Lean Mass Hyper-Responder: Is it the saturated fat?

It’s a question that comes up again and again: Could Lean Mass Hyper-Responders (LMHRs) just be eating more saturated fat?

Rather than repeatedly answering this question in cumbersome Twitter threads, I thought I’d save both Dave and myself some time by consolidating 5 points that challenge the saturated fat hypothesis of LMHR:

1. Magnitude of effect. Many LMHRs exhibit LDL-C levels of well over 300 mg/dl. Mean levels from the LMHR participants in our cohort study were 320 mg/dl (Table 3), and we certainly have a handful with LDL-C above 500 mg/dl. I’m not aware of any data suggesting saturated fat intake, even at extreme levels, can cause increases in LDL-C to such an extent. If you – the reader – are aware of such data, please do share.

2. LDL-C change has an inverse relationship to BMI. In the same study, we observed that LDL-C change has an inverse relationship to BMI on a carbohydrate restricted diet. If this is the case and saturated fat was the primary driver of the increase in LDL-C observed, then the logical implications are either that there is a dose-response effect of saturated fat on body weight loss (i.e. saturated fat makes subjects leaner) OR that persons who are lean and adopt low-carb diets preferentially eat higher proportion saturated fat diets. For example, if we had three subjects, Jamie, Nicky, Leslie, and Amir with BMIs of 24, 26, 21, and 30, respectively, and they were all to adopt low-carb diets, Leslie would eat more saturated fat than Jamie who would eat more saturated fat than Nicky who would eat more saturated fat than Amir. 

3. The triad. A critical point is that LMHR are defined, not by LDL-C alone, but the triad of high LDL-C, high HDL-C and low triglycerides. Therefore, any complete model explaining the LMHR phenomenon must account for this triad. Thus, we must ask, could eating more saturated fat cause to the triad of markers seen in LMHR? (And that’s assuming LMHR eat primarily high-saturated fat low-carbohydrate diets.) In our study, mean levels were 320 mg/dl LDL-C, 99 mg/dl HDL-C, and 47 mg/dl triglycerides.

4. Adding back moderate carbs attenuates the phenotype. In the case series associated with the aforementioned study, six LMHR or near-LMHR subjects were instructed to introduce 50-100g/d carbs to help replenish hepatic glycogen and, via the postulates of the Lipid Energy Model, lower their LDL-C. No further instructions were given, i.e. subjects were not told to lower saturated fat intake. Nevertheless, all subjects exhibited substantial reductions in LDL-C, including one who exhibited a drop from 665 mg/dl to 185 mg/dl. Even if saturated fat intake occurred spontaneously (without instruction), it seems unlikely it could explain the magnitude of the effect. 

5. Case series. Although it is an n = 1, we published a case series of an individual consuming a ketogenic diet relatively low in saturated fat (~82% unsaturated, ~18% saturated). His pre-low carb LDL-C was 95 mg/dl. But following carb reduction, LDL-C rose to a peak of 545 mg/dl, despite relatively low saturated fat intake. Furthermore, LDL-C trended inversely with BMI and, when saturated fat intake was altered for experimental purposes, LDL-C remained concordant with the BMI trend and, thus, inconsistent with the prediction that saturated fat drives LDL-C change in this subject. Even if this is only a case report, recall that these data represent a real LMHR patient and are consistent with both the LMHR cohort study and the Lipid Energy Model.

Certainly, none of these 5 points dispute that saturated fat could contribute to the increase in LDL-C seen in LMHR; however, they do suggest that saturated fat is not the primary driver of change. Disregarding point 5, could high saturated fat intake be permissive or even required for the LMHR phenotype? Possibly. However, unless one can explain how saturated fat intake could account for these data, we should assume there is more at play worth investigating. 

For more reading and viewing:


Lipid Energy Model: https://www.mdpi.com/2218-1989/12/5/460

Lipid Energy Model video abstract: https://youtu.be/AkzxESsTJyM

Lean Mass Hyper Responder study: https://academic.oup.com/cdn/article/6/1/nzab144/6446805

Lean Mass Hyper Responder video abstract: https://youtu.be/v4FXBtVXPhA

Lean Mass Hyper Responder Case report: https://www.frontiersin.org/articles/10.3389/fendo.2022.830325/full

Lean Mass Hyper Responder Case report video abstract: https://youtu.be/JSEqIsYBZxU

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1 year ago

I think I’m one of the lean mass hyper-responder as my LDL was passing 500…I’m still waiting for the results to be sent to me by email so I can review it. I don’t really remember the exact number but I think was 580?! Pretty insane. Been on clean keto for 4 months, was never fat (43kg) but I decided to remove sugar and grains from my diet. I’m 157cm, 41kg now, 31yrs and always active. my previous blood work LDL was 100 now sky high despite the highest fat I consume are only “avocado” (daily) and 2-3x a week “wild salmon” (I’m pescatarian but mostly vegetarian) and cheese 2-3x a week. I eat mostly veggies and hardly eat butter or EVOO as I was never a big fan of greasy food. I find it confusing why my LDL is super high despite I don’t consume crazy amount of fats.. Maybe because I am always doing 16:8 or OMAD? But I have been doing that my whole life…I’m confused, I can’t wait to receive the results so I can really review it all.

1 year ago
Reply to  Leen

Finally got the results.
LDL 582
HDL 80
Triglyceride 108
HbA1c 4.4
Fasting insulin 2.40 uU/mL

I also checked for hashimoto (which is negative) as I used to have slight hyperthyroidism years back but now all came out normal.

Seems to me it’s all good except the sky high LDL. Also I have always been lean. I have never pass 18.3 BMI. I’m always on foot and also exercising plenty (my whole life) but no more cardio since keto… My cholesterol level was always good prior to keto but always foggy brain and digestive issues. Now with keto better memory and focus and hardly have any digestive problems, except with cruciferous veggies.

Now I’m eating 50-100g of carbs(after reading all these and watching your videos on YouTube) will cut back some fat and will do another test in 3months that’s what my Dr. Wants.

1 year ago
Reply to  Leen

Hopefully you were fasting at least 12 hours and no coffee prior to your lab work given your TG look slightly suspect along certainly not alarming. Your activity level/leanness is dictating your LDL-c in conjunction with the depletion of your liver glucose stores (glycogen). I would venture to guess the addition of a sweet potato would probably cut your LDL-c in half if not more – if you can add slightly more carbohydrate without affecting your mental status, you could probably prevent the massive LDL-c rise. The rise in LDL-c likely has nothing to do with dietary fat and more to do with your activity level/leanness. If fact, if you ate a ton more fat, your LDL-c would probably go down. Hope you got your answers.

1 year ago
Reply to  Austin

Thank you for your time answering.

I dropped out of keto for 3 months now as I couldn’t stop losing weight but still only eat whole food & unrefined carb and of course still plenty of good fats. I follow pescatarian diet for yrs and still do and also I eat 1-2x a day no snack since I could ever remember because I never like eating. Exercise 4-6x a week 40mins to 2hrs per day depending on the intensity.

Last year I tried statin 10mg for 1 month my LDL then was still 400+ after taking statin it only went down 10mg hahahaha what a joke so I told my Dr. I tried her way and it didn’t work so I discontinued and just add more sweet potatoes and veggies… sad thing I’m forgetful again but not as bad as before..so after 7months my Results below

By the way my Age 32

Before every blood test I would be on 16 to 20hrs fast
Results of my current blood tests this month
HDL 86
LDL 253
Triglycerides 52
A1C 5.2 (much higher than last time)

My doctor also checked
Free T3 2.3 pg/mL (1.58-3.91)
Free T4 0.94 ng/dL (0.70-1.48)
TSH 0.634 uIU/mL (0.350-4.940)
B12 1315.4 pg/ml (187.0 – 883.0)
Carbohydrate antigen 19-9 (digestive tract) 9 U/mL (0-37)

Laura Isko Jacobs
Laura Isko Jacobs
1 year ago

So interesting! For this item 4. Adding back moderate carbs attenuates the phenotype – how long did the subjects eat more carbs? 2 days? More? thanks!

Siobhan Huggins
Siobhan Huggins(@siobhanh)
1 year ago

Hi Laura,
It doesn’t look like this information is in the paper, nor the supplementary material for most of the subjects – perhaps because it sounds like the subjects in the case series were in a clinical setting. However, it would be a good question for the Lean Mass Hyper-responder facebook group, as there are likely some people there who have tried carbohydrate reintroduction to reverse the profile and could comment on how long it took (especially if they were doing more frequent testing).

Austin Dudzinski
1 year ago

I wonder if this phenotype in combination with perhaps some genetic defect like ApoCIII GOF (if these even exists) or lp(a) or something could explain why some of these ultra marathon people or the fella who ran with the Tarahumara tribe dropped dead for CAD despite having (likely) excellent cardio respiratory fitness. Obv the excessive oxidative stress of taking environment hormesis to an extreme could account but maybe his apoB was astronomical in conjunction with some bad genes was really more of a driver? You got any insights on this Nick?

1 year ago

Honestly, couldn’t you make an argument based on the current lipid hypothesis in conjuction with the LEM that adding enough candy per day to replete hepatic glycogen stores to reduce ApoB should lower the risk of heart disease? How does that sound? A LMHR eating candy to lower the risk of ASCVD. This is a struggle for me.

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