In this educational monologue, Dr. Ashley Frazee explains why many people struggle to lose weight, emphasizing insulin resistance and hormonal dysregulation as core barriers. She then systematically reviews the current landscape of peptides and small‑molecule agents marketed for fat loss. The discussion begins with the clinically validated GLP‑1 family—semaglutide, tirzepatide, and the emerging triple‑agonist retatrutide—detailing their mechanisms (appetite suppression, insulin sensitization, increased energy expenditure), trial outcomes, side‑effect profiles, and regulatory status. She also covers the amylin analog cagrilintide (cagrisema) and speculates on potential combinatorial risks. The video moves to off‑label or research‑chemical approaches: growth‑hormone‑releasing peptides (tesamorelin, sermorelin), the GH‑fragment AOD‑9604, the NNMT inhibitor 5‑Amino‑1MQ, and two exercise‑mimetic agents—mitochondrial peptide MOTS‑c and the estrogen‑related receptor agonist SLUPP‑332. For each, Dr. Frazee summarizes pre‑clinical evidence, human data gaps, theoretical benefits, and safety concerns. She concludes by urging viewers to first identify the biological factors that block their own fat loss, maintain regular exercise, and treat these pharmacologic tools as adjuncts rather than shortcuts. The video includes explicit medical disclaimer language and a call to action for likes and subscriptions.
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A lot of people don't get enough help from their doctor or from their diet alone, so they start looking for quick fixes and biohacks to lean out. The truth is that many people want one thing more than anything else: to lose fat. And maybe that's you, or maybe you just want to shed 5 pounds. Either way, in this video, I'm breaking down peptides and small molecules that are designed to drive fat loss. We'll start with the obvious, the GLP peptides, including retatrutide. We'll talk about compounds that give your muscles a fighting chance of sticking around and some pure And by the end, you'll walk away with a systematic way of thinking about fat loss. And a quick reminder here, this is purely educational. Please do not ask me where to get these or how to dose them. Some of what I am talking about today is not approved for human use. And even though I am a doctor, I am not your doctor. It is not medical advice. I'm serious. Before we can talk about fat loss, we have to talk about weight gain and insulin resistance, because the inability to lose weight even when you're eating well and exercising is is a real phenomenon. Now, the problem isn't that the laws of calories in and calories out don't apply here. It's that insulin resistance and hormonal shifts break the calories out side of the equation, making it nearly impossible for some people to lose weight through effort alone. You see, fat gain can change your hormones. It can change insulin signaling, hunger cues, and energy expenditure. And once that system is broken, just trying harder doesn't always fix it. And that's where modern weight loss medicine and even Biohacking can come into play. We're trying to restore biology here. If you take that as cheating, okay, I'll let you be the judge of that. But now that I've made the case for hormones gone wrong, and I'm making a case that insulin resistance is at the root of a lot of it, let's dive into the agents that work to reverse insulin resistance. So we have to start with semaglutide and kind of build on it from here. Semaglutide is a GLP-1 agonist. It tells your brain that you're full, it slows down digestion, and it reduces appetite. And it works really well. It showed up at exactly the right moment, you know, during the post-COVID work from home and drink all the pounds on era. But it also came with a lot of downsides: nausea, vomiting, constipation, that overall ick feeling, pancreatitis, gallstones, etc. And also a couple of rare but serious side effects that understandably freaked people out. But then came tirzepatide. Tirzepatide stacks GLP-1 agonism with GIP, or glucose-dependent insulinotropic polypeptide. This hormone improves insulin sensitivity by putting energy into the muscles while pulling it out of fat cells, which is why tirzepatide has been shown to preserve more lean tissue than semaglutide. In clinical trials, people just lost more weight with tirzepatide than semaglutide, and it also had fewer side effects, and it became the new wonder drug with a price tag to match. Now the buzz is around retatrutide, the GLP-1 plus GIP plus glucagon triple agonist. This is where things get really interesting. You know, GLP-1 tells you you're full, GIP helps move into muscle while pulling it out of fat cells, and glucagon increases energy expenditure and lipolysis, or fat cell breakdown. While the hormone glucagon alone can be catabolic, when it's balanced with GLP-1 and GIP, it drives the body to burn more fuel and mobilize more stored energy for the muscles and the brain to use. And that matters because it's likely helping spare muscle while losing fat. Redetritide has exploded in underground peptide circles for a reason. And in clinical trials, weight loss is exceeding what we've seen with semaglutide and tirzepatide. And stay tuned because whether you like it or not, redetritide is likely close to getting FDA approval for weight loss. I can't predict this, but it's close. Another major player coming soon is cagrisema. That is semaglutide combined with cagrilintide, an amylin analog peptide. Amylin is a hormone released alongside insulin from your pancreas after you eat. It controls how fast the stomach empties, smoothing out blood sugar spikes, and it tells your brain that you've had enough food. You can think of it like this: insulin puts gas in the tank by driving sugar into cells, and amylin controls the fuel line so the engine doesn't flood. Biologically, amylin works by inhibiting bad glucagon spikes that you could get after a meal that would cause your liver to dump unnecessary sugar into the bloodstream. Which caused me to wonder, if retatrutide adds glucagon receptor agonism and cagrisema blocks it, Could they be stacked together? Now theoretically, it's a massive fat loss strategy, but maybe a combination that would cause dangerous levels of hypoglycemia or low blood sugar. I don't really know for sure, but I have seen that people are trying this with research chemicals, and it got my attention. And just for the record, I'm not telling you to do this. So that's how the GLP drugs work and a preview of cagrilantide entering the fat loss world, or at least in the big pharma space. And honestly, I'm a big fan of the GLP drugs because if we can reverse insulin resistance, we can reverse a huge chunk of obesity and we can lower disease risk, lower healthcare costs, better outcomes. Are there downsides? Yeah. I'm not pretending there aren't risks and side effects to these drugs, but for many people, the benefits clearly outweigh them. Now let's shift gears because what if someone can't tolerate GLPs or they don't want long-term appetite suppression or they just don't want to go that route? I get it. So let's talk about some things that actually burn fat versus blunt appetite. So let's start with the growth hormone-releasing hormone peptides like tesamorelin and serrmorelin. I have a whole video on how these work, but basically growth hormone-releasing hormone and ghrelin-mimetic peptides are designed to stimulate the pituitary to release growth hormone, and growth hormone is a powerful fat mobilizer when you're fasted. People in the peptide space do use them off-label in hopes for fat loss, but fat loss is usually modest unless the diet's dialed in, and also the person or the mice we're doing the research on is exercising. So the GHRH peptides and ghrelin mimetics are not magic bullet fat loss peptides, but they do subtly bring the body into more recovery and fat mobilization than it already does. Okay, let's talk about AOD-9604. The AOD in this peptide literally stands for anti-obesity drug. What is it? It's a synthetic peptide fragment of growth hormone. It's the piece we believe that has growth hormone's fat mobilizing properties. Growth hormone is a massive fat mobilizer when you're fasted. And so theoretically, if a subject were to have AOD-9604 available in a fasted state, possibly fat mobilization happens. The animal research on AOD-9604 is actually quite impressive. It showed mice and rats losing weight and body fat without increasing insulin resistance and blood sugar spikes, which full-on growth hormone does. So there was so much hype around AOD-9604 initially, but the disconnect happened when we tried to replicate those results in humans. It just didn't work. As much as we want to believe we're just massive rats, we don't actually have the same exact biology. I mean, people still try it. Is it gonna hurt? Well, theoretically, if it does work in humans and you're mobilizing all that fat but you're not exercising it off to burn it, you're just dumping a bunch of free fatty acids into your bloodstream, which can cause issues. So in my opinion, if this did work on people, exercise would just have to be mandated in order to get it to actually burn fat. That's all theory, of course. Now let's talk about 5-Amino-1MQ. I get a lot of questions on 5-Amino-1MQ. First, this is not a peptide. It's a small molecule often sold under a research chemical loophole. The research data on 5-Amino-1MQ is animal data only. No meaningful human weight loss trials exist on this. But in the research in mice, it's been shown to reduce fat cell size and it shifted their metabolism toward Higher energy use. 5-Amino-1MQ works by inhibiting an enzyme called NNMT. You can think of NNMT as like a leak or a sink in your metabolic gas tank. During stress or with highly inflamed states like obesity, NNMT activity gets too high and it drains your NAD levels, which is the fuel your mitochondria need to produce energy. And so if you block NNMT, You increase NAD recycling, you increase mitochondrial signaling, and you increase energy expenditure. In the real world, you'll see people taking it and reporting a, like, a slow hardening of the physique and getting better stamina during their workouts. But there are some theoretical risks with this. See, by blocking NNMT, you might be messing with your body's methylation, and this is a system that helps repair DNA and make neurotransmitters like dopamine. Plus, we don't know if plugging the sink long-term affects your body's ability to clear out waste through your liver and kidneys. It's just interesting science. Because I know this stuff is available and I know that people are trying it, if you've got any experiences with it, feel free to leave a comment. Now, if you really want to get weird, which is something I say a lot, imagine stacking fat loss drugs with exercise mimetics, compounds that turn on the same cellular pathways as endurance training does. And we actually have those, and I'll give you 2 examples. MOTS-c. MOTS-c is a mitochondrial-derived peptide in your body that's naturally made during exercise and stress. What you tend to see in the real world is biohackers will purchase it as a research chemical and use it specifically before exercise. And if you look at the research, that actually makes perfect sense. See, MOTS-c is usually hanging out in your mitochondria, But it only travels to the nucleus of the cell when it's under metabolic stress. So theoretically, if you took it and you wanted it to actually talk to your DNA and turn on those fat-burning and longevity genes, you'd have to give it a reason to move. So no exercise, no translocation of the genes. And interestingly, to me at least, MOTS-c seems to be a marker for cellular health. I love the research article that showed low levels of MOTS-c in ovarian cancer cells, but higher levels in healthy non-cancerous cells. I mean, that seems pretty promising to me. Safety-wise, it's already a peptide that we make, so generally it's thought to be low risk. But as with anything that signals cellular growth or movement, we have to be cautious about long-term use until we have more human data. And again, it's not approved for humans to be using it, just saying. All right, one of my favorite compounds lately is SLUPP-332. This isn't a peptide either. It's a small molecule that acts as an estrogen-related receptor agonist. In the research in mice, it made them run 70% further and they burned significantly more fat than their friends who didn't take it. It's basically been shown to be exercise in a bottle for rodents. Now, estrogen-related receptors have nothing to do with estrogen, by the way. They're called estrogen-related simply because of their structure, but their actual job is acting like a master switch for mitochondrial energy. These estrogen-related receptors are found in most tissues in the body, but they're very concentrated in places like the heart muscle and kidneys. And as excited as I am about this compound, I have to tell you that theoretically the downside here is that we don't know yet if faking a high endurance state 24/7 could lead to things like heart muscle thickening or scarier things like fueling cancer cells. So to sum all of this up, the things in the peptide and biohacker space for fat loss are the GLP-1 drugs, which have the strongest human data, the biggest real-world impact so far, and there's always more coming down the pipeline with these drugs. And then there are the things that people are either using off-label or they're using things that are not meant for human consumption at all yet. But I think the real question people should be asking isn't, you know, what peptide is trending now. It's what part of your biology is actually blocking fat loss. And please, for the love of health, if you're able, exercise consistently. Make sure you've got the muscle to support a healthy metabolism because most of us have the capability to lose fat. It just gets jammed up for a lot of reasons. I'm Dr. Ashley Frazee. I run a direct primary care clinic in Mesa, Arizona. I really like to nerd out on biology when it comes to fat loss, muscle building, energy, brain fog, all the good things and all the things that seem to matter to you. If you like this video, please hit like for me and subscribe to my channel and have the best day ever.
