lessthanhalf said:
If you have information about setmelanotide, please share it. It is prescribed for genetic forms of obesity, but I was unable to locate much evidence that it has actually been tested in broader obese populations, so the research base is thin beyond preclinical work and its behavior in particular syndromal obesities. I also have not come across anyone here who has used it, though since it acts at the last step of the neural circuit governing appetite, one would expect it might still work when other approaches failed. ChatGPT, however, tried to tell me it probably would not help with "normal obesity". Considering that I am working to keep off 56% of my body weight, any option that exists is worth knowing about.
The appetite control system is ridiculously complex and has evolved to be highly resistant to interference. At least 20 different hormones or neurotransmitters are involved, along with all their receptors and every downstream intracellular response circuit after that, and there are almost certainly variations in many of those proteins that change their sensitivity. The circuitry that governs weight set point remains more or less completely unknown; they essentially have no idea, unless it simply arises from the interactions among all the appetite control systems and no internal system sets a goal weight at all.
That side effects and effects of GLP drugs vary so widely does not surprise me in the least, and whatever variation makes them less effective in a given person might not even sit in that receptor directly; it could be in the downstream signalling system or even somewhere else entirely. The fact that new systems influencing appetite, weight and fat cell behavior are still being found every year is a strong sign that this is not yet well understood. And GIP was largely considered fairly useless until relatively recently, given how little effect it had on its own; only when combined with glp-1 agonism did genuinely useful effects emerge.
For ordinary obesity, I doubt setmelanotide would deliver much benefit. It is designed for the rare patients who have MC4R defects. Since MC4R sits largely downstream of leptin signaling, one could imagine it helping when poor leptin signaling produces downstream MC4R shortcomings. Metreleptin would be the better answer to that problem, but its cost is absurdly out of reach.
My skepticism about using it for typical obesity comes from the fact that pathways such as leptin are usually not deficient — they are already maxed out and then some. Targeting pathways that are working fine won't buy you much.
The more interesting angle is that after extreme weight loss we frequently observe leptin signaling deficits. Consider this (paywalled) study of bariatric surgery patients, measured before and after their loss and compared with controls matched for the same body fat post-loss.
I included the lower chart because the study ties this effect to fat cell size. While obese, the bariatric patients formed extra fat cells, and those cells remain after weight loss, so their average fat cell size ends up far smaller than the controls'. In vitro work indicates leptin secretion tracks cell size more closely than actual body fat, so the hypothesis is that having many smaller cells suppresses leptin levels relative to someone who was never obese.
With more extreme weight loss, as in the Biggest Loser study, the effect becomes even more pronounced.
I lost slightly more than 40% of my body weight, and my fat reduction exceeded both of those studies, so I had my leptin levels checked.
Given that MC4R is downstream of my almost nonexistent leptin signaling, I reasoned setmelanotide might work well for me, and it does seem to work reasonably well. I would not expect it to be broadly effective, and a real problem is that it addresses only one or two of leptin's functions, so even for me it isn't a great solution.
lessthanhalf said:
If you have information about setmelanotide, please share it. It is prescribed for genetic forms of obesity, but I was unable to locate much evidence that it has actually been tested in broader obese populations, so the research base is thin beyond preclinical work and its behavior in particular syndromal obesities. I also have not come across anyone here who has used it, though since it acts at the last step of the neural circuit governing appetite, one would expect it might still work when other approaches failed. ChatGPT, however, tried to tell me it probably would not help with "normal obesity". Considering that I am working to keep off 56% of my body weight, any option that exists is worth knowing about.
The appetite control system is ridiculously complex and has evolved to be highly resistant to interference. At least 20 different hormones or neurotransmitters are involved, along with all their receptors and every downstream intracellular response circuit after that, and there are almost certainly variations in many of those proteins that change their sensitivity. The circuitry that governs weight set point remains more or less completely unknown; they essentially have no idea, unless it simply arises from the interactions among all the appetite control systems and no internal system sets a goal weight at all.
That side effects and effects of GLP drugs vary so widely does not surprise me in the least, and whatever variation makes them less effective in a given person might not even sit in that receptor directly; it could be in the downstream signalling system or even somewhere else entirely. The fact that new systems influencing appetite, weight and fat cell behavior are still being found every year is a strong sign that this is not yet well understood. And GIP was largely considered fairly useless until relatively recently, given how little effect it had on its own; only when combined with glp-1 agonism did genuinely useful effects emerge.
Still on leptin: a recent study offered an intriguing detail — obesity is generally marked by hyperleptinemia and widespread leptin resistance, yet one particular set of leptin receptors stays sensitive. These are hypothalamic leptin receptors coexpressed with GLP-1 receptors. That's a tantalizing clue! If I had to make a wild guess, I wouldn't be surprised if our GLP-1 drugs act on these and perhaps further improve sensitivity, letting the "maxed out" leptin signaling of obesity act more strongly — though I haven't seen research connecting those dots yet. So far they've only placed the dots.
lessthanhalf said:
If you have information about setmelanotide, please share it. It is prescribed for genetic forms of obesity, but I was unable to locate much evidence that it has actually been tested in broader obese populations, so the research base is thin beyond preclinical work and its behavior in particular syndromal obesities. I also have not come across anyone here who has used it, though since it acts at the last step of the neural circuit governing appetite, one would expect it might still work when other approaches failed. ChatGPT, however, tried to tell me it probably would not help with "normal obesity". Considering that I am working to keep off 56% of my body weight, any option that exists is worth knowing about.
The appetite control system is ridiculously complex and has evolved to be highly resistant to interference. At least 20 different hormones or neurotransmitters are involved, along with all their receptors and every downstream intracellular response circuit after that, and there are almost certainly variations in many of those proteins that change their sensitivity. The circuitry that governs weight set point remains more or less completely unknown; they essentially have no idea, unless it simply arises from the interactions among all the appetite control systems and no internal system sets a goal weight at all.
That side effects and effects of GLP drugs vary so widely does not surprise me in the least, and whatever variation makes them less effective in a given person might not even sit in that receptor directly; it could be in the downstream signalling system or even somewhere else entirely. The fact that new systems influencing appetite, weight and fat cell behavior are still being found every year is a strong sign that this is not yet well understood. And GIP was largely considered fairly useless until relatively recently, given how little effect it had on its own; only when combined with glp-1 agonism did genuinely useful effects emerge.
Even that now looks uncertain, with Lilly working on macupatide.
