with the carbs and I sleep much better!

  3. Peter,
    After watching your TED video about a month ago (and then linking to your blog) I literally spent one week straight reading in chronological order your blog posts because everything you say (especially when it comes down to the known biochemistry) is spot on. I love it. DO NOT DUMB IT DOWN. Since then I have been trying to go ketosis keeping carb as low as possible, fat intake high, and about 100 grams of protein. There were a couple of times I got headaches and lightheaded. I was thinking this may not be the diet for me, but then I sucked down a bunch of bouillon and within an hour, boom felt great.

    FYI I am a personal trainer and it is so interesting to ask the clients that are overweight and having trouble losing it what they eat. I tread lightly when trying to convert anybody to this lifestyle because of such fervent pushback from misinformation. I usually refer them to your TED talk then to your blog and then over time educate them on the biochemistry. About half start to “get it” and come around to idea.

    I know somewhere in your blog you mentioned Ketone urine strips. I couldn’t find it. Are they accurate?

    Keep up the great work! You make me want to go to Med school. We need more doctors like you.

    • Paul, the urine strips test Acetoacetate (AcAc), but do so qualitatively. The blood meter tests BHB, and does so quantitatively. I much prefer the latter, but it is more expensive.

  4. I have been in ketosis for 3 weeks and have stopped loosing weight. I have therefore been scouring the net for advice as to why this is happening. I just found your site, and am delighted to read all that you have provided.

    I am specifically looking for where you might write about the proper balance between protein, carbs and fats required for ketosis. I understand this may vary person to person, but I don`t know how to calculate a starting fomula. I am a 52 year old female (4 feet 10 inches tall) and 89kg. I found where you suggested 1-1.5 gms of protein per kg of body weight (for me that would be say 100 gms = 400 calories of protein) and less than 50 gms of carbs = say 200 calories of carbs). Would I then assume I should be on a 1200 calorie diet and eat the remaining 600 calories in fat. I have only been eating between 650 and 950 calories because I have not been hungry, but I have read that this will cause my metabolism to slow down……can you please comment on how I determine a starting point, where I make changes if I am not in ketosis (according to a blood monitor), and if eating less than 1200 calories causes a metabolic slowdown.

    Fabulous site and thank you for your time.

    • Kathy–A good place to begin is with the book “Art and Science of Low Carbohydrate Living” by Phinney and Volek. Another beginning place is http://www.dietdoctor.com/lchf, the website of Dr. Andreas Eenfeldt. That particular page on his site is titled “LCHF for Beginners.”

    • If you aren’t in ketosis then cut the carbs down to 20g and if that isn’t enough drop the protein too. A ratio of fat grams to (protein + carb) grams might be helpful – if it’s too low you won’t be in ketosis. Google Skaldeman or Ketogenic ratio for the maths. Jimmy Moore’s n=1 ketosis experiment had less protein than 1-1.5 grams per kg from memory.

      Most if not all of this “metabolism slowing down” stuff appears to be nonsense prevalent in diet forums and women’s magazines. Find me a clinical trial with 600-800 calorie intake and no weight loss.

    • Thank you to the people who have replied to my question. I imagine us ‘newbies’ keep repeating the same questions! I have been reading copious amounts of information and my ketone monitor arrived last week. I find the protein numbers to be a bit confusing because there is quite a spread, and a variety of numbers quoted. Some will quote total body weight, some lean mass, some height, and then it depends on your activity level. But I will find my ‘sweet spot’ amongst all those numbers.

      Although the urine sticks showed I was in ketosis, my monitor reading was .6. After a 2-3 week stall, my weight had started to move, but I in an effort to get to the 1.5 – 3.0 range I cut back my protein to about 70gms a day, instead of 100. I have also added fat, fat and more fat (somewhat reluctantly) to get me to the 1100 calorie range. For the past 4 days I have been dropping one pound per day and my morning ketones are up from .4 to .9….I shake my head every morning, but am enjoying both the numbers and the challenge of figuring this out.

      Thanks again to those who took the time to comment. Much appreciated.

  5. Dr. Attia,

    Thank you so much for all the great things I have learned from you since I discovered your blog in January. Thanks to you I have eliminated most of the starch from my diet and finally started losing weight. I spend over an hour working out on the elliptical 6 to 7 days per week and was stuck for three months until I cut out the bread, potato’s and most other starches. My wife is type 2 diabetic so when possible I use Glycerol as a sweetener for drinks like home made lemonade so that it will not effect her blood sugar levels if she drinks it.

    How does excess glycerol effect TAG flux? I normally avoid eating anything close to bedtime or from the time I get up until I finish working out so I know my insulin levels are as low as I can get them during my workouts. When I started this routine back in late January it really made a difference and I started dropping pounds every week. I had a bad two month plateau when I achieved an early goal of 24 pounds off and stopped being as careful of how much starch I was eating but I am back on track now. My concern is the RE uses both Glycerol and free Fatty Acids from your blood stream after you work out. Will the glycerol used as a sweetener destroy the balance between the components and keep my efflux of fat from working properly? Does it matter when the glycerol is consumed compared to when I finish my exercise?

    Thank you for all your work, you are an inspiration and a blessing!

    Allen W.

    • Glycerol is brought into the fat cell via the GLUT4 transporter (just as glucose is). More glycerol would promote more synthesis of TG from FFA. So, in short, excess glycerol would promote fat storage (RE), rather than lipolysis (L).

  6. Hi Peter,
    I am a long time reader – but a first time poster.
    I have conducted my own n=1 experiment and found something quite interesting. I lost around 10kg on a low carb/high fat/high protein diet over a period of 6 months. Having worked for a pharmaceutical company selling exogenous insulin, the whole aim of my eating regimen was to control by body’s endogenous insulin response to food – and open up the pathways to utilise fat stores.

    Here is the interesting part. After sticking to a low carb diet for 9 months, I regressed back to eating my previously normal high carb diet – and for a number of months did not enter into a state of fat influx. I decided to give my n=1 experiment extra weight by increasing the amount of crap food I put into my system – and still didn’t achieve fat influx for 2-3 months. After this time, fax influx did begin to occur.

    From the results I came to this conclusion. Over the 9 months of eating high fat/high protein, my system made some adaptations to use fat as its primary energy source – which then made it more difficult to enter a state of fat influx for some time after.

    I realise the reasons for this will be due to a complex mix of factors – however I have thought that a possible theory is that it is due to an up-regulation of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL) and CPT-1 that allowed my body to continue to use fat as energy – and therefore not store as much.

    Just thought this may be another component to the Fat Flux Balance!

    Also, thanks for this fantastic resource.

    • Andrew, if I had to guess, I would assume that your 9 months of carb restriction increased your insulin sensitivity (IS). So for the first 2-3 months of your foray into “bad” eating, your cells were still sufficiently IS to partition fuel favorably (i.e., oxidize fat as the highest priority). Eventually, this effect wore off.

  7. Hi Peter

    Thank you for a very educational post. Could you possibly elaborate on the flux of fat cells themselves? How is the number of fat cells determined in the body? As a person burns fat do actual fat cells eventually get destroyed and reduce in total number or does the fat cell persist and merely shrink in volume?



  8. “Do they lose weight because they eat less? Or, do they eat less because they are losing weight?”

    This reminds me of something a heard on “The People’s Pharmacy” [NPR] when they had a guest doctor come on a talk about the different digestion pathways of glucose and fructose. One (glucose) was directly digested in cells, while the other (fructose) was digested by the liver. The pathway through the liver also produced hormones that increased appetite and decreased energy [and causing cirrhosis of the liver].

    So the doctor turned the common phrase “over eating and lack of exercise causes weight gain” on its head to “eating better increases energy levels and suppresses hunger causing weight loss”

    • Yes, I subscribe to that model. As I alluded to in this post, I believe the liver controls appetite, and it does so by sensing changes in energy availability.

  9. Dr. Atta,

    I would request that you also include more posts and research (and, if possible, clinical trials with your NuSI) on the neuroprotective properties of the ketogenic diet. I have come across some scattered evidence that a ketogenic diet has been an effective treatment for brain cancer in conjunction with standard treatments (currently, however, 99% of glioblastoma multiforme patients die within 2 years of diagnosis).

    Here’s an example:

    1.4. Other Clinical Applications of the Ketogenic Diet
    The fact that the KD is considered a proven therapy with relatively few adverse affects and wide clinical experience, particularly in children, led to recent studies investigating new potential uses for other neurological disorders [3]. One of the most intriguing and active fields of research is the effect of a high-fat caloric-restricted diet on the survival of brain tumors cells. Brain cancer cells have restricted metabolic flexibility and are dependent mainly on glucose metabolism. It is hypothesized that mitochondrial abnormalities impair the ability of brain tumors to generate energy from ketone bodies. Unlike normal cells, malignant tumor cells have impaired genetic adaptability due to their genetic abnormalities and, therefore, increased susceptibility to environmental stress, such as fasting or caloric restriction. The same genomic defects that are involved in the creation of brain tumors can be exploited for their destruction [3, 10, 11].
    In 1995, Nebeling et al. [12] reported two young girls with unresectable advanced stage brain tumors who had poor response to radiation and chemotherapy. They were treated with a KD and their response was remarkable, both clinically and according to positron emission tomography follow-up scans. Zuccoli et al. [13] described a patient with glioblastoma multiforme whose tumor, which is very malignant, improved on the KD. Surprisingly, despite the appealing efficacy of this treatment, no further human studies or clinical trials on the KD as a therapy for brain tumors have been conducted. Several laboratory studies in mouse and rat models have recently confirmed that inhibition of brain tumor growth is directly related with reduced levels of glucose and elevated levels of ketone bodies. Moreover, the KD was shown to reduce reactive oxygen species (ROS) in the brain [5]. Cancer cells need high levels of ROS for the induction of angiogenesis and the production of tumor growth factors [11], thus, through this mechanism the KD can be protective.


  10. Peter –

    You mentioned Ludwig’s JAMA paper. I love that study. However, I think the conclusion misses the most important point – and it’s a point you keep making.

    With the crossover design, each subject tried all three diets. As you noted in another post, most subjects had significantly different results from the different diets. Each diet was the best for some and the worst for others. In some cases the differences were dramatic, and for most subjects the individual differences dwarfed the average differences among the diets.

    Yet that was what the conclusion emphasized – how on average the low-carb diet was slightly better, etc. But who really cares about the average reactions? (Should anyone follow a diet that works better for the majority of other people?)

    The most important finding is that different people can react quite differently to these diets. Therefore, the key conclusion is that each of us should: (1) Experiment and find out which diet is best for us, and (2) follow it!

    (Which is what you keep encouraging us to do.)

    Thanks for that, and for another great post.

  11. Peter,

    Have just read Mark Friedman’s 1998 paper on fuel partitioning and food intake, I can’t thank you enough for referring me to his work.

    What I am really interested in is the relationship between simple carbohydrate/fat intake (dietary composition) on the body’s ability to metabolize fat efficiently and the change in this relationship over time (including the effect on individual fat and glucose fuel pathways). This could hopefully provide some insight into which type of diet different individuals are more likely to be suited to and how this could change over time.

    Is this a research area NuSI is likely to consider? Also if there are any of Mark’s papers in particular that you like, I would be eternally grateful if you could point me in the right direction. Otherwise, I will tried to read as many as I can find!

    • A recent chapter her wrote in 2008 titled “Food intake: control, regulation, and the illusion of dysregulation” is exceptional. I think the text is Appetite and Food Behavior. Go back to about 1976 for some of the real gems.

  12. Hi Peter,

    Thanks for the great post. Just a few questions about ketosis, macronutrients and hormones as I’m thinking…

    1. You mentioned that being ketosis doesn’t guarantee weight/fat loss, my thought is ketosis means our body could be more efficient with lipolysis but if our pancreas/ liver is not yet fully adapted to digesting high amount of fat, the excess fat would still be stored as fat? Or is there a fixed amount of fat that a liver can handle at one time??

    2. Re your mention about ketosis and hormones, I am quite interested in the fact that your cortisol level has decreased and would love to hear your thought on low carb, leptin and cortisol.

    Reason is I have gone very low carb (unintentionally, <30g including alcohol consumption) since April, I lost about 4kg in 3 months and decreased 5k running time with increased energy until 3 weeks ago, I hit the wall and my period has been 2 weeks late (sorry for TMI) plus 2kg weight gain in 2 week! Could it be just the low-carb/alcohol combination that has overworked the liver or do you think women general need more carb than men in terms of fat loss, normal menstruation and better athletic performance?

    3. Weight loss – it baffles me as I no longer know how much a person should consume regarding to the macronutrients. Is it just about hunger and activities control and therefore we lose fat from consuming less calories? Just imagine not every Olympic swimmer can handle Michael Phelps' diet….

    Also, there are days I experience constant hunger albeit a 2500+kcal fat/ protein based diet and I'm a 5'6/59.5kg female but sometimes hunger stops at the moment I ingest some carbs. Do you think it's leptin and other hormones regulation that plays a more important role in weight/ fat management?

    It would be fantastic if you can write a post to discuss hormones/ hypothyroidism/ adrenal fatigue in the near future!


  13. I love love love this post. Before you posted this I had to figure this out on my own. I have helped many people in my community lose weight with ketosis but have had trouble with post-menopause women. It will definitely be interesting to find out more about this. I’m also curious about your theory on the liver regulating appetite. I know there are quite a few bodybuilders now that use keto-diet to cut to 5% body fat. I personally get to about 10% and once I drop below that start feeling miserable. I’m also interested in why that is (shouldn’t I still be feeling alright since I have access to my fat stores?) Oh Peter, if you could only make updates like this everyday! You have no idea how much my curiosity tortures me! Thanks for the post. Look forward to the next.

  14. Peter,
    Thanks for another great post, I was greatly looking forward to this post on the topic for a while. Would you consider making another diagram with the adipocyte and the arrows that includes small sub-captions for each arrow that correspond to it’s effect on that particular arrow? Does that make sense? Sorry if it sounds confusing, I’m just trying to figure out the best way to word it. Basically, have little sub-points that denote how an item increases/decreases that arrow. The list doesn’t have to be all inclusive/exhaustive but serve as a basic reference as each person tries to figure out what needs to be (or can be) tweaked to get a desired outcome. Obviously, I think one can figure this out from reading all the quality text you have throughout the blog but I always found it handy in biochem/physiology courses to be able to reference a figure (diagram) that can go along with all the text. Thanks again Peter, I always get excited when my e-mail prompts me about a new post!

  15. I tried to post this on your heart disease risk related article, but comments are disabled, so I hope you don’t mind.

    I appreciate that you can’t give out medical advice on specific cases, but I’m looking for a more general view. What is your take on low sodium diets for those diagnosed with congestive heart failure? If you’ve already written about this, I’d appreciate direction to it. I understand that NK means higher sodium requirements so I was just wondering your take. Thanks Peter

    • I think the best evidence today (which is modest at best) is consistent with this view — i.e., those with CHF are best avoiding sodium and reducing plasma volume.

  16. Peter,

    I agree that you shouldn’t “dumb down” these posts. Many of us love the detail, and we like knowing there’s good science in your work, even if we don’t always understand it.

    Still, having said that, I think we need to simplify the key message. There can be great value a simple truth, or a memorable sound bite.

    I was talking to some folks about my no-carb diet at a party last weekend. I could see their eyes glaze over as I went on about insulin resistance, etc. Finally, at one point I called the growing epidemic “carbohydrate poisoning.” The glaze vanished and the conversation perked up. They were all curious and wanted to know what I meant. I explained that over time, many people have a severe reaction to eating too many carbs for too long. For millions, the result is insidious weight gain and a host of medical problems including metabolic syndrome, T2 diabetes, etc.

    Then I asserted (I believe correctly) that the single most effective cure for carbohydrate poisoning and all those related ailments was to drastically cut carbs. To that they all nodded — not a word of disagreement. (If you are being poisoned, then of course the first thing you should do is stop taking the poison.)

    I know, you’re a doctor and a scientist. There may be reasons why “carbohydrate poisoning” is not be the best term. But to gain popular appeal and help millions of people get it quickly, we need simple terms and concepts like that one.

    What do you think?

    • I agree, but when I’m having the same conversation with people I refer to it as a “carbohydrate intolerance” — we all have different levels of this. Some (e.g., my wife) appear to have none. Others (e.g., me) appear to have a great deal.

    • Well, you are the doctor. Plus this is the blog that changed my life when I found it last September. I’ve become a disciple of this movement and I have referred friends and family to your work. I wish I could do more, especially as I look around as see this growing epidemic.

      My background is in marketing, so perhaps that’s how I can help. It’s not polite to argue with someone on their blog, and “carbohydrate intolerance” might be more accurate from a medical perspective. But from a communication perspective, the word “intolerance” is nowhere near as powerful “poison.” (It will remind people of things like lactose intolerance — unpleasant for those of us who have it, but not a serious medical issue. It won’t kill me.)

      In short, when it comes to powerful messages and marketing punch, “carb intolerance” might get a 4 out of 10. Calling this an epidemic of prolonged “carbohydrate poisoning” is probably a 10.

      (Just want to help. I know you’ll do what you think is right.)

      • Richard, no need to change your views based on my mine. There is no “right” answer here. I don’t disagree with your point about the punch it packs.

  17. I think you aren’t getting the full picture. I think that obesity, outside of a controlled laboratory setting, is mainly caused by nutritional deficiency. I am quite obese, and just recently found that my copper level was low. It didn’t show up as dangerously low on the blood test, just borderline low. I started supplementing with extra copper and was surprised to notice that my appetite has dropped dramatically. Before, I could have eaten plates of food without getting full. It was like the nutritional deficiency shut off the “full” feeling in my brain, I assume until I had eaten enough food so that the trace amounts of copper in the food were sufficient to keep me from dangerously low copper levels. In that sense, being fat kept me healthy. Now my appetite matches that of a normal person, and I feel overfull after a large meal.

    In other words, I think many of us have the obesity equivalent of scurvy. Even though we eat food, maybe even healthy, organic food, because our soil is so depleted (and the feed we feed our livestock is similarly depleted), most of us are living in a state of chronic mineral deficiency. The studies of healthy, thin cultures are of cultures that engage in small-scale farming with soil preservation, often up in the mountains where mineral levels are higher in the soil. I’m not sure if for everyone it is copper deficiency causing obesity, but I think it is something that should be researched.

  18. Dear Dr Attaia,

    Like many others I ‘found’ you after your TED talk. At last, someone who makes sense – even if I don’t understand half of what you say on first reading (sometimes second & third readings also!). But please, please, don’t ‘dumb down.

    A quick question. Can you suggest a basic ‘palette’ of tests that you feel are useful/essential to have? You often mention a variety of blood, etc, tests in your blogs. Here in England my NHS doctor would keel over if I went and asked for them all! Obviously you, as a doctor, don’t have the same considerations to be made.

    If it makes a difference to your answer I’m 50, went through the menopause at 32 (no diagnosis made), and doubled my weight in the next two years (thyroid’s fine). I have kept a food diary for five years and average 1400 calories a day, but my weight remained constant within about 3lbs either side of 15 stone. I was fed up with being told to eat less and exercise more as I KNEW that wasn’t working and that something else was wrong. Your TED talk made perfect sense, so I gave up sugar. Result is that in three weeks I have lost 9.5lbs without feeling hungry.

    I hope you can give an answer to this question. Thank you so much for what you’re doing, we all appreciate it.

    • Teresa, I would suggest basic chemistry, but also include fasting insulin, TG, cortisol, CRP, LDL-C, HDL-C. If they can, I would also strongly lobby for apoB and ACTH. This assumes, of course, your doctor is comfortable interpreting the results for you.

  19. Hi! Thank you so much for all the information on this blog! I’m a newcomer here, and am delighted with all the learning I can do here!

    I’m pretty sure this is not the best place to ask this question, but I wasn’t sure where I should post new questions. I am really hoping you might write an article on fiber. I noticed that you are planning to write an article on “How can carbohydrate restriction be healthy if it means eating less fiber?”, but would you consider writing an article on whether fiber is at all necessary? I’ve always been told that fiber is an absolute must for regularity… but I would like to hear if you have anything to say about this assumption.

    Thank you, again, for such an illuminating blog!

    • I’ve addressed this in a few comments, but basically the “case for fiber” is pretty weak in cancer reduction and heart disease. There is a case to be made, however, for bowel comfort, though dietary fat, salt, hydration, and other factors play at least as great a role.

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