Human fatty acid metabolism: engineering a deficit for ketosis – Part 1

One of my longevity research acquaintances has spent considerable time investigating the scientific literature on very low carbohydrate (i.e. “ketogenic”) diets. I have not researched this topic as carefully as my acquaintance, and what I’m told makes me curious. Before I started scanning the science literature on this topic in past last week, some parts of what I’m told by this acquaintance immediately sound reasonable to me because of the apparent effect of ketosis on mitochondria. That is, one consistently observed effect of interventions which extend healthspan (e.g. calorie restriction, intermittent fasting, exercise) is that they preserve mitochondrial function. So in this article I ask: could ketosis give you some of the benefits of calorie restriction, without calorie restriction? What does a ketosis diet look like? How many grams of carbs, protein, and fat per meal?

Because mitochondria are required to oxidize fatty acids for energy (see beta-oxidation), it reasonably follows that in order to function on a very high fat (i.e. very low carbohydrate) diet, you’d need to develop large numbers of healthy mitochondria. Note, the other main macronutrient used for energy is carbohydrate. In contrast to beta-oxidation in mitochondria for fatty acids, most carbohydrate use (called “glycolysis“) is in the cytosol of a cell, i.e. this process is not as mitochondrially-intensive as is the use of fatty acids for energy. This is what I mean by the argument for a ketogenic diet (i.e. a very low carbohydrate diet) enhancing mitochondrial function, is reasonable.

I’ve considered arguing with this particular longevity research friend about the necessity to be on a ketogenic diet to achieve this high level of mitochondrial function, because I suspect it might be achieved by a moderate-to-high carbohydrate diet, combined with high-intensity exercise (a.k.a. HIIT). There are some other potential benefits of a higher carbohydrate diet, including higher peak exercise output, some potential cognitive and mood benefits, and possibly better wound healing and muscle protein synthesis (due to the presence of more insulin). But I decided not to argue (yet), because I haven’t found (or even yet systematically searched for) evidence to support this hypothesis. I’ll be saving the research on that hypothesis for another post.

In this post, I’m trying to answer the following Primary Question for myself:

  1. What proportion of carbs and fat should I adopt to achieve a personal body fat of < 10%? i.e. should it be high, moderate, or low carbohydrate, with the balance being made up with mostly fat?

I ask this question with the goal in mind to use the answer to engineer a fatty acid deficit (burning more fat than I take in), to reduce my body fat. Note this is distinct from what many people advise: to achieve a “caloric deficit”. Yes, a caloric deficit is needed to achieve a fatty acid deficit. But because the metabolism changes (both upwards and downwards – see my note on body temperature below) depending on macronutrient choice and feeding patterns, I need to take these into consideration too.

I have been trying many different things over the past 6.5 years to achieve < 10% body fat, and have consistently failed to achieve it. I have done many combinations of calorie restriction, low carb, moderate carb, isocaloric (maintenance) food intake, HIIT, hours of daily treadmill walking, endurance training, weight lifting, fasted cardio, etc. All of these have, in my experience, enhanced my athleticism and strength, but have done little to lower by body fat, even in the presence of a substantial caloric deficit (engineered by diet and exercise and tracked by me).

Moreover, this question is confounded by my observation that when I’m on CR and/or carb-restriction, my basal body temperature goes down quite substantially (as low as basal = 96.4 F). For readers acquainted with thermodynamics, maintaining 80 kg of human mass at 2.2 degrees F lower than normal equates to a substantially lower amount of kcal I’m burning per day. In other words, my “metabolism is slow”, and I strongly suspect this is the primary reason for my lack of fat loss in the past 6.5 years.

To answer the above Primary Question regarding macronutrient selection, in this post, I strive to find the answers to the following questions:

  1. How and in what amount is dietary fat stored in adipose tissue, particularly in the absence of significant insulin? I ask this to help define my limits for meal size (e.g. how much fat can I eat at one time without storing much or any of it?)
  2. What proportion of energy does fat contribute to energy expenditure, particularly in the absence of significant insulin, and particularly while walking at 2-3 mph? I ask these because I have a treadmill desk which I use nearly every day from 1-4 hours/day. This contributes upwards of 1,000+ kcal to my daily energy expenditure
  3. Are there any particular fats I should choose which are known to be resistant to being stored as fat? (Put another way, are there fats that are easily burned for energy?)
  4. Assuming a context of a low-insulin environment (i.e. a low-carb, moderate protein diet, high-fat diet), what kind of fatty acid flux can I calculate for a normal day for me, given my normal levels of exercise? (e.g. the treadmill activity I mention above) This assumes that my body temperature stays relatively normal (low-carb has been observed in some studies to reduce T3, which is presumed to lower body temperature, energy expenditure, etc.).

I’ll leave it to these questions, for now.

Here I go:

Question 1: How and in what amount is dietary fat stored in adipose tissue in the context of a low-insulin environment? 

First, I want to illustrate what is known about fatty acid metabolism. Here are some components making up what one might call the “fatty acid system”:

  • Circulating Fatty Acids: these include LDL and triglycerides, as well as free fatty acids bound to serum albumin. These are either transported into cells to be burned (what I want), or re-esterified and stored in adipocytes (and some in muscle tissue)
  • Stored Fatty Acids: in the form of triglycerides, mostly in adipocytes (fat cells)
  • Dietary Fatty Acids: ingested fatty acids go through a process of digestion, and end up as Circulating Fatty Acids. These, as I note above, either end up being burned as fuel, or re-esterified and stored as fat in adipocytes or muscle

I will want to ensure that I don’t eat so much fat in one sitting that it overwhelms the ability of my body to burn most of it (instead of store it).

Furthermore, I will want to ensure that adequate fatty acids are released from adipocytes (i.e. adequate lipolysis) such that I am maintaining a fatty acid deficit, and not just burning what I eat and “breaking even”.

Question 2: what percentage of energy expenditure is fueled by fatty acids in the absence of significant insulin? 

For this question, I’m going to slightly increase the estimate reported by in its article on substrate utilization during rest. There, they report that ~66% of energy is derived from fatty acids during rest. For the purposes of this article, I’m going to assume 70% (see more discussion on this below).

Question 3: Are there any particular fats that I should preference for dietary intake, which are known to be preferentially burned for energy rather than stored? 

Many readers will be aware of experiments done on medium chain triglycerides (a.k.a. “MCT”), in that they appear to be a bit preferred for energy production rather than storage in adipocytes. One such study is the one by Delany et al. in 2000. In general, they found that the shorter the fatty acid chain, the greater preference for oxidation it had over the 9 hour study period.

As for longer fatty acids, linolenate (a primary component of flax) and oleate (primary component of olive oil) also had a relatively high preference for oxidation.

Thus, I will mainly consume coconut oil, olive oil (and other primarily oleate sources), flax, and MCT (C8/C10 mixture), in descending order of intake.

Question 4: Given a low-insulin environment (low-carb diet), estimate the daily fatty acid flux I might expect for a “normal” day for me

Here are the parameters I’ll assume for these calculations:

  • Age 31; Body weight of 180 lbs; height = 5′ 8″
  • Body fat = 10%
  • Body temperature = ~98.6 F
  • Treadmill walking 2 hrs/day, flat surface, 2 mph
  • Heavy resistance training (weightlifiting) 45 min, 3 days/week
  • All the above results in an ISSA caloric requirement of 3,233/day (assumptions: “Moderate” activity level and “Athletic category” of “Adult Recreational Exerciser”; see this calculator)
  • Respiratory quotient and % fat utilization: I couldn’t readily find a good scientific reference for common respiratory quotients to a given % calories from carbohydrate, nor one relating respiratory quotient to % fat utilization. Instead, I’m going to assume I’ll be using 70% energy expenditure as fat. As a reference, I’m using an article from on substrate utilization, which reports a 66% energy as fat during rest. I’m bumping this up just a little (to 70%) because I’m estimating a low-carbohydrate diet. I suspect it should be closer to 80%, given one’s glycogen will be low, and protein intake is modest. But I’ll keep 70% for the purposes of this estimate (to be conservative on estimates of daily fatty acid flux)
  • This would yield a daily fatty acid flux of:
    • 3,233 kcal * 70% = 2,263.1 kcal/day of fatty acids oxidized
    • 2,263.1 kcal/day of fatty acids oxidized / 9 kcal/gram fatty acid = 251.45 g fatty acid throughput/day

To me, this suggests that, so long as my body temperature stays at 98.6 F (and I actually doubt it will, but we’ll see), I will burn just over 250 g fat/day. This includes both what I burn from my body, as well as what I burn from my food. So, to have a “fatty acid deficit”, I will need to consume fewer than 251 g/day of fat (251 g/day sounds like a huge amount to me), without altering my respiratory quotient, nor dropping my body temperature. To maintain respiratory quotient, I need to basically do a single thing: don’t let insulin increase substantially. This equates to eating a moderate amount of protein, and a low intake of carbohydrates. Increasing insulin by eating too much carbohydrate or protein will decrease the % of energy derived from fat, and increase the % energy derived from carbohydrate or protein.

Macronutrient ratios

So, I’ll start with protein.

There’s an awful lot of debate about how much protein one should get/day to maintain/grow muscle mass, increase thermogenesis, etc. I’m going to just use the 1.6g/kg/day recommended by Suppversity. For me at 180 lbs / 2.205 lb/kg = 81.63 kg * 1.6 g/kg/day = 130 g protein/day.

I’m going to assume I’ll do a 500 kcal/day deficit to start, but I’ll retain the 130 g/protein/day. This equates to:

3,233 kcal/day maintenance – 500 kcal/day deficit = 2,733 kcal/day

(130 g/protein/day * 4 kcal/g protein) / 2,733 kcal/day = 520 kcal protein /2,733 total kcal = 19% protein

As for carbohydrate, the scientist-acquaintance I mentioned at the beginning of this article suggested 5% carbohydrate. This equates to:

2,733 kcal/day * 5% = 137 kcal from carbs / 4 kcal/ g carb = 34 g carb/day

This leaves me with the calculation for calories from fat: 100% – 19% protein – 5% carbohydrate = 74% fat.

2,733 kcal/day * 74% = 2,022 kcal from fat / 9 g/kcal fat = 224 g fat/day

Interesting. Note that I get almost all of my 500 kcal/day deficit from simply eating ~27 g less fat/day. Not much difference than a “maintenance” (or isocaloric) day.

Meal planning

So, given the above macronutrient goals (130 g protein, 34 g carb, 224 g fat), for 4 meals/day, one can divide it evenly into four meals of:

  • 32.5 g protein
  • 8.5 g carbs
  • 56 g fat
  • = (130 kcal + 34 kcal + 504 kcal) = 668 kcal/meal (* 4 = 2,672 kcal/day: close).

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Maximus Peto is a longevity scientist focused on the biology of aging, health, nutrition, exercise, lifestyle, and longevity. In his scientific research, he has scanned 160,000+ scientific articles, read 8,000+ scientific abstracts, and studied 1,500+ full-text scientific publications. Maximus has worked with several leading organizations in aging and longevity, including the SENS Research Foundation, the Methuselah Foundation, and the Life Extension Foundation. He shares his knowledge of keeping people alive and healthy at Long Life Labs.