Tissue-specific fatty acid oxidation

Does it matter where fatty acids are oxidized, liver or skeletal muscle?  Of course, they’re oxidized in both tissues (quantitatively much more in the latter), but relative increases in one or the other show interesting effects on appetite and the regulation of fat mass [in rodents].

Warning: a lot of speculation in this post.

A LOT.

It’s known that LC diets induce a spontaneous decline in appetite in obese insulin resistant patients.  Precisely HOW this happens isn’t exactly known:  the Taubes model?  improved leptin signaling?  probably a little bit of both, other mechanisms, and possibly this one:

 

Exhibit A. Oxfenicine

 

oxfenicine

 

Oxfenicine blocks fatty acid oxidation in skeletal muscle in mice (Keung et al., 2013).  This enhances muscle glucose uptake and oxidation, which reduces insulin.  Fatty acid oxidation in liver increases.  This also leads to reduced fat mass despite similar food intake, and it’s possible that liver fatty acid oxidation is a signal to the brain of well-fed status.  When brain thinks the body is well-fed, energy expenditure is enhanced.  In other words, it’s pharmaceutically mimicking some aspects of carb restriction (enhanced hepatic fat oxidation); this might also work with coconut oil.., as it is primarily oxidized in liver and there are some studies supporting this.

 




 

Exhibit B. Etomoxir

 

etomoxir

 

Etomoxir blocks liver fatty acid oxidation which makes brain think the body is starving: energy expenditure declines, fat mass goes up (Horn et al., 2004).

 

 

Exhibit C. C75

 

C75

 

C75 enhances liver fatty acid oxidation (net effect similar to oxfenicine in this regard, but by a different mechanism): this increases energy expenditure and reduces fat mass despite similar food intake (Thupari et al., 2002 and 2004).

 

 

Summary

-Three different drugs, findings consistent with: enhanced liver fatty acid oxidation leading to increased energy expenditure and reduced fat mass (and vice versa)… the thing is, the effects on fat mass are secondary to changes in liver fatty acid oxidation.  I think.

-Liver fatty acid oxidation: increased with coconut oil and low carb diets (ie, ketosis), and signals “well-fed status” to the brain which increases energy expenditure and reduces fat mass (by a little bit, but still…)

-Insulin: decreases fatty acid oxidation and energy expenditure (in some contexts).  This could explain, at least partially, why low carb diets & some of these drugs produce modest increases in energy expenditure (see above rodent-drug studies and study by Ebbeling).

 

[don’t take any of these drugs; that’s not the point of this post]

 

The fatty acid oxidation inhibitor & enhancer studies are exclusively rodent studies, but the metabolic effects are in agreement.  This may also explain the subtle advantages of LC diets (in some #contexts).  In other words, theoretically, maybe it’s not ketones per se (because I don’t think any of these critters were ketotic), but rather something related to the process of ketogenesis (ie, liver fatty acid oxidation), signaling the brain to regulate energy metabolism.

 

Just some thoughts.  Maybe leptin is involved.

[or I could be totally wrong]

 

calories proper

 

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  • Martin

    >> Oxfenicine blocks fatty acid oxidation in skeletal muscle
    Is this is really a good thing? Shouldn’t fatty acid oxidation in muscle be a sign of healthy metabolism and the main source of energy?

    >> Fatty acid oxidation in liver increases.
    I’m not sure about this either: I’m a big fan of MCT that is metabolized in the liver and its ketone output, but we cannot expect liver to process any large amounts of fatty acids and produce enough ketones to fuel all the muscle activity, can we?

    >> it’s possible that liver fatty acid oxidation is a signal to the brain of well-fed status.
    Apart from the issue I still have with liver processing too much fatty acids, it makes sense: eating coconut oi/MCT does reduce appetite.

    • “[don’t take any of these drugs; that’s not the point of this post]”

      • Martin

        Yeah, I get this 🙂

        But I would be truly interested in your view: fatty acid oxidation in liver might seem very beneficial for fat loss or, considering your hypothesis, hunger control and so MCT might sound like the true miracle fats, but we should really obtain the energy from oxidizing fats in the muscle, shouldn’t we? Overloading liver with MCT is probably as bad idea as pumping too much fructose into it. What do you think?

        • “but we should really obtain the energy from oxidizing fats in the muscle”

          We still are. Liver fatty acid oxidation doesn’t replace or shut down skeletal muscle fatty acid oxidation.

          “Overloading liver with MCT is probably as bad idea as”

          Overloading [any tissue] with [any fuel] is a bad idea. Key is to not overload.

  • Wab Mester

    We need more speculation along these lines, so thanks!

    There’s similar appetite regulation in ketogenic, moderate low-carb, and paleo diets. That suggests to me that it’s probably related to leptin rather than ketones or other liver metabolites.

    Ketones seem to provide an additional boost, but the MCT study you referenced suggests that it’s a short-term boost.

  • Eve

    I do keto, but never experienced any decline in appetite, and thus, never lost weight. I do it for other reasons, but it still surprises me, considering I tracking calories and macros, weigh food, etc.

    • Wab Mester

      There are multiple theories about why that might be. Check Mike Eades’ recent post on PUFA’s, for example. Another could be protein intake. There’s a famous example of all-you-can-eat vending machines. Participants ate too much and gained weight. Researchers said “see, it’s due to high availability and hyperpalatability!” But none of them increased protein intake. They all stopped eating once they had sufficient protein.

      • Eve

        I consume more than enough protein for my weight, minimize PUFAs (my only source comes from nuts), and supplement with o3 oil. Also take ACV in the AM and EGCG. Measurements haven’t changed. I’m not obese, but was always the second largest female in the room.

    • this mostly applies to obese insulin resistant populations

      • Eve

        I know. 🙂 I just wonder at what point “spontaneous appetite reduction” disappears.

        • I guess, “ymmv”

        • Jack Kruse

          It is determined by how much sun you get and how long you ground……..the deficit that remains has to be filled by food. Sunlight makes intermittent fasting normal. That is why SIRT 1 and NAD+ are also solar gene products.

  • Jack Kruse

    You said, ” Insulin: decreases fatty acid oxidation and energy expenditure” Might that be because insulin is a solar hormone? Don’t carbohydrates growing when the sun is strong? Might we be missing this key point in some way in a mitochondria? Might exposure to the sun by your eye and skin reduce the need for food intake? You said, Might leptin be involved? Yep. It too, is solar hormone and it controls oocyte selection and fecundity. It counts electrons and photon frequency because of this “idea” called the photoelectric effect. Leptin specifically counts the frequency of light electrons carry and ECT speeds are tied to the amount of free radicals and superoxide burst made at cytochrome 1. All foods break down to electrons and fall into ECT in quantized fashion too. Electrons from carbs that more highly powered enter at the NADH/NAD+ couple. That is 340-380 nm light. Light = electrons says something called the photoelectric effect. Food = light energy and information and this is why photosynthesis forms the basis of the entire food web. Fat electrons enter at FADH2 that operates at a higher frequency in the violet blue range. There is a reason for this: Redox potential of the cytochrome proteins is also quantized to light and that light creates free radical signals to mimic the seasonal power of the food electron. Free radicals that have unpaired electrons that transfer the energy and information of electrons from foods to signal cells from the environment to tissues to transfer this information. This is why every mammalian gene has a clock gene in front of it. That clock gene pays attention to energy and information assimilated in cells and tissues to change epigenetic signaling as season shift. Why don’t people understand light? They cannot conceive of how many frequencies we actually sense via our eye or skin and that hit our retina. Amacrine cells in our retina are cells that control bio chemicals can handle 8,683,317,618,811,886,495,518,194,401,280,000,000 different frequencies at once. Neuropsin is a sensory opsin designed to deal with UVA light. Melanopsin handles 435-465nm light as light dims to dusk but not as it brightens from sunrise. This is a staggering level of power and control when you understand the math behind how waves really work in our sensory systems. All waves interacts in our thalamus. Our sensory systems are designed to pay attention to the waves in different ways to gain different information about different aspects of the environment. What happens when you cover or silence these sensory systems? You get problems with insulin and leptin signaling in cells. You get diseases like Bill talks about or I do; I often refer to epigenetic circadian disruptions as “an alternative reality”. Everything we put on our bodies today or use around our bodies distorts our sensory perception for light. This alters our reality, but yet few look have my perspective in wellness or illness for that matter. The senses are specific to our morphologic development from the germ line that was given to us by our mothers. That sensory organ is a mitochondria. It is present for us to use in our specialized sensory organ and tuned to the specific spectrum of frequencies that our local environment gave to our grandmother and mother. In this way the germ cell that you came from become more finely tuned to read and react the environment you’re born in to. Your mitochondria are pliable life long but your sensory organs hard wire to the free radicals signals they get from fertilization to about six years old. This is why if you learn a foreign language below six you can still have the metabolic flexibility in your mitochondria to do this because heteroplasmy rates remain low. This also allows the child to acquire the dialect of accent but after six you lose the ability. This is instructive about how sensory integration works in humans. This is Dr. Doug Wallace work. This tunes us in the best ways ways possible to our environment. So when a kid is born with a sensory deprivation syndrome what do you think that should mean to an clinician? It means leptin resistance at some level. The amount of LR = % heteroplasmy = phenotypic expression of a disease. In this way diseases are sliding scales of leptin resistance and mitochondrial energy production. The less energy you get from the sun the more food one has to eat = you get hungry to make up the deficit. When you move away from your ideal adapted environment things change don’t they. Why? Blocking one part of the spectrum alters biochemistry because it often regulates another. This is akin to having sex with your clothes on. We can do this, but nature wants us naked for a reason. Moreover, it’s probably not a good thing to consider. Mother Nature perspective is the one makes the point we should adhere to. Our surfaces are designed to decipher wave forms from the space around us; they are invisible to us unless we have our senses intact. This video illustrates what I am trying to teach you about light coming into your eyes. There is a lot more to the interaction than meets the eye. https://www.youtube.com/watch?v=FjHJ7FmV0M4

    • Mike

      “8,683,317,618,811,886,495,518,194,401,280,000,000”

      This is an approximation. It has recently been determined to be 8,683,317,618,811,886,495,518,194,401,280,000,082 exactly.

    • Ketard Aesthetic Bodybuilder

      You are mentally ill, hope this helps.

    • MarcT1

      Jack Kruse – What a wonderful video and illustration!!