Bio-Hacking Leptin

I mentioned somewhere that I was leptin resistant somewhere and in the comments of the blog someone asked how I knew that I was. My immediate response was, “because I’m fat.” But also, “because I have a high desaturase index (DI), indicating high activity of the enzyme SCD1.”

A high DI is an indicator that you are leptin resistant. You are running your metabolism on the wrong enzymes. You are torpid.

Leptin is a hormone produced by fat cells. As you become fat, your levels of leptin go up. Animals need to store the right amount of fat. Enough to get through a period of food scarcity but not too much that it slows you down if you have to run from a lion. Leptin’s job is to keep you from storing too much fat. Leptin causes satiety by signalling in the hypothalamus, but this article is going to focus on leptin’s role in stimulating thermogenesis – the burning off of extra calories as heat.

This is admittedly dense with names of things.  Enzymes.  MicroRNAs.  Transcription factors.  Don’t worry about it too much.  Don’t try to memorize them.  Just follow the narrative.  I think it will come together at the end.

The Function of Leptin

The primary function of leptin in skeletal muscle is to increase the rate at which fat is burned.  Leptin does this both by directly binding the leptin receptor in the muscle tissue and by signalling in the hypothalamus which in turn stimulates the adrenergic receptors in the muscle tissue.​1​  Both the leptin receptor and the adrenergic receptor activate AMPK, a sensor of low cellular energy and/or high organismal energy (stored fat).  AMPK de-activates an enzyme called ACC which catalyzes the first step in lipogenesis (making fat).

The downstream effect of this action is increasing levels of an enzyme called CPT1 – the rate limiting enzyme that shuttles fat into the mitochondria.  It adds the fuel to the fire. Activating CPT1 and de-activating ACC increases the rate at which fat is burned.

When fat is burned quickly in the mitochondria, especially if the fat is highly saturated, Reactive Oxygen Species (ROS) are produced.  If enough ROS are produced, the redox state of the cell tips towards oxidized, which activates a transcription factor called Nrf2.​2,3​  Nrf2 does two very important things in this context.  It suppresses a desaturase enzyme called SCD1 which turns saturated fat into monounsaturated fat.  It also increases production of an uncoupling protein called UCP3.​4​

The primary source of thermogenesis (burning fat as heat) in humans is UCP3 in skeletal muscle.  UCP3 short circuits the mitochondrial “battery”, lowering the voltage across the inner and outer membrane, allowing energy to flow more easily through.​4​  Uncoupled mitochondria in skeletal muscle leads to an inefficient, wasteful metabolism where whenever you move around you waste calories as heat.  This is the way leptin keeps you lean.

The more ROS you produce, the higher the activity of NRF2 will go, the more UCP3 will be produced, the more heat you will burn.  Mice overexpressing Ucp3 in muscle have smaller fat depots and have increased energy metabolism.​5​  The balancing of the redox state of the cell by Nrf2 is a beautiful example of the body’s homeostatic mechanism.  It’s incredibly potent at relieving oxidative stress.  This is how all of these animals are living just fine in the long shadow of the Chernobyl disaster.

Avoiding Leptin

Hibernating animals have a vested interest in avoiding the fat burning effects of leptin.  In late summer they consume linoleic acid – the main polyunsaturated fat (PUFA)  in acorns and soybean oil – to enter a state of torpor.  Ground squirrels who do not consume enough linoleic acid fail to hibernate.

The echidna. An egg-laying mammalian hibernator. It gets torpid by eating hign-MUFA ants. ANy unsaturated fat will do if you eat enough of it.

Linoleic acid is a natural activator of a transcription factor called PPAR gamma – the body’s “master regulator of fat making”.​6​  Linoleic acid is prone to oxidation and in fact we have enzymes called lipoxygenases which convert linoleic acid into it’s oxidized metabolites (OXLAMs – Oxidized Linoleic Acid Metabolites).  Two of the most common of these metabolites – 9-HODE and 13-HODE – activate PPAR gamma nearly as strongly as the pharmaceutical PPAR activator Rosiglitazone.​7​  Rosiglitazone is used as a diabetic drug to reduce certain symptoms of diabetes.  A well known side effect of rosiglitazone is weight gain.​8​

PPAR gamma does several things to stop the fat burning effects of leptin.  The first one is that it switches on the “lipogenic” (fat making) genes.​9​  This includes activating ACC​10​ – the enzyme that AMPK de-activates in response to leptin.  So here you see leptin and PPAR gamma directly at odds.  ACC starts the process of taking fuel (Acetyl-CoA) out of the mitochondrial furnace and redirecting it towards fat making rather than fat burning.  It is aided by the other lipogenic genes – fatty acid synthase (FAS), elongase (ELOVL) and our friend SCD1.  Again – leptin lowers levels of SCD1 and PPAR gamma increases them – leptin and PPAR gamma are at odds.

The end products of ACC, FAS, ELOVL and SCD1 are saturated and monounsaturated fats.  FAS makes the 16 carbon saturated fat palmitate.  ELOVL – elongase – extends the 16 carbon palmitate into the 18 carbon stearic acid.  SCD1 desaturates stearic acid into oleic acid.  The relative activities of FAS, ELOVL and SCD1 determine amounts of saturated fat, monounsaturated fat, 16 carbon length fats and 18 carbon length fats.​9​  You can read the activity levels of the enzymes based on the signatures they leave in body fat composition.  The ratio of oleic acid to stearic acid is known as the desaturase index (DI18).  SCD1 also converts palmitic acid to the monounsaturated palmitoleic acid.  This is the DI16.

Oleic acid itself both upregulates and activates PPAR gamma.​9​  This is a positive feedback loop.  The enzymes that are increased by PPAR gamma make a product – oleic acid – which increases production and activity level of PPAR gamma.  Why?  During hibernation PUFA are preferentially oxidized.​11​  If the body fat of the animal becomes too saturated it will wake up from hibernation.  Once the animal is torpid, its prerogative is to remain torpid until winter is over.  So torpor is a self-reinforcing metabolic state.

The other thing PPAR gamma does in direct opposition to leptin is to increase the expression levels of microRNA 103​12​ and microRNA 122​13​.  A third microRNA – 107 – seems to be co-regulated with microRNA 103.  MicroRNAs 103 and 107 are upregulated in obese mouse models and directly affect insulin sensitivity.​14​  The more miRNA 103 and miRNA 107 that mice produce, the more insulin resistant they are.  miRNA 107 is a suppressor of CPT1​15​ – the rate limiting enzyme of fat burning that is increased by leptin signalling via AMPK.  

MicroRNA 122 is even more devious.  Part of leptin signalling is carried out through the transcription factor (turns on genes) STAT3.  Stat3 produces a protein called SOCS3, which suppresses leptin signalling.  This is a classic negative feedback loop.  Leptin signalling turns on a thing that turns off leptin signalling.  Increased SOCS3 causes leptin resistance.​16​  SOCS3 can be turned off by methylation of its promoter (epigenetics).  miRNA 122 causes the SOCS3 promoter to become unmethylated – turned on.  If you inhibit miRNA122, the SOCS3 promoter becomes methylated and SOCS3 is turned off.​15​  PPAR gamma causes leptin resistance by increasing expression of miRNA 122, which in turn allows expression of SOCS3.

Evidence in Humans

There is an incredibly tight correlation between the desaturase index in humans – the indicator of a torpid metabolism – and BMI.​17​ The muscle tissue of obese humans compared to that of lean humans has a high DI, burns less fat and stores more fat: PPAR gamma is in control.  The muscle tissue of obese humans is leptin resistant.​18​  Overexpressing SCD1 in muscle tissue from lean humans is sufficient to cause it to behave just like the muscle tissue of obese humans – burning less fat and storing more fat.  Thermogenesis in the muscle tissue of humans who have lost weight through caloric reduction drops dramatically and leptin restores it.

All of this makes human obesity look like a “nutrient partitioning disorder” – your muscle cells are making a choice to store fat rather than do thermogenesis.

The correlation between DI and BMI in humans.

Bio-Hacking Leptin

First you may want to test your Desaturase Index. I’ve been recommending the OmegaQuant Complete Test. It’s 100 bucks. You can compare your numbers to traditional cultures and to me.

Break The Cycle of Torpor

This is where sterculia oil comes in. Sterculia oil comes from the seed of a tropical tree that is eaten most everywhere that it grows. It is sometimes referred to as the java almond, although it is not a true nut. The seed is about 50% oil by weight. The primary fat in the oil is called sterculic acid. Sterculic acid blocks the enzyme SCD1, which breaks the cycle of torpor. Sterculia oil prevents fructose induced insulin resistance and liver fat accumulation in rats.

I have found that just 1200 mg of sterculia oil per day – two dropperfulls – breaks the cycle of torpor. It’s probably the equivalent of 2-4 seeds.

I saw a rapid decrease in my DI over 6 weeks of using SO. When I stopped taking it for 6 weeks, my DI rebounded to almost as high as it was at the start. The test measures the fats in red blood cell membranes. This is clearly a much more dynamic situation than stored body fat. I suspect that it will take months to change over the saturation level of your body fat and eliminate the extra monounsaturated fat. I’m not sure how many.

Stomp the Gas Pedal


Astaxanthin is a very interesting molecule.  It’s the red coloring from salmon, lobster and flamingos. It is said to be a potent antioxidant.

The term antioxidant is terribly misleading.  Did you know that the “antioxidant” vitamin C can be used as an oxidant source to generate hydrogen peroxide to kill cancer cells?​19​  Antioxidants are really “molecules that are involved in electron flow”.  Depending on the reaction, they flip back and forth between antioxidants and oxidants, giving and taking electrons as the situation warrants and depending on whether they are oxidized or reduced.  It’s more accurate to call antioxidants “redox active molecules”.  Life can be defined by the flow of electrons, so redox active molecules are central characters in the story of life.

Look where astaxanthin lives and what it does!!​20​

Astaxanthin localizes in mitochondrial membranes.  It crosses the entire membrane and is exposed on both sides.  It can transmit electrons like a tiny wire due to its conjugated bond configuration.  So it can directly bridge the voltage gap that turns the mitochondria into a battery and send electrons through!

It’s unclear exactly how this results in astaxanthin doing the things it does, but somehow it produces a small amount of ROS, resulting in an increase of Nrf2 and therefore increased UCP3 expression and therefore thermogenesis​21​.  It also leads to massively increased CPT1.  The WAY that it produces ROS might simply be its up-regulation of CPT1.

Did I mention that astaxanthin directly binds PPAR gamma and turns it off and directly binds PPAR alpha (the master regulator of fat burning) and turns it on?​22​  So there’s that.  That might be all there is to it, but the way it can bridge the mitochondrial membrane and send electrons through leads me to think there’s more to it.  This is a very active area of research at the moment.

Astaxanthin is well-absorbed enough to make a real difference in mammals.  In a mouse model it reduced SCD1 by 38% in liver and 25% in fat tissue; increased CPT1a almost five fold and CPT1b more than two-fold; increased UCP3 more than 50%!!​23​  That is fat burning and thermogenesis!  It also led to a small decrease in PPAR gamma and a small increase in PPAR alpha.

In human studies, UCP3 (thermogenesis) is rarely measured but Superoxide Dismutase (SOD) often is.  SOD is a crucial component of the body’s antioxidant system, so in human trials, when something increases SOD everyone says, “See, it worked because of antioxidants!”  SOD is controlled by Nrf2, so it is an indirect indicator of UCP3.​3​  So the next time you hear that it worked because of antioxidants, you’ll know that it REALLY worked because of thermogenesis.

With that in mind, a Korean study of overweight humans showed a steady increase in SOD levels that was still increasing at 3 weeks time.​24​  Astaxanthin induces thermogenesis in humans at levels that are easily achievable through supplementation and that builds over time.

I’ve been taking 12mg per day all at once with meals.


I’ve recommended berberine on this site before.  It’s a Chinese herb whose mechanism of action is (probably) partially blocking mitochondrial complex I​25​.  This creates a false sense of energy shortage in the cell.  Remember how I said that AMPK is a sensor of low cellular energy and high organismal energy?  Leptin signals high organismal energy – stored fat.  Berberine signals low cellular energy.  So it’s for opposite reasons but both things lead to the same result – activated AMPK.  AMPK de-activates ACC and activates CPT1.​10​

Human trials using berberine have shown weight loss and lowered LDL.​26​

Several people who have tried berberine have reported bad effects on their digestion.  If you have digestion issues you may want to skip this one.  Berberine has a short half life – 3 to 4 hours.  You might want to consider taking it more than once a day.  I’ve switched to mostly relying on astaxanthin for the purposes of activating metabolic rate but I still take 2000mg of berberine with my coffee some mornings, more or less at random.

One paper suggests combining berberine and astaxanthin.​27​

Let Off The Brakes!

Citrus Flavenoids

Citrus flavenoids work by reducing expression of miRNA 122​28​.  That’s right, they suppress the thing that increases the suppressor of leptin signalling.  Got it?

Citrus flavenoids are well absorbed.  They have a half-life of around 3 hours and return to baseline levels within around 24 hours. ​29​ Here I’d make an argument to use them several times per day.

In human trials, citrus flavenoids were shown to reduce waistlines and increase SOD.​30​  Thermogenesis!!

Since the regulation in microRNA 122 is controlled through epigenetics, think of it as a slow-moving change.  It will slowly improve over time.

I’ve been taking 500 mg hesperidin.  Once I’m done writing this it’s margarita night.


Resveratrol is famously found in red wine.  But you’d have to drink about 40 liters per day to get 500mg.  Even I can’t drink that much red wine.

Resveratrol reduced the expression of miRNA 103, 107 AND 122 by more than half when rats eating an obesigenic diet were supplemented with it.​15​  The rats supplemented with resveratrol had a more than two-fold increase of CPT1 in their livers.  Fat burning!!

In human trials, resveratrol supplementation increased the levels of Nrf2 and SOD.​21,31​ Thermogenesis!!

Resveratrol is relatively well absorbed but 99% gets metabolized by the intestines and liver.  Nonetheless, this doesn’t seem to stop it from increasing thermogenesis in humans.  Like the other polyphenols, it has a short half life in humans – a couple of hours – so this one may make sense to supplement several times during the day.​32​

I’ve been taking 500 mg.

How’s It Going For Me?

At the moment my metabolic testing device is broken, so I unfortunately don’t have that data.

Around 10 days ago my body temperature hit 98.6.  It’s been that way ever since.  The range of temperatures I’ve measured in the afternoon are between 98.4 and 99.1.  Just now it was 98.8. 

I’ve been eating one meal a day of meat and potatoes around 5PM.  Around a pound and a half each of meat and potatoes.  I’ve been eating a lot of Firebrand Meats Low-PUFA rump steak because I had it and because It’s delicious.  I’ve been boiling the potatoes in broth with salt and then I let the broth cook down and it makes a poor man’s gravy.  Desert is a stearic acid shake and red wine.  I figure I’m consuming around 3000 calories per day, fairly low in fat.

I’m not struggling with hunger during the day.  I hope this means I’m getting a bit more leptin sensitive.  The scale seems to be dropping – perhaps a lb or two a week.  My fasting blood glucose – which had been high (around 120) is now dropping a bit.  It was just 100 even.  Not ideal but for me that’s pretty good.  

So everything seems like it’s heading in the right direction? 

  1. 1.
    Minokoshi Y, Okamoto S, Toda C. Regulatory role of leptin in glucose and lipid metabolism in skeletal muscle. Indian J Endocr Metab. Published online 2012:562. doi:10.4103/2230-8210.105573
  2. 2.
    Deshmukh P, Unni S, Krishnappa G, Padmanabhan B. The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases. Biophys Rev. Published online December 6, 2016:41-56. doi:10.1007/s12551-016-0244-4
  3. 3.
    Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends in Biochemical Sciences. Published online April 2014:199-218. doi:10.1016/j.tibs.2014.02.002
  4. 4.
    Dinkova-Kostova AT, Abramov AY. The emerging role of Nrf2 in mitochondrial function. Free Radical Biology and Medicine. Published online November 2015:179-188. doi:10.1016/j.freeradbiomed.2015.04.036
  5. 5.
    Horvath TL, Diano S, Miyamoto S, et al. Uncoupling proteins-2 and 3 influence obesity and inflammation in transgenic mice. Int J Obes. Published online March 27, 2003:433-442. doi:10.1038/sj.ijo.0802257
  6. 6.
    Yu C, Chen L, Luo H, et al. Binding analyses between Human PPARgamma-LBD and ligands. Surface plasmon resonance biosensor assay correlating with circular dichroic spectroscopy determination and molecular docking. Eur J Biochem. Published online January 2004:386-397. doi:10.1046/j.1432-1033.2003.03937.x
  7. 7.
    Vangaveti V, Shashidhar V, Collier F, et al. 9- and 13-HODE regulate fatty acid binding protein-4 in human macrophages, but does not involve HODE/GPR132 axis in PPAR-γ regulation of FABP4. Therapeutic Advances in Endocrinology. Published online February 27, 2018:137-150. doi:10.1177/2042018818759894
  8. 8.
    Chaput E, Saladin R, Silvestre M, Edgar AD. Fenofibrate and Rosiglitazone Lower Serum Triglycerides with Opposing Effects on Body Weight. Biochemical and Biophysical Research Communications. Published online May 2000:445-450. doi:10.1006/bbrc.2000.2647
  9. 9.
    Kobayashi T, Fujimori K. Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPARγ in 3T3-L1 cells. American Journal of Physiology-Endocrinology and Metabolism. Published online June 15, 2012:E1461-E1471. doi:10.1152/ajpendo.00623.2011
  10. 10.
    Thampy GK, Haas MJ, Mooradian AD. Troglitazone stimulates acetyl-CoA carboxylase activity through a post-translational mechanism. Life Sciences. Published online December 2000:699-708. doi:10.1016/s0024-3205(00)00973-5
  11. 11.
    Rosner E, Voigt CC. Oxidation of linoleic and palmitic acid in pre-hibernating and hibernating common noctule bats revealed by 13C breath testing. Journal of Experimental Biology. Published online January 1, 2017. doi:10.1242/jeb.168096
  12. 12.
    John E, Wienecke-Baldacchino A, Liivrand M, Heinäniemi M, Carlberg C, Sinkkonen L. Dataset integration identifies transcriptional regulation of microRNA genes by PPARγ in differentiating mouse 3T3-L1 adipocytes. Nucleic Acids Research. Published online February 7, 2012:4446-4460. doi:10.1093/nar/gks025
  13. 13.
    Song K, Han C, Zhang J, et al. Epigenetic regulation of MicroRNA-122 by peroxisome proliferator activated receptor-gamma and hepatitis b virus X protein in hepatocellular carcinoma cells. Hepatology. Published online September 17, 2013:1681-1692. doi:10.1002/hep.26514
  14. 14.
    Trajkovski M, Hausser J, Soutschek J, et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature. Published online June 2011:649-653. doi:10.1038/nature10112
  15. 15.
    Gracia A, Fernández-Quintela A, Miranda J, Eseberri I, González M, Portillo MP. Are miRNA-103, miRNA-107 and miRNA-122 Involved in the Prevention of Liver Steatosis Induced by Resveratrol? Nutrients. Published online April 4, 2017:360. doi:10.3390/nu9040360
  16. 16.
    Olofsson LE, Unger EK, Cheung CC, Xu AW. Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance. Proceedings of the National Academy of Sciences. Published online February 5, 2013:E697-E706. doi:10.1073/pnas.1218284110
  17. 17.
    Mika A, Kaska L, Korczynska J, et al. Visceral and subcutaneous adipose tissue stearoyl-CoA desaturase-1 mRNA levels and fatty acid desaturation index positively correlate with BMI in morbidly obese women. Eur J Lipid Sci Technol. Published online February 4, 2015:926-932. doi:10.1002/ejlt.201400372
  18. 18.
    Steinberg GR, Parolin ML, Heigenhauser GJF, Dyck DJ. Leptin increases FA oxidation in lean but not obese human  skeletal muscle: evidence of peripheral leptin resistance. American Journal of Physiology-Endocrinology and Metabolism. Published online July 1, 2002:E187-E192. doi:10.1152/ajpendo.00542.2001
  19. 19.
    Bonilla-Porras AR, Jimenez-Del-Rio M, Velez-Pardo C. Vitamin K3 and vitamin C alone or in combination induced apoptosis in leukemia cells by a similar oxidative stress signalling mechanism. Cancer Cell International. Published online 2011:19. doi:10.1186/1475-2867-11-19
  20. 20.
    Kidd P. Astaxanthin, cell membrane nutrient with diverse clinical benefits and anti-aging potential. Altern Med Rev. 2011;16(4):355-364.
  21. 21.
    Niu T, Xuan R, Jiang L, et al. Astaxanthin Induces the Nrf2/HO-1 Antioxidant Pathway in Human Umbilical Vein Endothelial Cells by Generating Trace Amounts of ROS. J Agric Food Chem. Published online February 6, 2018:1551-1559. doi:10.1021/acs.jafc.7b05493
  22. 22.
    Jia Y, Kim J-Y, Jun H-J, et al. The natural carotenoid astaxanthin, a PPAR-α agonist and PPAR-γ antagonist, reduces hepatic lipid accumulation by rewiring the transcriptome in lipid-loaded hepatocytes. Mol Nutr Food Res. Published online June 2012:878-888. doi:10.1002/mnfr.201100798
  23. 23.
    Kim B, Farruggia C, Ku CS, et al. Astaxanthin inhibits inflammation and fibrosis in the liver and adipose tissue of mouse models of diet-induced obesity and nonalcoholic steatohepatitis. The Journal of Nutritional Biochemistry. Published online May 2017:27-35. doi:10.1016/j.jnutbio.2016.01.006
  24. 24.
    Choi HD, Kim JH, Chang MJ, Kyu-Youn Y, Shin WG. Effects of Astaxanthin on Oxidative Stress in Overweight and Obese Adults. Phytother Res. Published online April 8, 2011:1813-1818. doi:10.1002/ptr.3494
  25. 25.
    Turner N, Li J-Y, Gosby A, et al. Berberine and Its More Biologically Available Derivative, Dihydroberberine, Inhibit Mitochondrial Respiratory Complex I: A Mechanism for the Action of Berberine to Activate AMP-Activated Protein Kinase and Improve Insulin Action. Diabetes. Published online February 19, 2008:1414-1418. doi:10.2337/db07-1552
  26. 26.
    Derosa G, D’Angelo A, Bonaventura A, Bianchi L, Romano D, Maffioli P. Effects of berberine on lipid profile in subjects with low cardiovascular risk. Expert Opinion on Biological Therapy. Published online February 27, 2013:475-482. doi:10.1517/14712598.2013.776037
  27. 27.
    DiNicolantonio JJ, McCarty M, OKeefe J. Astaxanthin plus berberine: a nutraceutical strategy for replicating the benefits of a metformin/fibrate regimen in metabolic syndrome. Open Heart. Published online August 2019:e000977. doi:10.1136/openhrt-2018-000977
  28. 28.
    Su D, Liu H, Qi X, Dong L, Zhang R, Zhang J. Citrus peel flavonoids improve lipid metabolism by inhibiting miR-33 and miR-122 expression in HepG2 cells. Bioscience, Biotechnology, and Biochemistry. Published online September 2, 2019:1747-1755. doi:10.1080/09168451.2019.1608807
  29. 29.
    Khan MK, Zill-E-Huma, Dangles O. A comprehensive review on flavanones, the major citrus polyphenols. Journal of Food Composition and Analysis. Published online February 2014:85-104. doi:10.1016/j.jfca.2013.11.004
  30. 30.
    Dallas C, Gerbi A, Elbez Y, Caillard P, Zamaria N, Cloarec M. Clinical Study to Assess the Efficacy and Safety of a Citrus Polyphenolic Extract of Red Orange, Grapefruit, and Orange (Sinetrol-XPur) on Weight Management and Metabolic Parameters in Healthy Overweight Individuals. Phytother Res. Published online April 3, 2013:212-218. doi:10.1002/ptr.4981
  31. 31.
    Seyyedebrahimi S, Khodabandehloo H, Nasli Esfahani E, Meshkani R. The effects of resveratrol on markers of oxidative stress in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial. Acta Diabetol. Published online January 22, 2018:341-353. doi:10.1007/s00592-017-1098-3
  32. 32.
    Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK. HIGH ABSORPTION BUT VERY LOW BIOAVAILABILITY OF ORAL RESVERATROL IN HUMANS. Drug Metab Dispos. Published online August 27, 2004:1377-1382. doi:10.1124/dmd.104.000885

58 thoughts on “Bio-Hacking Leptin”

    1. Yes, that is “the banana milkshake study”, as I call it. Good stuff! And coconut oil has almost no stearic acid, I’ve yet to fully embrace it although I’m open to being wrong, it IS very low in PUFA (and MUFA).

  1. After reading Dr. Greger’s book, I gave vinegar a try. It’s supposed to increase AMPK, but I didn’t see any change in the thermometer. Have to give these a try. Great stuff!

  2. I haven’t totally confirmed this yet, but I feel like taking berberine in a fasted state tanks my blood sugar. Does that make sense, given the mechanisms it interacts with?

    1. Yeah, I could totally see that. My blood sugar tends to remain high in general.

    2. I had some hypoglycemia issues when I would take berberine in the evening and then go on a long walk.

  3. Something I’ve been wondering about is, how do hibernating mammals get out of torpor, and could we use whatever strategy they use? Do they just lose all of their body fat, or is there a cutoff point where if your body fat gets low enough the feedback loop ends?

    1. This. PUFA are oxidized preferentially. If we went on a long enough fast, our remaining stores of fat would be highly saturated. To me, it seems that nature shows us our way out of torpor. I’d love to hear more about the metabolic shift animals undergo after hibernation.

      I’m surprised no one has suggested fasting to cure torpor yet. It works for hibernating mammals, why not us?

      1. Actually, Max in the comment threads HAS been suggesting it. I have my doubts – humans aren’t squirrels, we’re large bodied mammals, closer to bears. Bears emerge in the spring after a six month fast still with large fat stores (this is when Native Americans hunted them) and still torpid based on their DI. Of course their metabolic rate drops very far in the winter and so will yours if you fast that long.


    2. This is certainly an area of future research. They definitely switch their molecular machinery back around but I’m not sure if the trigger is in fact increasing saturation or lowered body fat or something that is triggered by weather.

  4. What do you think of the results presented in this study:
    Ramadan diurnal intermittent fasting modulates SOD2, TFAM, Nrf2, and sirtuins (SIRT1, SIRT3) gene expressions in subjects with overweight and obesity
    I’m not able to see the data but it seems interesting.

    1. That IS interesting. That is similar to the IF protocol I’m doing. It’s multifaceted, but the increase in Nrf2 is intriguing.

  5. Brendan-not Brad, but I’ve heard doctors say this (re: when your body fat gets so low, it actually raises your metabolism). Specifically, the author of “the five bite diet” makes this claim.
    Seems hard to believe, but it must be related to this (and maybe getting rid of all PUFA)?
    I’ve known anorexics, that had to eat 4K calories+ a day, while trying to recover, and still have a hard time gaining weight.

    1. That is an interesting anecdote! Maybe anorexic level fasting could work, but I’d have real concerns about metabolic issues going forward.

    2. Yes, this was my experience last year while losing weight. I am a 45 year old woman, and as expected I had to gradually lower my calories over 9 months until I lost 55 lbs. Once I had a normal BMI, my appetite suddenly increased and I discovered that I could eat 500 more calories and still lose weight slowly. Almost a year later, I’m averaging 700 more calories than my lowest during weight-loss and maintaining the loss. Hopefully, the trend continues! My BIL said that once he lost his extra weight, it was like a switch flipped and he began to struggle to keep weight on.

  6. Brad,
    Thanks for all the work you do connecting these dots!
    Question—wasn’t the resveratrol research falsified?

    1. It’s possible that there was a resveratrol study with falsified data but there is quite a body of evidence for resveratrol in rodents and humans. What’s interesting is that resveratrol seems to have positive effects on insulin sensitivity yet mechanistically what it’s doing is preventing leptin resistance. This suggests an insulin-leptin connection. Interestingly, leptin and insulin both activate the PI3K/Akt pathway. Hmmmm…..

  7. Hi, do you know where I can buy unprocessed Java Almonds/Sterculia seeds? I’ve bought two bottles of your Sterculia oil, they work great for my body temperature (has gone up about half of a degree F since I started taking this stuff three weeks ago) but I want to try the original seed.

    1. I think there is a nursery on Amazon that sells small packets of the seeds to grow as nursery plants.

  8. John St Pierre

    Hi Brad,
    Found you through the Peak Human podcast and all I have to say is Wow! My question is, is there a list out there that you can point to that shows the linoleic acids / PUFA amounts in most or all foods? There has to be a good comprehensive one out there? (anyone know of one?) I have been Keto for years now and stuck at a point where the fat loss has stopped and I still have weight to lose. Very frustrating till I found your information. You mentioned popcorn as in your can eat it, is that true? Doesn’t corn have too much PUFAs? Does that go with mustard as well? I am giving this type of way of eating a full year to see what happens. Again, please help me find a good comprehensive list of PUFA amounts in most foods (outside of obviously processed foods). Like mustard and popcorn etc for example. This content is absolutely as huge as the content I found with Morely Robbins and mineral functions within the mitochondria, and Jim Stevenson Jr with Vitamin D. Absolutely game changing stuff. Thanks Brad!
    John S in Victoria BC

    1. Thank you! I honestly don’t know of one but it’s a good idea for a post, I’ll put one together soon. In the meantime, this is my go to reference: “PUFA 18:2 c” is the listing for linoleic acid. If you stick with 100g portion sizes (the default), that number becomes a percentage.

      As to popcorn… The fat in popcorn is high in PUFA and corn is relatively high in oil FOR A GRAIN. But grains are low in fat in general. Pocporn is 4.5%. If you are a growing pig getting 75% of your calories from popcorn this small can accumulate. But 100g of popcorn has 2.25g of linoleic acid – the exact same amount as 100g of butter.

      Lastly, I will say that your personal response to the diet in terms of weight loss will be highly dependent on how leptin resistant/torpid/etc you are. You should probably at a minimum get your DI tested.


  9. Couldn’t we also try to bio-hack leptin resistance by seeking to increase leptin sensitivity? (Thank you for all the references, reading them now!)

    1. This is actually the point. Using citrus flavenoids to reduce SOCS3, we are reducing the factor that causes the resistance to leptin signalling. By re-saturating our fat stores, we will give leptin the ability to drive ROS production again.

      By mimicking leptin now, the end goal is to ultimately become sensitive to it again.

  10. Great article.

    We might be missing the forest for the trees though. Using all these herbs and eating more saturated fat etc is great and all. How about ending torpor al naturale? That js by not eating. Isn’t that how torpor ends in an animal come the end of winter? They don’t eat for the whole time and they lose a ton of weight. Then come spring they eat foods that are more saturated etc.

    Instead of trying to fix a cog wheel while its running by throwing sat fats and cocktails of herbs how bout use the most potent medicine known to end torpor? Fasting.

    Once you fast your fat to the bone you can resume your eating by eating saturated foods and remain lean. Your leptin resistance will fade away. Perhaps that’s all there is to it.

    I hate to sound like a broken record hut seriosuly burn all your “bad” fat fasting until you’re out of torpor or e.g. 12% body fat and when you go back to eating stay away from seed oils and linoleic acid? Heck throw in the berberine and sterculia also if you think the train tracks need to be mended.

    I really think fasting is more powerful than any herb you might consume. If you think about it trying to fix your body with herbs is kind of ridiculous. The body is more complex than you think. Throwing in some herbs into the complex machinery of metabolism is like trying to make the ocean less salty by throwing a glass of fresh water in it. Fasting or not eating or “hibernating ” is the best way to stop the gears so you can change or fix the system or reboot. It doesn’t have to be rocket science.

    Would you rather believe in order to fix post obesity you must intake a coktail of herbs after years of scientific experimentation because tje body is simply too stupid to fix itself after you’ve messed it up, or would you rather believe that the body is actually frickin smart smarter than you think and its already capable of fixing itself if you actually do what would be normal and not eat? Occam’d razor people.

    1. I’ve lost 40 pounds twice recently through fasting. The short amount of time it took to regain that weight was shocking. I probably had another 20-30 pounds to lose before I would have been lean.

      Point being, it’s not easy to fast yourself to the bone, especially if you’ve been fat for a long time. Your body is fighting you the whole way.

      The more you fast the more you de-saturate the fat you already have. Unless you can go all the way, it might be safer to just take a detour to end up in the same place.

      1. I would appreciate a source on fasting and SCD1, if you have one. Either way, assuming that it is true, it makes sense as a defense mechanism to make sure we “hibernate through winter.” Either way PUFA is burned preferentially, PUFA<-MUFA<-SFA. If you fast and desaturate your fat, you'll be burning through your PUFA stores which is the worst for you metabolism. After the PUFA is gone (or low), the body will burn more MUFA, which won't have as bad PUFA oxidation detox symptoms during the fast, so it does get easier.
        Also, if desaturation is an issue, why not take calorie free SCD1 inhibitors during the fast? Take berberine and Pu'erh tea in the morning, and you might find you burn through your winter PUFA & MUFA quicker (in theory).

    2. Perhaps this could work for some. I suspect most don’t have the iron will this would require. I know that I don’t. Nor am I certain that fasting would fix the torpid metabolism. It works for squirrels, but I’m not convinced bears – large body hibernators like us – ever come out of it.

      Also, fasting has the unfortunate consequence of a huge metabolic drop.

      1. Most studies I’ve seen on fasting show a short-term increase in metabolism the first few days — it’s only after you go over the 120h mark where your TDEE starts going below its baseline. I suspect that a strict fasting cycle of doing 72-96h fasts, refeeding well above your TDEE for a couple of days, and then resuming the cycle for a few years will eventually fix your leptin reception/metabolism if you’re not eating a lot of triglycerides and Omega-6s.

        My body temperature before I started a fasting regime in March was in the low 97s. My fasting regime is OMAD for a couple of days, eating above maintenance and doing HIIT/strength training those days. Then I do a 72-96h fast. My body temperature crept up to the high 97s during this period of time until about three weeks ago, when I started taking Brad’s Sterculia Oil/Butter substitute and it shot up to the mid-98s. I eat mainly keto, though I also pig out on starches now and again. I have not eaten anything with fructose or ethanol except were it creeps into everyday products like fast-food cheese. Until three weeks ago I have not paid any attention to Omega-6s.

        What I’m getting at is that while I do think that, if you’re careful, you can repair your metabolism just with fasting/exercise/diet. But… you know, why wait? Why do in six months (estimated time to raise body temperature by a degree with my fasting + exercise + no sugar/low carb) regime what I could do in three weeks (that with coming out of torpor)?

        That said, I’m mostly interested in coming out of metabolic torpor for increased energy. Getting down to a proper weight and sustaining it is all well and good, but if my TDEE is now permanently at 1700 calories and my body temperature is at around 97.5F as a 6′, reasonably muscular, otherwise healthy male then something else needs to be fixed besides my BF%. I want the increased energy so I can do more in my time off from work. I do rotating shifts right now and I have about 2.5h between shifts that I’m basically just using to unwind. I’d like to increase my increase not just to get to 3.5h (by sleeping only seven hours a night, RN my body really does need eight to recover from the high level of physical activity) but also to make those 3.5h more productive. Cutting out breakfast and dinner has helped a lot, but I’m still mostly just in ‘zombie mode’ where the last thing my body wants to do is work out or study.

        1. > That said, I’m mostly interested in coming out of metabolic torpor for increased energy.

          I’m glad to hear someone else with this goal as well. I’m in the same boat. My oral temp usually fluctuates around a 24-hour daily average of 97.0 F. I’m skinny fat (my total bodyweight is nearly ideal, but I’m probably about 20% bodyfat, and my DI was 1.9 as of a couple months ago). I’m also constantly struggling with fatigue regardless of diet–carnivore, keto, TCD, etc.

    3. In The Immunity Code Joel Greene (the other Peak Human guy) makes the claim the running a calorie deficit is actually worse for you. Fasting would be the ultimate calorie deficit. He says the fat cells are held in place by the extracellular matrix, and shrinking them down goobers up the ECM. He uses the analogy of a brick wall where the bricks are fat cells and the mortar is the ECM. If the bricks shrink the the wall becomes unstable. The body treats fat loss as an injury, so it promotes inflammation as an immune response.

      Brad , have you tried cooling the potatoes to make resistant starch?

      1. The entire point of fat stores is to provide energy when there is a calorie deficit. The ECM is flexible and not at all like a brick wall. Fat loss always results in lower inflammation, not higher. The idea that the body treats fat loss as a injury makes no sense from an evolutionary viewpoint.

      2. I’ve thought about cooling the potatoes to make resistant starch. Does that count?

        1. Refrigerate overnight to get more resistant starch. There are some resistant starches even in cooked/baked/boiled potatoes but the amount increases dramatically by chilling plus time. Apparently steaming is better than boiling and roasting is even better than both, plus chilling afterwards. So you could pre-cook/bake a big batch, portion, stick in the fridge and eat over several days. Pretty much what David Tillman is doing. I have kept cooked potatoes chilled in the fridge for 4-5 days without a problem. I find them more filling chilled than freshly cooked.

          Then there is the camp that says reheating them won’t affect the RS, another camp says it will. If you just warm them before eating it should be ok. You can rechill left overs again. In summer I eat them cold. You can make a quick potato salad on the spot with a dressing made of Kefir or yogurt, plus sour cream, salt, pepper and herbs, maybe some lemon juice or mustard poured over the cold potatoes just before serving. No seed oils in the dressing.

          Or you can add some raw potato starch which has about 65% RS, as long as you don’t heat it. It loses its RS once cooked, even when chilled again after cooking. You can put straight potato starch in smoothies or the SA shake. Makes them smoother, you won’t taste the starch. Mind you, when I use it I only add about 10-15 grams of it per portion. It has to be potato starch and not potato flour.

          Everything else you need to know about RS is here

          There is a link up top that is basically a guide to all things RS plus a link in the text to a pdf with a more detailed list of foods and RS content.

    4. It seems like we cant always fix a problem that comes from unnatural causes (evolutionarily inconsistently high levels of PUFA intake causing extreme states of torpor which become much harder to get out of) wont always be easily fixed by the usual natural solution. It’s hard to say, but its possible some of us have been pushed a little too far to get out the simple way.

  11. I’m sure from reading some Ray Peat information in the dim and distant past that he recommends improving thyroid levels to increase body temperature and get out or torpor.

    1. At the end of the day, uncoupling seems to be the mechanism by which metabolic rate is improved. Yes, DNP is an example of this, but they’ve taken it off the market – it was too effective and apparently some people were killed due to excessive internal heat production. Also, I think getting our enzyme systems working again is probably a better long term solution than DNP.


    1. Kind of arbitrary, honestly. I think I saw an article about it first and then bought some. I’m not sure it’s better.

    1. The human study I linked to in the article showed a near doubling in superoxide dismutase levels in obese subjects in three weeks at only five grams!

      1. 5mg of Astaxanthin. Not grams. Also the level of Astaxanthin seemed to keep going up. Supplementation over a longer term may yield even better results. Looks like loading in the first week with the higher dose (20mg/day) would also get you there faster. Then after week 1 reduce to 5mg a day for maintenance.

        Interesting in that paper that the obese group eats less fat, less protein, but more carbs and fiber vs the overweight group. And has much higher cholesterol. Too bad they did not gather that data for the control group.

  12. I can only speak for myself and people I know. I have a super fast metabolism. I went up 20lbs and lost it all in 14 days fasting on and off 48s. It was easy peasy. It takes me months to gain weight and it’s a struggle. Not eating for a whole day can be daunting at first but you would be surprised how easy it is. And all the extra time you have. 48s or 72s are easy. 96s are a bit tough with day dreaming of food. But it also makes you appreciate food a lot.

    My friend who for my whole life I knew to be fat and “torpid” or “slow metabolism” or easy gainer who loves food and wish he didn’t gain so easily, we all know one of those or I am sure a lot of people here are like that, lost all his weight to normal levels fasting 48s 72s then eating and rinse wash and repeat. Its easy because you can eat all you want when you refeed but then you can’t eat so much because you only have so much stomach to eat in one sitting. So you end up burning tons of fat. That’s how animals in the wild eat. They don’t have refrigerators and stuff. They have to eat as much in one sitting. And may not eat for days because they don’t get lucky with another kill or they can’t store the food. So they are forced to fast.

    He’s now 180lbs from always being 230 250 etc. Its crazy to see him skinny actually. His IG photos seems photoshopped.

    It’s funny cause I had been telling him why don’t you fast. Its easy. Etc but people don’t listen until they want to listen or find out for themselves. But now he’s so into it and even I am wondering what he did. And basically just that fasting for as long as you can before you cant do it anymore, eat, and fast again. Until you fast to the bone.

    Now he just eats omad to mantain. He even eats seed oils without care. He doesnt even know any of this. Fasting is just that powerful. I mean your not eating and you still need energy so literally your bound to lose fat no matter what.

    I don’t think it takes an iron will. It’s just 1 day. If you can do 1 day without eating and make it. You can do it. Once you clear a day 2 days doesn’t seem that hard. Just try 1 day and it will be eye so opening its dumb

    Anyway I love these articles. I love the science brad breaks down and reading how stuff works. And I love how east he makes it to understand. I feel though the ovbious should be ruled out first before its dismissed for more complicated methods. That’s what’s wrong with modern medicine. Trying to fix a b c d e with x y z and g. When doing just one thing can solve it. And its funny cause the one thing your doing is actually literally doing nothing. That’s the beauty of it.

    There might be something to all these supplements and breaking the cycle of torpor but if you havent tried fasting which is the 1st logical step into getting out of torpor then your not being logical or your not really wanting it bad enough or maybe you have legitimate concerns, but mostly its the 1st two. Anyway. Thats my 2 cents

    1. Not everyone is the same. I experimented with a year of fasting for a week a month, and while I did lose weight, I also damaged my small intestine, and it’s never been the same.

    2. I plan on doing both. My <100 calorie limit on fasting days is spent on supplements and Brad's Sterculia butter. I've lost about 50 pounds in 12 weeks of OMAD + extended water fasts, but it's only been very recently where I've gotten my body temperature up to 98.5F.

      Moreover, while I suspect that eating keto and cutting out fructose and dropping visceral fat will eventually overpower the leptin resistance and torpor mechanisms of high Omega-6s/long-chain trigylcerides after my bodyfat becomes more saturated simply by losing excess weight… why wait? I don't want just the six-pack, I want the increased energy. TBH if I had to choice, I'd rather look like a potato-man but have the energy I had as a 16-year old than look like I did in my early twenties but had a 1700 calorie sedentary TDEE with an energy level to match.

      1. I know what you mean about wanting more energy. I only feel that way when I eat enough calories. Otherwìse im lethargic and even get depressed or have anxiety. I’ve never really had much appetite my whole life. I am not sure why. But if I eat a hefty meal of carbs and meats I’ll have so much energy. I think being in a calory deficit and having energy is kind of impossible for me. So you may want to pay attention to your mood and energy according to how much you’ve eaten.

        Of course if I eat a lot of carbs and meat I dont get fat anyway. I simply put on tons of glycogen in my muscles and get rather hot. My body feels more cold during deficits like its shutting down.

  13. I’ve followed your blog and your insights for the last year and really enjoyed what I’ve read and the changes I’ve seen. I don’t have the scientific background to really dig into the cellular mechanisms, but I’d like to suggest another angle to consider. Every significant female hormone shift is accompanied by a positive feedback loop that causes weight gain that is primarily fat. The reasons for this are evolutionarily evident–puberty, pregnancy, and menopause all require that extra fat. If you were to take a picture of women from 100 years ago, you would see a good number of comfortable, matronly looking women of all ages (not saying that women today aren’t significantly larger, just that this type of weight gain is normal).

    With that in mind, one huge change that happened in the 1970s, when resting metabolic rate started to go down and obesity started to skyrocket, was the wide availability of hormonal contraception. In 1972, the Supreme Court made hormonal contraception available to unmarried women. By the 1980s and 90s, it had become extremely common among all women of child-bearing age. Although drug companies deny that excess weight gain is a significant effect, anecdotal evidence as well as knowledge of what hormonal shifts in women are designed to do make me doubt that.

    Trace amounts of these contraceptives have been found in city water supplies. This has caused interesting issues with fish in the Potomac (3/4 of certain types becoming intersex). I think these hormones–even in trace amounts–are the key to why torpor and obesity have skyrocketed. I don’t know what could be done about it on an individual level, although changing your saturated fat index is certainly a key.

    For me personally, when I’ve been caught in a positive feedback loop (both after pregnancy and in perimenopause), when nothing else has worked, I’ve done a fat fast which somehow signaled to my body that it could end the loop and function in a more normal way. Most recently I’ve done a saturated fat fast (cocoa butter and stearic acid in tea, about 2000 calories a day), which has reversed the steady weight gain that has come with each cycle over the last year. I’ve yet to see if this is sustainable, but from previous experiences, I think it will be.

    1. Interesting points. Certainly hormones play a role in all of this. I’m not trying to be an expert at everything, though, I stay in my rabbit hole 🙂

    1. Hi Brad,

      First time commenting, I’ve been really enjoying the blog and appreciating all your hard work. Thanks!

      In this post, you’ve extolled the virtues of astaxanthin and in the past you’ve written that fish oil stimulates PPARa and inhibits SCD1. This leads me to conclude that wild salmon is a highly thermogenic food from an epigenetic / informational perspective.

      Have you considered Alaskan bears gorging themselves on salmon before hibernation?

      Do the high levels of 03 PUFA send the bear straight into torpor by failing to generate ROS at the mitochondrial level?

      Or does the DHA/EPA and astaxanthin counteract the high PUFA to some degree?

      Are the bears forced to seek out a source of PUFA that isn’t “buffered” by thermogenic compounds (astaxanthin)?

      My instinct based on, your work, the protons thread and the obvious reality that bears hibernate through the Alaskan winter is that the lack of mitochondrial ROS is a first order driver of obesity/torpor and the epigenetic effects from the fish oil and astaxanthin are secondary. Curious to hear your thoughts on this scenario (salmon feasting).

      1. Actually, my next article is about Omega 3 and torpor, so your comment is well timed. It’s a U-shaped curve. A LITTLE bit of PUFA lowers SCD1. A LOT of PUFA raises SCD1. This is true of all PUFA but probably even more true of EPA and DHA in salmon. Unlike resveratrol in wine, astaxanthin is present in salmon in amounts that are absolutely biologically relevant, especially considering how much salmon bears eat.

        Yet we can see at the end of the day, salmon make bears torpid. So we have to conclude that the torpor promoting effects of DHA and EPA taken in large doses outweigh the torpor preventing effects of astaxanthin.

        As to mitochondrial ROS… Yes, that is at the basis of all of this. And like I say, PUFA is the trigger for torpor – which upregulates SCD1, desaturating our body fat. SO it starts with PUFA but ends with eliminating out stearic acid stores and replacing them with oleic acid.

        1. Would taking sterculia oil when eating salmon possibly mitigate the torpor inducing effects of the DHA and EPA?

          What about eating a moderate amount of wild salmon (around 100 grams), plus taking some pure stearic acid and additional astaxanthin (12 mg)?

      2. Brad,

        Also curious if you’ve heard of molecular hydrogen / hydrogen rich water?

        Interesting properties of molecular hydrogen (H2):

        Smallest molecule in universe, can freely diffuse through entire body and into individual cellular components

        Selective antioxidant, scavenges damaging hydroxyl and peroxinitrite free radicals while ignoring redox signaling molecules (NO, H2O2)

        Signaling molecule, activateS Nrf2 and PGC1a

        Appears to modulate excessive autophagy

        Here is a nice review of the mechanisms:

        Loads more information available from Tyler Lebaron and the Molecular Hydrogen Institute.

        It seems to me that H2 has an amazing safety profile and appears regulate (but not block) oxidative stress and autophagy while treating metabolic syndrome. I’m curious if/how you think it may fit into your metabolic repair protocol?


  14. Heya Brad, love your work, and the pork is great!

    I just wanted to point something out about your diagram of astaxanthan spanning the membrane. Your text mentions that’s a mitochondrial membrane, but I looked at footnote 20’s original source, and it’s a cell membrane, not a mitochondrial membrane. There are clues in the diagram: areas labeled “cytoplasm” and “extracellular” space are not references that would be accurate in a diagram of a mitochondrial membrane. At least that’s what jumped out at me.

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