Recently I posted an article recommending combining sterculia oil with berberine and/or fish oil as a way to escape torpor. I chose this combination because they mimic the effects of leptin, the hormone produced by our fat cells whose job is to keep us lean but to which most of us are resistant.
As discussed in The SCD1 Theory of Obesity, Part 1, leptin has several jobs.
- leptin stimulates satiety in the hypothalamus.
- leptin increases the rate of fat oxidation in skeletal muscle by increased the rate-limiting enzyme CPT11
- leptin stimulates the MAPK/SIRT1/PGC1a pathway2,3
- PGC1a is a master regulator of mitochondrial biogenesis and function4
- PGC1a plays a key role in adaptive thermogenesis, the burning off of extra calories as heat5,6
- leptin down-regulates both SCD1 and its upstream activator PPAR gamma7,8
- SCD1 deficient mice have high metabolic rates and are resistant to leptin-deficiency induced obesity9
- High expression of PPAR gamma and SCD1, especially in response to dietary polyunsaturated fat (PUFA), induce a torpid metabolism characterized by low body temperature and metabolic rate
- Since leptin is down-regulated by PPAR gamma10 and many of leptin’s effects are mediated by ROS production which is in turn minimized by the activities of SCD1, PPAR gamma and SCD1 are pitted in a battle versus leptin over whether the metabolism is in fat storing mode or fat burning mode
Since I am leptin resistant, I am using the sterculia oil – which inhibits SCD1 – to replace leptin’s role of down-regulating SCD1 and PPAR gamma. I think that once my body fat reaches a certain level of saturation due to this down-regulation, this itself will trigger adaptive thermogenesis and a high metabolic rate. I don’t know how long that will take, though, so in the meantime I’m using berberine to stimulate AMPK and adaptive thermogenesis. Make sense?
My hope is that ultimately I’ll be able to saturate myself, get to a target weight and maintain it without supplementation once I have reset my body fat. It’s an ambitious goal and time will tell.
Turning Off PPAR gamma – A Double Edged Sword
Since I’ve already talked about the danger inherent in shutting down PPAR gamma after you’ve built your torpid metabolism on it and therefore why it makes sense to combine it with berberine, a potent stimulator of AMPK/SIRT1/PGC-1a11, I may as well quote myself:
But it’s not without danger. PPAR alpha seems to be the master regulator of fat burning, but PPAR gamma can increase fat burning as well! I think that PPAR gamma is a crutch. It’s keeping us upright for now and sometimes when you kick the crutch out, it can cause problems. For this reason, in my current trial I am using a PPAR agonist (turns it on) in addition to the sterculia oil.Brad Marshall, Sterculia Oil: How to Escape Torpor!
The idea is that the sterculia oil will shut down the positive feedback loop of PPAR gamma/SCD1/ELOVL3-6 that has been dominating my torpid metabolism and that the berberine will step in to stimulate adaptive thermogensis. I am using a two-pronged approach to restore the functions of leptin since my body is actively ignoring it. The hope is that over a period of months I will be able to saturate my fat stores, lose weight and ultimately regain leptin sensitivity.
Monitoring The Metabolic Changes
Remarkably, I think I actually captured my metabolic changeover in action.
As explained here, I’ve been using a metabolic testing device to track my metabolic response to different trials. I also reported that in my first “safety and let’s see what happens” trial of sterculia oil I thought I had shut down my PPAR gamma activity based on a dramatic drop in the very long chain saturated fats nervonic and lignoceric acid. After that I stopped taking sterculia oil for 8 weeks to see if I would revert right back to where I used to be, which I did (disappointingly).
This gave me an opportunity to monitor my metabolic changes more closely as I again began taking the sterculia oil.
The device measures Respiratory Exchange Ratio (RER), which is the amount of CO2 you exhale versus the amount of O2 you consume. If the number is 1.0, you are (in theory) burning all carbohydrate. If the number is 0.7, you are (in theory) burning all fat or ketones or alcohol. In practice, I’ve found the number to be less straight-forward than that, but that’s for a later post. Here I’m going to focus on the changes I saw in my RER while walking at a steady pace as I began taking sterculia oil at 1200mg per day (March 4th, 2021) and then added in berberine at the two week mark (March 17th).
Two weeks prior to beginning this trial, I had been taking 600mg sterculia oil. At the beginning of this trial (March 4th, 2021) I upped my dose to 1200mg. My eating was “normo” – two meals per day of starch, protein and saturated fat sources like butter but WITHOUT supplementing stearic acid. At the two week point (March 17th), I began taking berberine.
I measured my RER every day around 11am while walking on a level surface at 2.7 miles per hour (pacing).
Over the first two weeks of 1200 mg of sterculia oil, my RER rose steadily, from a low point of 0.8 on March 7th (65% of burned calories from fat) to a peak of 0.94 on March 16th (24% of burned calories as fat). After beginning the berberine my RER steadily fell, reaching 0.78 on March 22nd (76% of burned calories from fat).
My Current Strategy
Many have asked about timing of supplements and my current dietary strategy. I am at a point where I have been using the SO long enough to see some changes. My Desaturase Index dropped from 1.9 at the end of February to 1.5 in the beginning of April – my current target is 1.1.
I am following a time restricted eating window where all of my solid food is consumed between 3 and 8 PM. I’m taking berberine, in the mornings, sterculia oil with dinner and I have just begun supplementing with stearic acid again (last night). I’m hoping to hit new metabolic highs but unfortunately I’m having problems with my testing device so I may have to rely on my body temperature and monitoring my breathing to know. This morning my body temp ticked up to 98.1 from 98.0 yesterday.
I’m taking berberine in the morning because of it’s mechanism of action and it’s short half-life. Berberine is a partial blocker of mitochondrial complex 1, which temporarily impedes energy production in the cell, leading to a buildup on cAMP, which in turn stimulates AMPK/PGC1a/adaptive thermogenesis. It has a short half-life, similar to caffeine12. I’m taking it in the morning because I want the AMPK to up-regulate fat oxidation, so that when I eat my big meal the stearic acid gets shuttled straight in the furnace. At that moment I want mitochondrial energy production to be fully open to generate ROS (which is to say I want the berberine out of my system) to further increase adaptive thermogenesis.
- 1.Wein S, Ukropec J, Gašperíková D, Klimeš I, Šeböková E. Concerted Action of Leptin in Regulation of Fatty Acid Oxidation in Skeletal Muscle and Liver. Exp Clin Endocrinol Diabetes. Published online May 3, 2007:244-251. doi:10.1055/s-2007-956166
- 2.Minokoshi Y, Kim Y-B, Peroni OD, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. Published online January 2002:339-343. doi:10.1038/415339a
- 3.Kakuma T, Wang Z-W, Pan W, Unger RH, Zhou Y-T. Role of Leptin in Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Expression1. Endocrinology. Published online December 2000:4576-4582. doi:10.1210/endo.141.12.7804
- 4.Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. The American Journal of Clinical Nutrition. Published online February 2, 2011:884S-890S. doi:10.3945/ajcn.110.001917
- 5.Miller KN, Clark JP, Anderson RM. Mitochondrial regulator PGC-1a—Modulating the modulator. Current Opinion in Endocrine and Metabolic Research. Published online March 2019:37-44. doi:10.1016/j.coemr.2019.02.002
- 6.Bagattin A, Hugendubler L, Mueller E. Transcriptional coactivator PGC-1 promotes peroxisomal remodeling and biogenesis. Proceedings of the National Academy of Sciences. Published online November 8, 2010:20376-20381. doi:10.1073/pnas.1009176107
- 7.Abbasi A, Moghadam AA, Kahrarian Z, Abbsavaran R, Yari K, Alizadeh E. Molecular effects of leptin on peroxisome proliferator activated receptor gamma (PPAR-γ) mRNA expression in rat’s adipose and liver tissue. Cell Mol Biol (Noisy-le-grand). Published online August 15, 2017:89. doi:10.14715/cmb/2017.63.7.15
- 8.Lu R-H, Liang X-F, Wang M, Zhou Y, Bai X-L, He Y. The role of leptin in lipid metabolism in fatty degenerated hepatocytes of the grass carp Ctenopharyngodon idellus. Fish Physiol Biochem. Published online December 2012:1759-1774. doi:10.1007/s10695-012-9673-6
- 9.Miyazaki M, Sampath H, Liu X, et al. Stearoyl-CoA desaturase-1 deficiency attenuates obesity and insulin resistance in leptin-resistant obese mice. Biochemical and Biophysical Research Communications. Published online March 2009:818-822. doi:10.1016/j.bbrc.2009.01.183
- 10.Goetze S, Bungenstock A, Czupalla C, et al. Leptin Induces Endothelial Cell Migration Through Akt, Which Is Inhibited by PPARγ-Ligands. Hypertension. Published online November 2002:748-754. doi:10.1161/01.hyp.0000035522.63647.d3
- 11.Yu Y, Zhao Y, Teng F, et al. Berberine Improves Cognitive Deficiency and Muscular Dysfunction via Activation of the AMPK/SIRT1/PGC-1a Pathway in Skeletal Muscle from Naturally Aging Rats. J Nutr Health Aging. Published online March 6, 2018:710-717. doi:10.1007/s12603-018-1015-7
- 12.Ye M, Fu S, Pi R, He F. Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research. Journal of Pharmacy and Pharmacology. Published online July 2009:831-837. doi:10.1211/jpp.61.07.0001
27 thoughts on “n=1 on Escaping Torpor: Turning off PPAR gamma and turning on Fat Burning”
Great observations, Brad. Presumably one could tweak this by using metformin 1g in the mornings as a berberine replacement?
Yes! Metformin and Berberine have the same mechanism of action as I understand it.
Thanks for all the info. Are you taking anything like Milk Thistle to improve the berberine absorption?
I’m not but that’s an interesting suggestion.
What if one takes both metformin(2x500mgs) plus Berberine(2x600mgs). Will it have an additive effect?
My understanding is that the mechanism is the same, so I don’t know that it would be beneficial. But who knows?
In your first sentence under the “Results” heading you wrote, “Over the first two weeks of 1200 mg of berberine”. I think you meant sterculia oil instead of berberine. Feel free to delete this comment.
I’ve been finding your blog fascinating by the way. Thanks for being willing to be your own guinea pig.
Thanks for the feedback!
Chris Masterjohn, PhD posits that reducing PUFA to a minimal amount might co, . He says that the most important part of diet design should be getting all of your vitamins & minerals up to optimal levels and that if it comes down to a tradeoff between getting vitamins & minerals and increasing PUFA, one should increase PUFA (while still keeping it as minimal as possible). He says especially to have adequate levels of arachidonic acid (deficiency indicated by: eczema, anxiety, elevated stress response, poor immunity, gut function) & DHA (deficiencies: poor cognitive function, declining vision, peripheral neuropathy). Was wondering what you thought about this and how it relates to your worldview. Best.
Yikes, I didn’t finish the comment above before I posted it. I meant to say that Chris Masterjohn, PhD posits that reducing PUFAs too low might end up having the opposite effect that one is looking for.
I’m guessing that eggs would be good for that. Every brand of eggs that I have seen indicate that, in a large egg, one yolk has 4-5 gms of fat, but only 1.5 gm of that is sat. fat, the rest PUFA/Mono. What I do to bring up the sat. fat is add cheese, sour cream, butter to it.
One thing I’ve noticed based on the OmegaQuant test is that there are large differences in people’s D6D – a desaturase that is the limiting enzyme in converting linoleic acid (LA) to arachidonic acid (AA). I have twice as much linoleic as arachidonic, suggesting low levels. Many others I’ve seen have roughly equal amounts. But the range in different cultures is HUGE! Americans in 1962 had almost twice as much AA, the French in 2004 had equal amounts and rural Chinese in 1992 had more than three times as much LA. My numbers, for better or worse, look the most like the Chinese.
I followed The Zone Diet (and had best results with it) for 15 years before going low carb. He shouted from the rooftops of the dangers of arachidonic acid and warned of eating too many egg yolks. In fact he cooking only the whites in olive oil, and making deviled egg with hummus instead of yolk/mayo.
I know bodybuilders who buy arachidonic acid supplements (yes, it is a real thing) to enhance their training.
What are your thoughts on taking a PPAR-alpha agonist like fenofibrate instead?
Fenofibrate is certainly a potent and specific PPAR-a activator! It’s probably even better than berberine but you need a prescription! Someone also sent this. It both illuminates the relationship between fenofibrate and metformin but provides a potential natural alternative to fenofibrate. Very interesting:
You mentioned supplementing stearic acid: is this the powdered form from your shop and if so at what dosage?
What I sell is the purest food grade stuff available. The banana milkshake study showed mitochondrial fusion at 27g.
How much berberine are you taking in the mornings?
I’ve been taking 3000mg. Because why not?
What about CLA? Why or why not.
Am following in your footsteps.
CLA is good, I think. The fact that it’s relatively high in grassfed ruminants and dairy makes me think it’s a good, natural product. It definitely lowers SCD1 and I think there’s some evidence it raises PPAR alpha?
Brad- What kind of Berberine do you recomend? Brand? I read somewhere that they differ a lot in absorbtionrate.. I might remember it wrong though.
You’re probably right – absorption IS poor – but I’m no expert on brands! Lots of brands claim to have more absorbable versions…
I was just digging through some literature for something I’m writing up and thought I would pass along a study. This is about DHEA mentions DHEA as a potent PPAR-alpha activator.
Indeed it does. Interesting. I’ll add it to the list to research.
It’s exciting to see that you have moved your Desaturase index so significantly. Do you have thoughts here as to what you’re doing that is paying off?
How has your weight been? Are you seeing any correlation with body weight changes related to the decrease in your Desaturase index?
Well, keep in mind that my DI changed in my red blood cell membranes. As soon as I stopped taking sterculia oil, it went right back to what it had been. This suggests two things:
1) Red Blood Cell membranes is a more dynamic system that stored adipose tissue
2) It will take a long time to saturate our adipose
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