A Key to Nutrient Partitioning is… Lipoprotein Lipase?

Preface: My revelatory moment

I’ve spent the good part of the last month looking for the ‘Holy Grail’ of Cheat Mode. Something that would influence nutrient mobilization into muscle cells and not fat cells. Exercise does this to a degree, and doing the exercise in an insulin resistant state (ie. the evening) potentiates this as well. That being said, I wanted a supplement to add onto this; for no real reason other than a ‘more-is-better’ hubris mentality I get sometimes, and because I like supplements.

Thus starts my long exposure into looking at GLUT4. Its logical to assume that if I want to influence glucose metabolism I would look at the main glucose transport. That being said, muscle already accounts for up to 85% of glucose uptake and the Cheat Mode paradigm only furthers that, after reading this paper (free, btw) I figured perhaps I should not supplement to hinder adipose glucose uptake further. It might adversely affect adipokine status as well, and not be the smartest idea in the long run.

That being said, this incredible review (also free, I’m good at Pubmed searches) opened up my eyes to the possibility of Lipoprotein lipase being the key to nutrient partitioning. What fuelled me even further was that a nutrient in existence actually does have the ability to further a difference between muscle and fat LPL activity; Biotest’s Cyanidin-3-Glucoside. (Link to Pubmed).

Of course, I have to find a cheaper alternative than that… I cannot start recommending such an expensive product. (6 week supply for $480)

So in order to find said product. I have to fully understand LPL receptors. Since I cannot use examine as a deposit of knowledge since one cannot supplement LPL, I am using my blog.

LPL receptor physiology

(First, I should note that human LPL is incredibly similar to other species such as rodent and bovine; extrapolation on interspecies studies is possible)

LPL is a two domain receptor; possessing an amine-terminal (which has the catalytic site and cofactor binding site) and a carboxyl-terminal, which contains a heparin binding site. [x] Both components are critical to LPL function, as it loses function when they separate. [x]  The catalytic site is where any Triglyceride rich substance gets hydrolyzed; this includes the conversion of chylomicrons into chylomicron remnants, and vLDL into IDL (intermediate density Lipoprotein). These reactions require a substance called ApoC-II as a cofactor to induce LPL activity, ApoC-II is normally carried around on lipoproteins. [x]

Dysregulation between ApoC-II levels and active LPL levels induce hypertriglyeridemia, either if you have too much ApoC-II relative to LPL [x] or vice-versa. [x]

It is highly expressed in adipose, muscle, brain, heart, and macrophages. It can also dissociate from cell membranes and kinda just float around in the blood to later be taken up by the liver. [x] Regulation of LDL proliferation and expression, and thus relative LDL activity, is tissue specific and regulated from internally.

Tissue specific expression

Tissue specific expression comes as a cumulative effect of differences in the regulatory processes of LPL, which vary between tissues. Below is a diagram (replicated from Wang, H; Eckel RH. 2009) which illustrates the sum of processes.

Metabolic regulation of Lipoprotein Lipase


It’s so important and informative that I can invade my Twitter feed in the sidebar.

Generally the top left bubble (Nutrient state and hormones) are what we can manipulate with diet, whereas the top right bubble (proteins) are potential therapeutic targets in the future for supplementation; both act vicariously through the four mechanisms in the middle square to induce unique tissue specific expression in the tissues listed in the bottom square.

The areas we want to concern ourselves with (for our ego) is the locus of control central to adipose tissue. [x] There is another locus in the heart, but it seems to be more critical during birth and growth rather than maintenance of one’s body.

In the cell, preliminary studies have noted that there is one main intermediate which has differences in muscles and adipose. This difference is phosphorylation of (AMP)-activated protein kinase, an enzyme involved in energy metabolism. Phosphorylation reduces LPL transcription and activity in adipocytes [x] yet increases LPL activity in skeletal muscle. [x] If we look at the study done with C3G, it seems that we can indicate a very high correlation between the AMPK phosphorylation and overall LPL activity (of which the C3G study is the first study to my knowledge investigating this potentially new cellular lever in vivo), this correlated with a decrease in plasma triglycerides (due to more LPL activity on muscles) and a decrease in body fat. Interesting to note was suppressive effects on visceral adipose tissue, enhancing effects on muscle, but overall no real effect on subcutaneous adipose tissue. Although this alleviates my concerns about ‘starving’ fat cells of glucose and killing adipokine secretion, it cannot be determined whether this is due to the AMPKp pathway or if it is unique to C3G.

So basically it seems that, in the end, compounds or techniques which are conducive to phosphorylation of (AMP) protein kinase will then create a lipid partitioning effect towards muscles rather than adipose tissue.

This ratio (adipose LPL:skeletal muscle LPL) has already been linked to body composition in rats [x] and humans. [x]

Why does this create a partitioning effect overall?

Mainly because when a triglyceride (fatty acid package) gets hydrolyzed in adipose, there is a chance it gets stored. Although this can occur in skeletal muscle as well (as evidenced by intra-skeletal muscle fatty acid deposits) there is a much greater chance that it will be oxidized for energy [x] and subsequently burnt off as heat (given the skeletal muscles are an incredible source of adaptive thermogenesis).

There might be more indirect benefits as well (a general increase in energy substrate in a cell, for example, will induce a more anabolic environment and impart effects on mTOR), but I have seen no direct evidence for this but just logical extrapolation which may or may not be true.

To my knowledge, the actual action of AMPKphosporylation does not induce any special muscle building effects; it just shunts metabolic activity towards muscles and away from fat.

Non-supplemental modifications to manipulate partitioning

It takes a while to come to a formal conclusion on supplementation, so that will be a future article. As for now, I will leave you with some actions which favorably affect lipid partitioning.

(Note: This section is talking about LPL again. LPL is what we are concerned with overall, but the previous was just talking about the mechanism which explains the differentiation between what is seen with LPL)

Stress. Stress has been associated with both an increase in skeletal muscle and heart LPL activity and a decrease in white adipose tissue LPL activity. [x] Not sure if these effects can be extrapolated to humans (as if you read the abstract, its a cute little form of rodent medieval torture), but if they are mediated by catecholamines as the authors hypothesize then there will be various supplemental interventions to address that.

Fasting. This one is tricky. LPL activity only changes in white adipose tissue (which is sufficient for a partitioning effect given myocytes are unaffected) via a gene dependent reaction to a hypocaloric state [x] and decreases early on into a fast. [x] Activity of LPL returns to baseline 4 hours after feeding, so this suggests that for either intermittent fasting or alternate day fasting, your first meal upon return will be favorably placed in the body. (These effects might be acting through adiponectin, which is an agonist of AMPKp and is higher when insulin is lower) [x]


As suggested by that last blurb, the adipokine ‘Adiponectin’ also acts upon AMPKp of both muscle and fat. I cannot recommend manipulating it or not at this point in time though, as nutritional history has a very bad track record of finding a compound sexy and then injecting enough of it or increasing its presence in the body to the point of side effects (which is how we found out insulin and leptin are both pro-inflammatory in high levels).

Hypothyroidism. This one is counter-intuitive, but it seems that in a state of deficient thyroid hormone output adipose LPL is reduced. [x] However, aside from not recommending this avenue for various reasons, skeletal muscle LPL was not measured and thus we cannot be sure if a partitioning effect exists.

Growth and sex hormones (GH, IGF-1, Testosterone) have been linked to inhibiting adipose LPL activity [x] while growth hormone increases muscle LPL activity. [x] [x]

Resistance training upregulates muscle LPL activity rapidly [x]  with no effect on fat LPL levels, probably though direct stress on muscle cells. [x]

FWIW, Insulin and glucose both increase LPL activity and mRNA content, but do so indiscriminately. No partitioning effect will be gained from them, but it should be noted.

Finally, although not directly manipulable but interesting none-the-less, LPL activity on an adipocyte correlates fairly well with the size of the adipocyte (bigger cell == more LPL activity).   This suggests that those who are currently obese may not have as much lee-way with the above mechanisms. Also interesting (irrelevant to the topic at hand, sort of) is the fact that women have bigger fat cells and more LPL activity in the thigh region and men in the abdominal region. [x]

What really sucks is that when you lose weight, your fat cells tend to express LPL more. [x] [x] [x] Possibly a homeostatic mechanism to preserve bodyfat, it indicates that LPL should be a concern to people who recently lost a lot of body fat or are in the process of doing so. Another problem is that when you lose weight, you tend to get loose skin, for this people can get a loose skin removal surgery, but exercise is also very important.

Final Note: Applications to Cheat Mode

As to whether this research changes anything about Cheat Mode, for the most part no. However, the “4 hours after you eat, LPL is normalized” intrigues me a little bit. It takes about 60-90 minutes to start your workout nutrition and finish a weightlifting workout, which leaves a possible 2.5 hours where your body will favourably partition calories. Workout nutrition would definitely be out of gastric bypass surgery by this time (and be under the time with downregulated LPL) and lipids in the gut are taken up faster than carbs and proteins (which require membrane transports that have a limited rate, but would already be in circulation if you had caloric workout nutrition). It is possible that by omitting the pre-workout solid meal one can have a higher energy expenditure overall. In addition, rhinoplasty in Washington DC, facelift and neck lift, eyelid surgery, brow lift and otoplasty, and laser skin treatments performed by a board certified facial plastic surgeon in Washington DC. It would be a partitioning effect augmented by the fast and the workout, and more nutrition will be lost as heat.

Although, I should clarify, that omitting the pre-workout meal has been shown to be a really bad idea for those who have power as their primary goal (solid food seems to be godly before heavy lifting). So this modification would be more of a body composition idea. With Dermal Fillers, you pay less at a time, but since the results aren’t lasting, your procedures will add up to about the same cost of a face-lift in the long run. Nevertheless, I will be experimenting a second time with this (as in the past I have had success with it, but never gave it a fair trial) and will report on the changes.

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  1. jelta says:

    “Generally the top left bubble (Nutrient state and hormones) are what we can manipulate with diet, whereas the top left bubble (proteins) are potential therapeutic targets in the future for supplementation”

    Typo – should be top right bubble (proteins)

    You can delete this comment if you’d like.

    • Silverhydra says:

      Thanks, having a one-man editing team makes me prone to errors.

      Although that reminded me of an abstract I was reading today where they wrote “Diabebetes”, somehow that slipped past peer review; makes me feel more normal.

  2. martynj says:

    Great article. Just discovered cheat mode recently and really enjoy reading your blog. I did a degree in biochemistry so the details you go into are great, making me feel like doing some research too!

  3. Dion Cooper says:

    Very well done article on a subject that deserves more recognition. Been looking for a good article on LPL. Planning on referring several people to this soon. I have several comments/questions:

    1. Although its rather conclusive that Growth Hormone decreases AT-LPL in humans, GH’s effects on SM-LPL in humans is far from conclusive, with most data showing no or conflicting results. [1,2]

    2. While you are correct that Insulin increases AT-LPL, it actually DECREASES SM-LPL. [3,4]

    3. A high carbohydrate diet changes lipid partitioning/metabolism to increase adipose tissue lipid storage and to decrease skeletal muscle lipid oxidation, partially through regulation of LPL [4,5]

    4. The amount that AT-LPL is increased and SM-LPL is decreased by a high carbohydrate meal (or by insulin), is a very good predictor for future weight gain. [5]

    And i was wondering if you have found anything that increases Brown Adipose Tissue LPL without increasing White Adipose Tissue LPL, the only logical thing i could think of was cold exposure but i have yet to see any conclusive data on the subject in humans.

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