My experience with leptin injections to maintain very low bodyfat

#1

Over the years, I have experimented with dozens of hormones and prescription drugs (I am an MD so I can just self-prescribe). However, one of the most fascinating and fruitful experiments I ever did was with recombinant leptin injections.

I recently posted an article about my experience on my blog: My Experience With Leptin (Metreleptin) – The Most Expensive Hormone on Earth

Anyway, I am posting this here because @AustraliaLongevity told me to post about my experience here in the forums because some of you might find this useful.

Leptin is a crucially important hormone and IMO completely flying under the radar and I have never encountered a doctor who looks at leptin levels – not even endocrinologists or other hormone specialists. In my opinion, many unsolved problems with energy levels and hormone problems may be due to undiagnosed hypoleptinemia. Many try testosterone and thyroid replacement but still suffer from some symptoms of hypogonadism or hypothyroidism because symptoms of leptin deficiency mimic these.

This stuff is powerful and why it is not widely known (or used) is beyond me. It is weird that big pharma has not captured even a fraction of its therapeutic value other than in the ultra-rare orphan disease niche of lipodystrophy.

TL;DR

I dieted down to very low body fat (4.8% at my lowest) and stayed there for about a year. Everything fell apart: energy, mood, libido, hormones, thermoregulation, emotionality. I became obsessive, rigid, restless, and anhedonic, and a huge chunk of my mental bandwidth went to food. I replaced testosterone, thyroid, and cortisol. It only partially helped, as did GLP-1 agonists.

The actual culprit was leptin. Leptin is the hormone fat cells secrete in proportion to how full they are, and it functions as a starvation signal when low. Below a threshold, the hypothalamus shuts down reproduction, sympathetic tone, endocrine output, and non-food interests, while ramping up appetite and food preoccupation. My level was under 1 ng/mL.

I got hold of metreleptin (a leptin analog, very expensive and hard to source) and injected a low daily dose for four years. Effects were fast, within hours of the first shot. Background hunger gone, hormones normalized, obsession and restlessness dropped, energy and emotionality returned.

Hormones recovered within days (TSH & fT3 up, IGF-1 up, fasting insulin down, T/E2 up and SHBG down).

At 8% body fat I functioned like I was at 20%. Unlike every other intervention I tried (T3, moclobemide, semaglutide), it never pooped out. It got stronger over time. Also majorly changed my fat distribution patterns. Before, fat I gained went to my face and trunk and on leptin, face got very lean and fat distributed in a gynoid fashion and went to my extremities. (DEXA scans).

When I was on leptin, my fasting insulin levels were always below baseline (because my insulin senstivity was so high) and on a DEXA scan I only had 66g of visceral fat, which is essentially nothing. Furthermore, even low doses of leptin made it nearly impossible to gain body fat even if I tried. I became “that guy” that could eat whatever he wanted without ever gaining an ounce of body fat.

For me, GLP1 agonists (semaglutide & tirzepatide) only partially helped but nowhere near in the same zip code as leptin.

This is quite a unique experiment because metreleptin is very hard to get hold of and it is also one of the most expensive drugs on the planet.

The science:

Leptin is an adipokine, a cytokine secreted by fat tissue. It signals through a cytokine receptor via the JAK-STAT pathway, which is directly linked to widespread gene expression changes. Contrast this with GLP-1 agonists and most other appetite-related peptides, which act on G-protein-coupled receptors and mostly produce acute changes in cellular activity.

This is also why the common framing of “leptin vs. ghrelin” as opposing satiety and hunger hormones is wrong. They are not in the same league. If ghrelin disappeared tomorrow, not much would happen. If leptin disappears, the entire organism goes into crisis. Google congenital leptin deficiency.

I discuss the science of leptin in much more detail in my article.

Versus GLP-1 agonists

They are mirror images. GLP-1s work at high body fat and fail at low. Leptin does the opposite (at high body fat it does little, since signaling is near-saturated). Interestingly GLP-1s also sensitize cells to leptin, upregulating leptin receptor expression ~40 to 70%. For me, GLP-1 agonists were nowhere near as powerful as leptin. They helped with appetite and sympathetic tone a little but did not too much in terms of satiation and energy levels, libido, mood, obsession, etc.

GLP1-agonists help with satiety. Leptin helps with satiation. This means that on semaglutide, I feel satiated quite quickly but if I have low body fat (=low leptin levels) I get hungry soon after. On the contrast, on metreleptin I get the feeling of satiation. I can eat something, and not get hungry for hours. More detail in the article

Where it is interesting for longevity.

  • Allows to keep body fat levels very low (which is good for metabolic health, insulin sensitivity, etc.) without the endocrine, metabolic, emtional, behavioral downsides.
  • Reduces insulin levels and fasting glucose levels directly
  • Directly reduces visceral fat

Also covered in the article but too much to share here:

  • My personal experience in detail
  • why leptin is a plausible candidate treatment for anorexia nervosa (it may dissect the biological component from the psychological one, making patients amenable to therapy)
  • and why starvation appears to “imprint” durably on the brain, via network-level LTP/LTD or epigenetic changes in POMC neurons. The Biggest Loser participants still had suppressed leptin seven years out. It was the only hormone still off.
  • Musings on energy regulation
  • Science of leptin & how leptin is regulated

Link: My Experience With Leptin (Metreleptin) – The Most Expensive Hormone on Earth

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Optimizing thyroid levels for longer lifespan?
#2

Could it be taken as a supplement vs injection?

#3

Leptin is a protein hormone, 16kD, a little bigger than insulin and a little smaller than growth hormone, so, no. Needs to be injected as ingesting it would cause it to be broken down like other proteins.

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#4

This is fascinating. Thanks for posting.

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#5

I have really high T and SHBG. I think this is megadosing melatonin.

#6

So your total T is likely not representative of your actual T levels. You need to calculate free T. Fasting, keto, etc. can skyrocket SHBG.

#7

Just curious, you mentioned it being very expensive. How costly was it?

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#8

I read through the “full version” and the account of your experience with leptin is really quite remarkable, especially after taking it for 4 years. This statement really stood out to me:

  • Furthermore, despite the lethargy, I was also quite restless, driven, and my mind was racing all of the time. I was plagued by an inability to sit still and had an irresistible urge to always be productive (presumably a proxy for “foraging behaviors”).

It is fascinating that your personality returned somewhat to the direction of your “adolescent” days, how much better your mood/energy became, and how you became a “well-rounded” human being again.

I personally maintain about an 11% bodyfat year-round and have done so for over a decade. This is about the level I can do and avoid becoming “neurotic” as you described, as well as experiencing most of the symptoms you outlined. It’s a razors edge in my experience too… any leaner and things start to “fall off a cliff.”

This also stood out to me and makes me think about all of the studies on CR’d mice out there:

  • If mice are starved and a running wheel is put into their cage – they paradoxically run themselves almost to death (presumably a proxy of foraging behavior). If you then inject leptin, these mice stop running.

Your note about dating the endocrinologist who hadn’t connected her symptoms to leptin was also quite interesting.

The article is extremely well-written and I’m looking forward to reading more of what you publish.

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#9

Thank you! Glad you found some value in it!

The connection between low leptin levels and obession/neuroticism is fascinating. When I did my internships in psych, I always wondered why anorexia patients are so restless/obsessed/neurotic, I guess leptin might have something to do with in the arrow of causality goes both ways.

Also makes me wonder about the connection between Bryan Johnson and his neuroticism/obsession - he has been maintainig very low body fat levels for quite some time

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#10

You make a great point about Bryan Johnson and his neurotic behavior. As an aside, I read through a great deal of content on your website this morning and your “ranking” of longevity interventions really stood out to me. Specifically, the fact that you place “Human connecting & finding purpose” at the top of the list. I couldn’t agree more and find it really fascinating that an extreme biohacker like yourself embodies this belief.

Here is the list for anyone interested. The link is available here.

  • #0 – Human connection & finding purpose: Without emotional or “spiritual” health, feeling good and performing well does not matter.

  • #1 – Sleep hacks: With regularity, darkness, ear plugs, a morning daylight lamp, glycine, magnesium, and a Chili Pad in the summer, I have a refreshing sleep on most nights, which has far-reaching effects on everything I do, think and feel.

  • **#2 – Exercise: **Other than high-quality sleep, there is little that has a greater effect on my vitality than consistent, high-quality exercise, especially cardiovascular exercise.

  • #3 – My TRT Lite Program: Benefits I have noticed include more energy, slightly less need for sleep, greater emotional intensity, an easier ability to build muscle, and a higher libido.

  • #4 – Semaglutide & increasing caloric intake: I find hunger distracting and semaglutide is a potent appetite suppressant. For me, the increase in productivity and well-being can hardly be overstated. I should note that I do not use semaglutide to lose weight but rather to decouple my caloric intake from my appetite. I eat the highest possible number of calories that does not result in fat gain, which made an enormous difference to my vitality. Of note, while increasing my caloric intake may be great for my vitality, it is probably not optimal for longevity. However, vitality is more important to me.

  • #5 – Moclobemide: While I was on it, moclobemide was a great all-in-one solution for energy levels, mood, and all while feeling natural and having few to no side effects. The downsides included a very slight cognitive and emotional blunting.

  • #6 – Psilocybin: Friends use it occasionally to enjoy a day off, or to get some “deathbed” clarity in their life.

  • #7 – Ketamine: Ketamine is very effective at reversing the neurobiological aspects of depression. Unlike most other antidepressants, ketamine does not distort neurotransmitters. Furthermore, it is perhaps the only antidepressant that enhances emotions instead of blunting them. Other than being hard to get hold of, the major downside is that it is potentially neurotoxic.

  • #8 – Bupropion: Bupropion is a milder but more sustainable derivative of amphetamine. It is an effective mood brightener, stimulant, antidepressant, ADHD medication, weight loss drug, and anti-addiction agent.

  • #9 – Vortioxetine: As I was taking it, it boosted my mood, energy levels, stress resilience, and cognition while having a very benign side effect profile.

  • #10 – Nicotine gum: I find nicotine gum useful for increasing task salience and for boosting executive functions while working on cognitively demanding tasks. I can also take it at night without it affecting my sleep.

  • #11 – Modafinil: A great stimulant to take occasionally. It lasts all day. However, as with all stimulants, the price is counterregulation, worsening of sleep, a change in personality, and doing things more thoroughly than intended.

  • #12 – Rapamycin: While not directly helping with vitality in the short term, rapamycin helps to preserve vitality in the long term. According to the currently available data, rapamycin is presumably the most potent geroprotective molecule currently available to mankind. I have been on it for a little over four years.

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#11

Nice list and I shouldn’t complain since I don’t have a web site or a list. Sunlight doesn’t make the list? Photobiomodulation + UVB = 0 ?? You have a few things for depression and really if you spend time in the sun or under lamps there will be no need for these, which don’t work as well or as safely. Take astaxanthin and stand in the sun, you won’t burn. It’s a freaking miracle.

Also not mentioned is nutrition, balancing safe fat, protein and carbs and getting all the nutrients your body needs. As a farmer who has fed animals including many pets for my whole life, and grown crops for a living, if there is a problem usually there is a deficiency. Almost never a poison which our bodies are pretty good at getting rid of. We learned long ago when confining animals to concrete feed floors, many things are needed in the feed. They’re getting pretty good at feeding animals now, but humans are a problem still.

I didn’t mean to take away from your list, it’s a great list. And I loved your post about leptin too. Thanks.

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