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