Studies show that the obesity and diabetes medication also reduces heart attacks, cancer risk, migraines, and memory loss. How is that even possible? And at what point should we all be on it?
Great article. In my reading of the biomed literature, these drugs spoof the same pathways that the microbiome uses to tell the body that it is sated (namely the production of short chain fatty acids SCFA from soluble fiber in the colon). In that sense, besides the effects of obesity, these drugs offset many of the deleterious effects of not eating a predominantly plant based, high fiber diet (and having a microbiome to match).
Not to go 'paleo' but it is clear that while early humans ate meat, it is clear from fossil evidence (e.g. fossilized human poop) that early humans often ate up to 50-100 grams of fiber a day, indicating a plant based diet. The genetic differences between us and the great apes are all adaptations for eating large amounts of starch, not animal protein. The greatest early invention might not have been the spear, but rather the digging stick for accessing deep tubers. Fire might have been a way to make those tubers edible, rather than a prehistoric BBQ.
There is plenty of evidence that the meat heavy western diet is bad for us. GLP-1 drugs are amazing because the spoof our Western-diet fed bodies into thinking we are eating vegan.
I wish I could say eating whole food plant based for 6 years (pre-GLP1) was the perfect solution, but alas, no. I still eat mostly WFPB (never meat, very rarely cheese) because I thrive on that way of eating, but the GLP-1 has allowed me to lose 80 lbs and get my a1C to 5.2. No “spoofing” here, just results - finally.
You have to unpack what "plant based" means. Food weight? Almost certainly. Majority of digestible calories? Doubt it. And there is no evidence a meat heavy diet is bad for us. Epistemological association studies. Give me cohort of high meat eaters who arent eating French fries and soda but are also eating fruits, vegetables, lowish starch and no/low sugar and I bet in an rct they'd be healthier than vegans. Meat is selection effects for fast food. It would make zero sense if meat was bad for us as we are human because of meat.
I think you mean epidemiological. Many control for fast food consumption. Have you read them?
Also there are LOTS of human RCTs that show that plant fats (including seed oils) are healthier than animal fats, and that plant proteins are healthier than animal proteins (mostly bc they are lower in methionine).
You might want to read more paleoanthropology. Early humans (and genus Homo) were hunter/gatherers. Modern hunter/gatherers get most of their calories (and a boatload of fiber) from plants. Hunting is a great resource, but very intermittent. Our big hungry human brains don't run on meat... they run on sugar, in particular starch. What is on the savannah in Africa but not in the forest? Lots of starchy plants. Humans have evolved much more starch-digesting amylase enzyme in our saliva than any other animal on earth. Why would that be? We even evolved a unique bacteria in our mouth that eats that enzyme. Neanderthals had the same bacteria in their mouth... suggesting that starch eating was fundamental to our way of life from our common ancestor with them... Homo erectus or earlier.
I have read them. I’m an academic librarian and was a medical/science librarian for years before entering administration. Know a bit about this in addition to being a top 1% masters athlete at 54 and married to a world ranked powerlifter/bodybuilder. You learn a bit about diet after 40 years as an athlete. I dont think I've ever had this debate with anyone fitter or with better health markers than me. I probably eat a half pound of meat plus full-fat dairy and eggs every day by design but rarely sugar and only moderate carbs solely for endurance exercise needs.
Shall I post proof of my high HDL/low triglycerides? A pic maybe? We simply do not do research that controls for selection effects for high meat almost always being a proxy for high other things. You need an RCT of very healthy but no meat diet compared to very healthy plus meat diet. Not weak epistemological crap that is wrecked by healthy user effects. Very hard to do proper diet research. But biochemistry tells us otherwise. Admittedly very hard to do proper research but no evidence is no evidence. Most of the anti meat nonsense is driven by an admirable concern for animal suffering, a separate and compelling issue that happens to be irrelevant to health.
(1) What do you make of the brouhaha around the recent Lean Mass Hyperresponders study? The one that showed rapid progression of atherosclerosis?
(2) What is your LDL? High HDL has not been shown to be protective. Billions were spent on HDL raising drugs, and then abandoned bc they provided no detectable health benefit. Genetic studies show the same.
I dont think it would follow that if high HDL tends to track with better cardiovascular outcomes the the HDL itself protective. And also on saturated (or any) fat you have a situation where again it is very hard to control varies. Saturated fat in the context of a modest low glycemic low sugar diet very likely has different effects than in the context of a high sugar high glycemic diet. And it is very hard to assemble the cohort to study this and to control the intake (diet studies very hard because people lie and also just dont know what they eat very well). But when you do cohort studies of athletes who manage their diets toward low sugar, lowish slow carbs and and highest protein and (relatively) higher fat you just dont see the predicted cardiovascular risk. And I'm not even sure what high meat means. I eat 4000 calories a day, so 5-8 ounces of meat ain't that high as a proportion of calories.
LDL only matters is the particle size is small. My vldl is very low. My triglycerides were 30 on my last blood test. My blood pressure in 110/70 and I can do high intensity exercise comfortably fasted with a blood sugar of 75. I agree with you on fiber and probably in many diet things, but grass fed ruminants, fatty fish, eggs, butter improve that diet. Saturated fat is good for you in normal "as it comes in natural whole foods/long history of preparation" forms.
In the end. the choices you make to experiment on your body (with atypical diet and exercise regimens) are aligned with your ideas about health and "we are human because of meat". What you consider to be 'health markers' are also out of the mainstream.
The rest of us can rely on expert opinion regarding diet and exercise guidelines, which has not changed much in the last 50 years.
Eat a variety of whole foods, limiting saturated fat (<6% of calories), animal protein (to a few 4 oz servings per week) and sugary foods.
Remain active, with a mix of strength and light aerobic exercises (e.g. at least 150 min/week moderate exercise like walking).
But experts disagree. There was never consensus on this. I agree in general "trust experts" is way better than "do your own research" but nutrition science was never a consensus. Thimk for example of the current collapse of the alleged consensus on medicalization of youth gender distress. Other factors led to some research being ignored and other research pushed despite bad quality. Why do we integrate animal proteins so well and vegan protein so poorly? We co-evolved with our foods. Why is ruminant meat so otherwise nutritious and vegetables not particularly unless a variety that isnt easily found year round in a small geographic area? It would be weird if meat were bad for us and novel/modern foods better. Butter is better than margarine.
There is surprisingly little disagreement among nutrition experts. Comparison of guidelines around the world shows this while eliminating political biases in the US. The widespread belief (in the US) that nutrition science is not settled is the result of decades of work by the 'Merchants of Doubt'... basically the same folks that spread disinfo about smoking and climate change.
Read about the McGovern Cmte in the 1970s. Big Food saw what happened to Big Tobacco after the Surgeon General's report (a few years earlier), and acted swiftly to take over the McGovern Cmte, even to the point of the new Cmte retracting the earlier report! And we have been in disinfo land ever since... with paid food influencers (whose ideas you appear to embrace) being the latest distributors.
We did co-evolve with our foods (over millions of years). Since humans have essentially no major adaptations to meat eating, this suggests it was never more than a useful supplement to our nutrition. Relative to apes, our adaptations are to eating more starchy foods (enzyme overexpression) and cooked foods (reduced dentition, jaws and GI tract). These adaptations provide ample energy (glucose) for our much higher metabolisms and larger brains.
Human protein needs are rather low compared to many other animals (e.g. human breast milk is very low protein). This suggests that we are adapted to eating lower protein foods. Poor human health outcomes from eating excess methionine (common in animal proteins) suggest that animal protein was not the major source of dietary protein.
“I think you mean epidemiological”. I am on my phone without my contacts in (my vision is -12) so I make lots of typos and my edit button is missing from my menu on this thread.
You could as easily say they spoof the body into thinking it´s eating keto or even carnivore. These diets also result in weight loss and lower inflammation -- and with less onerous side effects than the medication. Nutritionist Maria Cross puts it better than I can: https://mariacross.substack.com/p/weighing-up-the-pros-and-cons-of
I am so tired of hearing that we would not need these drugs if only we ate a specific diet. I’ve tried a dozen very different diets and none of them worked very well if at all. These drugs do work.
Keto was a game changer for me. I was up and down my entire life. Keto, along with intermittent fasting - which is easier with keto - totally stabilized my weight. But you have to look at keto as a lifestyle, not a diet. It's not for everyone, but for whatever way my body is configured, it works for me. I never ran for the first 45 years of my life, and now I'm running full marathons at 57.
I'm not opposed to the drugs, to be clear. With the COVID lockdowns, I drifted off of keto and put on 40 lbs. I looked into GLP-1 drugs as a way to get back to where I was, and they were just way to costly for me. I manned up and went back on strict keto and within 5 months I dropped those 40 lbs.
I hear you! I think we´re all different so you´ll get no argument from me. Personally, I like the idea of trying to lose weight through keto but that´s me. What´s right for you might be something very different. We all have to find our own way -- I didn´t mean to imply otherwise.
Nope. The science is well known... soluble fiber in your colon gets digested to SCFAs, which are then taken up by your colonic cells which release endogenous GLP-1 hormone into your bloodstream. Less soluble fiber, less GLP-1. So Ozempic, etc literally tickle the same receptors throughout the body that endogenous GLP-1 works on.
Your body literally gets a 'colon full of soluble fiber' signal from the drug. For many people that reduces appetite and helps with weigh loss, but these drugs presumably have myriad other biochemical effects other than weight loss, which mimic the effects of a high soluble fiber diet (and healthy microbiome). And in that way, it mimics a plant heavy (e.g. Mediterranean) or fully plant based diet.
I´m sure you´re on to something about the effects of soluable fiber (from a plant-heavy diet) mimicing the effects of Ozempic. All I´m saying it that the keto diet does likewise, albeit through a different mechanism. Like Ozempic, keto regulates appetite and thus helps people lose weight. Like Ozempic, keto helps people with diabetes lower their blood sugar. Keto has many other beneficial health effects for many, without the side effect profile of Ozempic.
I don´t think there´s any one diet that´s right for all of us. For some, a vegan or mediterranean-style eating pattern may indeed be ideal. For others, keto is the better option.
This. I think one of the most dangerous aspects of modern medicine (food planning included) is the way we misinterpret statistics in the public eye. For instance if a treatment is said to be 65% effective that doesn't mean that if you take it you will improve by almost 2/3. It means that 35% of the study participants did not have the positive results. Thus 35% of the broader population is not going to see those results.
Whether you are discussing diet or medicine or any other treatment, I think one of the best things our modern society could do would be to recognize the need for radically tailoring any kind of treatment for the individual.
This is difficult to do and thus not very profitable.
Indeed. Keto is an excellent strategy that many people use effectively to lose weight. Ketosis also sends myriad signals throughout the body to change lots of metabolic factors. These signals are different from the GLP-1 signals (and downstream effects) that Derek is discussing in this post, that are independent of weight loss. Unfortunately, many who use a ketogenic diet for weight loss find that they regain their weight after a couple years.
Importantly, there is no large human population on earth that is living long-term in ketosis, to demonstrate long-term safety. Inuit peoples are the closest examples, and they developed a mutation long ago that causes them to NOT be in ketosis on a meat heavy diet! And they still suffer from rampant cardiovascular disease. This strongly suggests that long-term ketosis (and a mostly meat diet) is not healthy for humans. Short term RCTs suggest the same thing.
People attempting to live in long-term ketosis are doing a risky science experiment on themselves. Please be careful out there.
Of course, with ANY "diet", when you go off it and back to bad habits, you regain weight. I mean, if you go on a low fat diet for a year, then go back to a high fat, high carb diet, you'll regain the wait also. Keto is no different.
Keto has to be looked at as a lifestyle change, not a temporary "diet". Really any of them. I come from a family of short, fat Italians. I'm battling genetics. Keto is the only thing that has stabilized my weight over the long term. If I want to maintain a healthy weight, my body requires me to eat a ketogenic "diet". It's just what I've been dealt and it's up to me to live that way, or eat whatever I want and be overweight.
"microbiome uses to tell the body that it is sated (namely the production of short chain fatty acids SCFA from soluble fiber in the colon"
Except that's obviously not the full story. Try to overeat on just steak. It's really hard. The satiety index of just meat is crazy high.
Which is why the weight just melts off people doing carnivore diets (which doesn't mean those diets are optimum for health, but they do help you lose weight like crazy)
Really interesting article, Derek! A secondary issue is how the GLP-1 variations on the market (like Zepbound, for example) pan out with respect to the proposed benefits. I think the proposed explanation that these artificial agonists work by reducing metabolic inflammation wherever they land is a good one - it is very well known that cellular inflammation is VERY bad for every part and parcel of the body that is subjected to it.
Having studied metabolism and neurophysiology in a former life, I can say with absolute certainty that the intricacies of the workings of many systems of the human body are mind-blowing - are true miracles - and we are just at the edges of beginning to understand how the systems work and interact with each other. As a student and then a researcher I can tell you without reservation that the more you learn about how your body operates, the more amazed you are at the processes, and the wilder it is to you that, for the most part, every single second of every single hour of every day all those myriad, intricate operations proceed successfully.
I’ve been on a GLP-1 for sleep apnea for about 10 weeks. I’ve lost 5% of my body weight and my migraines have improved. The sleep apnea is still there, but maybe it’ll get better when I get up to the therapeutic dose. I’m still on the lowest dose.
Curious why you omitted any mention of the muscle loss, which is a larger magnitude of the general loss of weight than is typical for weight loss programs?
Seems to me this is a under-discussed piece to GLP-1 drugs which is why not just healthy, but specifically very fit people, will have hesitancy even with all the other benefits.
This muscle loss is due to a lack of exercise and inadequate amounts of protein as well as the speed of the weight loss, rather than an effect of GLP-1s directly.
Easily avoided if you do both but i guess you could say they wouldnt need the drug if they had the will power to do both consistently.
Probably not the case. Exercise and protein dont overcome a catabolic fuel partitioning state. Work with bodybuilders on a cut. Eat hundreds of grams of protein and train and you still lose as much muscle as fat once BF is under a certain amount, even with anabolic. Bodies are not dumb fat storage machines. Bodies are fuel partitioning algorithms.
Sure i agree that some muscle loss is inevitable when losing weight but Bill seems to be asserting that the GLP-1 directly catabolizes muscle(beyond what you’d expect from fast, large deficits, low protein, and no resistance training.) which hasn't been proven to be true.
High protein, resistance training and a controlled sensible weight loss rate wont completely eliminate muscle loss that comes along with weight loss but it will certainly help.
I've lived through a few miracle pharmaceutical interventions for obesity that didn't pan out in the long term so I'll wait and see. Its hard to this easily tamper with a complex system by interventions in one part. What we need to wonder to wonder is why almost nobody was fat when I was a kid in the 70s. People haven't gotten worse at being hungry and lean people arent just better at being hungry.
decline of smoking may partially account for it. tobacco also complements caffeine (both in their effects, and you metabolize caffeine faster so it doesn't disturb sleep as much). it's too bad that the positive health effects of tobacco are outweighed by cardiovascular disease and lung cancer.
I don't think we need to wonder. Wide variety of tasty, often cheap, processed, high-calorie food. Americans making more money to eat in restaurants more often where they are generally optimizing for taste, not health. More sedentary lifestyle, both at work and in free time. All kinds of couch-based entertainment available, not the least of which is your phone, why go outside? And finally, probably because of our online malaise, people do seem worse at tackling challenges. Take all the griping there is now about Daylight Saving Time.
I dont think people overeat because food is tasty exactly (tastiness likely being a surface manifestation of deeper biochemical causation) - i think the food changes how we partition the energy we eat and hunger results. Of uour fat storage algorithm overprioritizes gat storage, more energy is taken from circulation resulting in hunger and low energy to replace what fat storage is taxing. I think fat people are as hungry when they are overeating as I am when staying lean. Its native biological differences and native susceptibility to biochemical changes caused by the food itself unmasked by a food environment. I'm pretty sure i find junky food as tasty as anyone else but I genuinely dont have the sensation of willpower being exercised to avoid it. Im pretty bad at sitting around hungry but I'm lean. My exercise mostly just makes me hungrier, which i dont white knuckle through.
Many people are actively hoping for some disastrous outcome like the one for phen/fen in the 90s. The pent-up desire to say "I told you so" is depressing.
Scott Alexander has noted that there absolutely will be a backlash, because there *always* is. Some new drug has good results, people claim it cures everything; it doesn't cure everything, the media summarize that as "Drug is Huge Failure." Eventually it all balances out.
That is usually how it goes, there is no free lunch. But there are exceptions, like the birth control pill has some side effects, but obviously women overwhelmingly are willing to put up with them. Ditto antibiotics, etc.
Yes, but it's been 65 years since the bc pill was introduced! The dosage of contemporary pills is much lower now, too. If you're young, you have no memory of the screaming about bc pills and their physical effects in the beginning. Even in the late 1970s, people were still yelling about hormones interrupting your moon cycles and your syncronicity with the moon, or whatever the hell.
Everyone I’ve talked to who’s described how they feel after starting GLP-1s just describes how I feel all the time. I can fast easily. Never feel hungry. Rarely feel thirsty. Wrestled throughout childhood and never struggled to cut 8-10 pounds as needed. I can’t wait for more research to come out about this. I’m convinced there’s a population whose base state is what others need these compounds to reach.
I suspect there's a population whose base state better matches the factory food society we live in. And I'm not talking about McDonald's. I mean the vast majority of the foods we eat are monoculture. Our bodies did not evolve in a monoculture. They evolved with variety and some thrive with one kind of food other side with another kind of food.
And then there's the amount of food we have available to us. In the West we are so crazy wealthy, especially regarding food. Hunter-gatherer societies and, I suspect, even farmers for most of the time we've been living with agriculture, did not have access to this much food.
*This much monoculture food.*
The fact that neither of these is what our bodies evolved to eat can't be healthy.
I guess we won't starve so we've got that going for us.
When I was talking with a research doctor about GLP-1s, he highlighted how many neurons we have in the stomach and intestine to begin with (I believe this is the enteric nervous system?) and that the "brain drug" effects may be more distributed than just the literal brain. Is that consistent with the effects you were describing here?
It made me wonder if that is a common root cause of all these other symptoms, that essentially something in modern life is pressing on the ENS and it's creating these diverse symptoms. So when that pressure is relieved, a bunch of seemingly unconnected symptoms resolve. It doesn't really fit with GLP-1s binding throughout the body, which strikes me as the most obvious candidate, but I hadn't seen anyone else highlight it as plausible pathway.
As someone who's on a compounded version (even still) and only knows other people still on a compounded version are your numbers accounting for that or just actual prescribed dosages? Cause that could change the math a LOT.
Great article, Derek. Thanks as always. I've written about this topic a few times on my substack (for a more technical audience), but wanted to draw your attention to one post that specifically addresses GLP-1s for diseases of the brain and hits on some supplementary points to what your post holds: https://www.bigpharmasharma.com/p/0739ae62-98e6-4e81-a38d-6de618058a98
The biggest readout in this space is Novo's P3 Alzheimer study, which is supposed to readout some time this year. That will be a major inflection point for the future of this class. If positive, we could get an Alzheimer's label for GLP-1s within 9-12 months of that readout. Pretty monumental.
Regarding mechanism of action, my read of the literature suggests that all three of the theories you propose can co-exist, but a deeper understanding of which effects are direct or indirect (and for which molecules) is still being unveiled. For example, with the "it's a brain drug" theory, the quirk about the most popular versions of these molecules, notably tirzepitide and semaglutide, are that neither of these molecules are any good at penetrating the blood brain barrier. So if these are having central (brain) effects they are in large part operating through the gut-brain axis (is one theory).
Taking that one step further, when drug co's do design the next generation of GLP-1-based drugs that are more brain penetrant and can hit the GLP-1 receptors, which do exist even in deep brain regions where the current generation of drugs cannot penetrate, does this dial-up the brain health benefits of this class or are the indirect actions through the gut-brain axis enough? We will discover answers to this soon given the number of scientific minds, companies, and risk-on dollars flowing into this space.
You would love Dr. Chris Palmer’s book BRAIN ENERGY. Metabolic health is at the root of all human health - and although mitochondrial research is in its infancy - decades of scientific research supports these theories.
And as Dr. Georgia Ede says… “the brain IS part of the body”. Metabolic health is at the root of our health - including our mental health.
Enjoying the ongoing GLP-1 coverage! I excitedly brought the subject up for discussion with someone who’s medically adjacent and fairly well versed on that front. They tossed some cold water on the topic due to the ‘black box warning’ pointing to the risk of thyroid cancers. Citing the following article. Curious how serious that warning is intended to be taken, especially when this piece points out how GLP-1s are correlated with reduced cancer risk?
Thank you Derek for this dive of a wonderful drug. The thing is, you have to stay on the drug for life. How do I know this you may question. After a year I went off it. Yea, I gained all my weight back. So I'm back on that train again to drop the lbs and stay on it to feel better. However I'm fond of spaghetti, so I have to monitor my pleasure with my favorite staple. 😎
Important avenue of inquiry, Derek, keep it coming. I am generally skeptical of taking any drug (especially for life) when a non-drug avenue exists, i.e. diet and exercise. That's great if GLP-1s reduce general inflammation, but what is the cause of that inflammation? Is it something that all humans are doomed to experience, or is it a product of the modern American diet and lifestyle? As with weight-loss surgeries, I would not feel good about resorting to such an intervention, knowing that if I changed my behavior without the surgery I would receive the same results. Also, there are benefits to diet and exercise beyond losing weight; I assume any doctor would recommend them over GLP-1s if their patients would stick to them.
You're right of course, at least these days. Didn't used to be a problem! This is why I am not opposed to weight loss drugs or weight loss surgery, even though I would never partake of them myself. As an individual I have agency, have been able to eat a healthy-ish diet and do some exercise, but for the population as a whole the forces of our current society and culture are very strong, pushing people to eat all manor of high-calorie processed foods and spend most of their day gazing at phones. As long as that condition exists, some sort of artificial remedy to our artificial problem is welcome.
Obviously it would also be good to address the root of the problem: our society and culture that leads us to these habits. Just a simple fact that the immediate pleasure from eating delicious high-calorie food while doomscolling on your phone is tangible, while the long-term ill effects on our bodies and sanity are not.
I have eaten a very good diet for years and I get decent moderate exercise. Without changing anything, I’ve lost about 68 pounds in a year. A slightly smaller portion of food satisfies me. Previously, I ate larger portions of healthy food, and if I didn’t, I felt hungry. Nobody can sustain hunger for life unless they develop an eating disorder.
I think, as you surmise, generalized metabolic inflammation is almost inescapable if one lives anywhere but 3d-world subsistence countries...the current diets in the US and Europe are chock-full of natural and synthetic molecules that our bodies were simply never evolutionarily developed to consume and therefore register as "alien" and cause inflammation...everywhere. Chronic inflammation is understood at this point to be absolutely anathema to the healthy functioning of the human body, and the greater the inflammation and the longer it is present works adversely on all genetic variations of people. So, although "diet and exercise" is vastly important in consideration of gradients of health (in the developed countries, at least) isn't going to have the effect you presume on weight and health in general. We have woven our environment with too many toxins and molecules that we ingest that our amazing bodies were never made to process. And those toxins and "foreign" molecules are, unfortunately, inescapable in modern life.
Some are inescapable (microplastics?) but clearly diet and exercise do work for losing weight and general health (see Derek's article "Why Exercise Is a Miracle Drug"). Nobody is forced to eat all that processed food. But can the average person resist all the temptations we've put in front of them and stick to a diet and exercise regimen? Perhaps not. We have made it harder and you see the results.
I'm actually not sure diet and exercise does help much once you're already fat. I think it can keep you from getting fat, and I think the story has to be make sure you don't get fat. But once you have the fat, the body has a strong, strong predisposition to making sure you don't lose it. When it comes to weight, we are primed to not losing it like those one-way traffic spikes when driving out of a pay parking lot.
My granddaughter was born with Prader Willi Syndrome. PWS is known for hyperphagia, inability to feel sated, resulting in morbid obesity if diet is not controlled. Of course, the PWS community thought that GLP-1 drugs would be a game changer. Apparently not. GLP-1s have no effect on PWS cravings or obesity. But why? I don't understand!
Great article. In my reading of the biomed literature, these drugs spoof the same pathways that the microbiome uses to tell the body that it is sated (namely the production of short chain fatty acids SCFA from soluble fiber in the colon). In that sense, besides the effects of obesity, these drugs offset many of the deleterious effects of not eating a predominantly plant based, high fiber diet (and having a microbiome to match).
Not to go 'paleo' but it is clear that while early humans ate meat, it is clear from fossil evidence (e.g. fossilized human poop) that early humans often ate up to 50-100 grams of fiber a day, indicating a plant based diet. The genetic differences between us and the great apes are all adaptations for eating large amounts of starch, not animal protein. The greatest early invention might not have been the spear, but rather the digging stick for accessing deep tubers. Fire might have been a way to make those tubers edible, rather than a prehistoric BBQ.
There is plenty of evidence that the meat heavy western diet is bad for us. GLP-1 drugs are amazing because the spoof our Western-diet fed bodies into thinking we are eating vegan.
I wish I could say eating whole food plant based for 6 years (pre-GLP1) was the perfect solution, but alas, no. I still eat mostly WFPB (never meat, very rarely cheese) because I thrive on that way of eating, but the GLP-1 has allowed me to lose 80 lbs and get my a1C to 5.2. No “spoofing” here, just results - finally.
You have to unpack what "plant based" means. Food weight? Almost certainly. Majority of digestible calories? Doubt it. And there is no evidence a meat heavy diet is bad for us. Epistemological association studies. Give me cohort of high meat eaters who arent eating French fries and soda but are also eating fruits, vegetables, lowish starch and no/low sugar and I bet in an rct they'd be healthier than vegans. Meat is selection effects for fast food. It would make zero sense if meat was bad for us as we are human because of meat.
I think you mean epidemiological. Many control for fast food consumption. Have you read them?
Also there are LOTS of human RCTs that show that plant fats (including seed oils) are healthier than animal fats, and that plant proteins are healthier than animal proteins (mostly bc they are lower in methionine).
You might want to read more paleoanthropology. Early humans (and genus Homo) were hunter/gatherers. Modern hunter/gatherers get most of their calories (and a boatload of fiber) from plants. Hunting is a great resource, but very intermittent. Our big hungry human brains don't run on meat... they run on sugar, in particular starch. What is on the savannah in Africa but not in the forest? Lots of starchy plants. Humans have evolved much more starch-digesting amylase enzyme in our saliva than any other animal on earth. Why would that be? We even evolved a unique bacteria in our mouth that eats that enzyme. Neanderthals had the same bacteria in their mouth... suggesting that starch eating was fundamental to our way of life from our common ancestor with them... Homo erectus or earlier.
I have read them. I’m an academic librarian and was a medical/science librarian for years before entering administration. Know a bit about this in addition to being a top 1% masters athlete at 54 and married to a world ranked powerlifter/bodybuilder. You learn a bit about diet after 40 years as an athlete. I dont think I've ever had this debate with anyone fitter or with better health markers than me. I probably eat a half pound of meat plus full-fat dairy and eggs every day by design but rarely sugar and only moderate carbs solely for endurance exercise needs.
Shall I post proof of my high HDL/low triglycerides? A pic maybe? We simply do not do research that controls for selection effects for high meat almost always being a proxy for high other things. You need an RCT of very healthy but no meat diet compared to very healthy plus meat diet. Not weak epistemological crap that is wrecked by healthy user effects. Very hard to do proper diet research. But biochemistry tells us otherwise. Admittedly very hard to do proper research but no evidence is no evidence. Most of the anti meat nonsense is driven by an admirable concern for animal suffering, a separate and compelling issue that happens to be irrelevant to health.
I'm sure your VO2Max would put mine to shame. :)
Two questions.... I am actually curious.
(1) What do you make of the brouhaha around the recent Lean Mass Hyperresponders study? The one that showed rapid progression of atherosclerosis?
(2) What is your LDL? High HDL has not been shown to be protective. Billions were spent on HDL raising drugs, and then abandoned bc they provided no detectable health benefit. Genetic studies show the same.
I dont think it would follow that if high HDL tends to track with better cardiovascular outcomes the the HDL itself protective. And also on saturated (or any) fat you have a situation where again it is very hard to control varies. Saturated fat in the context of a modest low glycemic low sugar diet very likely has different effects than in the context of a high sugar high glycemic diet. And it is very hard to assemble the cohort to study this and to control the intake (diet studies very hard because people lie and also just dont know what they eat very well). But when you do cohort studies of athletes who manage their diets toward low sugar, lowish slow carbs and and highest protein and (relatively) higher fat you just dont see the predicted cardiovascular risk. And I'm not even sure what high meat means. I eat 4000 calories a day, so 5-8 ounces of meat ain't that high as a proportion of calories.
LDL only matters is the particle size is small. My vldl is very low. My triglycerides were 30 on my last blood test. My blood pressure in 110/70 and I can do high intensity exercise comfortably fasted with a blood sugar of 75. I agree with you on fiber and probably in many diet things, but grass fed ruminants, fatty fish, eggs, butter improve that diet. Saturated fat is good for you in normal "as it comes in natural whole foods/long history of preparation" forms.
In the end. the choices you make to experiment on your body (with atypical diet and exercise regimens) are aligned with your ideas about health and "we are human because of meat". What you consider to be 'health markers' are also out of the mainstream.
The rest of us can rely on expert opinion regarding diet and exercise guidelines, which has not changed much in the last 50 years.
Eat a variety of whole foods, limiting saturated fat (<6% of calories), animal protein (to a few 4 oz servings per week) and sugary foods.
Remain active, with a mix of strength and light aerobic exercises (e.g. at least 150 min/week moderate exercise like walking).
Maintain a healthy body weight.
But experts disagree. There was never consensus on this. I agree in general "trust experts" is way better than "do your own research" but nutrition science was never a consensus. Thimk for example of the current collapse of the alleged consensus on medicalization of youth gender distress. Other factors led to some research being ignored and other research pushed despite bad quality. Why do we integrate animal proteins so well and vegan protein so poorly? We co-evolved with our foods. Why is ruminant meat so otherwise nutritious and vegetables not particularly unless a variety that isnt easily found year round in a small geographic area? It would be weird if meat were bad for us and novel/modern foods better. Butter is better than margarine.
There is surprisingly little disagreement among nutrition experts. Comparison of guidelines around the world shows this while eliminating political biases in the US. The widespread belief (in the US) that nutrition science is not settled is the result of decades of work by the 'Merchants of Doubt'... basically the same folks that spread disinfo about smoking and climate change.
Read about the McGovern Cmte in the 1970s. Big Food saw what happened to Big Tobacco after the Surgeon General's report (a few years earlier), and acted swiftly to take over the McGovern Cmte, even to the point of the new Cmte retracting the earlier report! And we have been in disinfo land ever since... with paid food influencers (whose ideas you appear to embrace) being the latest distributors.
We did co-evolve with our foods (over millions of years). Since humans have essentially no major adaptations to meat eating, this suggests it was never more than a useful supplement to our nutrition. Relative to apes, our adaptations are to eating more starchy foods (enzyme overexpression) and cooked foods (reduced dentition, jaws and GI tract). These adaptations provide ample energy (glucose) for our much higher metabolisms and larger brains.
Human protein needs are rather low compared to many other animals (e.g. human breast milk is very low protein). This suggests that we are adapted to eating lower protein foods. Poor human health outcomes from eating excess methionine (common in animal proteins) suggest that animal protein was not the major source of dietary protein.
“I think you mean epidemiological”. I am on my phone without my contacts in (my vision is -12) so I make lots of typos and my edit button is missing from my menu on this thread.
>plant fats (including seed oils) are healthier than animal fats
LIterally the complete opposite.
You could as easily say they spoof the body into thinking it´s eating keto or even carnivore. These diets also result in weight loss and lower inflammation -- and with less onerous side effects than the medication. Nutritionist Maria Cross puts it better than I can: https://mariacross.substack.com/p/weighing-up-the-pros-and-cons-of
I am so tired of hearing that we would not need these drugs if only we ate a specific diet. I’ve tried a dozen very different diets and none of them worked very well if at all. These drugs do work.
Keto was a game changer for me. I was up and down my entire life. Keto, along with intermittent fasting - which is easier with keto - totally stabilized my weight. But you have to look at keto as a lifestyle, not a diet. It's not for everyone, but for whatever way my body is configured, it works for me. I never ran for the first 45 years of my life, and now I'm running full marathons at 57.
I'm not opposed to the drugs, to be clear. With the COVID lockdowns, I drifted off of keto and put on 40 lbs. I looked into GLP-1 drugs as a way to get back to where I was, and they were just way to costly for me. I manned up and went back on strict keto and within 5 months I dropped those 40 lbs.
I hear you! I think we´re all different so you´ll get no argument from me. Personally, I like the idea of trying to lose weight through keto but that´s me. What´s right for you might be something very different. We all have to find our own way -- I didn´t mean to imply otherwise.
Nope. The science is well known... soluble fiber in your colon gets digested to SCFAs, which are then taken up by your colonic cells which release endogenous GLP-1 hormone into your bloodstream. Less soluble fiber, less GLP-1. So Ozempic, etc literally tickle the same receptors throughout the body that endogenous GLP-1 works on.
Your body literally gets a 'colon full of soluble fiber' signal from the drug. For many people that reduces appetite and helps with weigh loss, but these drugs presumably have myriad other biochemical effects other than weight loss, which mimic the effects of a high soluble fiber diet (and healthy microbiome). And in that way, it mimics a plant heavy (e.g. Mediterranean) or fully plant based diet.
I´m sure you´re on to something about the effects of soluable fiber (from a plant-heavy diet) mimicing the effects of Ozempic. All I´m saying it that the keto diet does likewise, albeit through a different mechanism. Like Ozempic, keto regulates appetite and thus helps people lose weight. Like Ozempic, keto helps people with diabetes lower their blood sugar. Keto has many other beneficial health effects for many, without the side effect profile of Ozempic.
I don´t think there´s any one diet that´s right for all of us. For some, a vegan or mediterranean-style eating pattern may indeed be ideal. For others, keto is the better option.
This. I think one of the most dangerous aspects of modern medicine (food planning included) is the way we misinterpret statistics in the public eye. For instance if a treatment is said to be 65% effective that doesn't mean that if you take it you will improve by almost 2/3. It means that 35% of the study participants did not have the positive results. Thus 35% of the broader population is not going to see those results.
Whether you are discussing diet or medicine or any other treatment, I think one of the best things our modern society could do would be to recognize the need for radically tailoring any kind of treatment for the individual.
This is difficult to do and thus not very profitable.
Indeed. Keto is an excellent strategy that many people use effectively to lose weight. Ketosis also sends myriad signals throughout the body to change lots of metabolic factors. These signals are different from the GLP-1 signals (and downstream effects) that Derek is discussing in this post, that are independent of weight loss. Unfortunately, many who use a ketogenic diet for weight loss find that they regain their weight after a couple years.
Importantly, there is no large human population on earth that is living long-term in ketosis, to demonstrate long-term safety. Inuit peoples are the closest examples, and they developed a mutation long ago that causes them to NOT be in ketosis on a meat heavy diet! And they still suffer from rampant cardiovascular disease. This strongly suggests that long-term ketosis (and a mostly meat diet) is not healthy for humans. Short term RCTs suggest the same thing.
People attempting to live in long-term ketosis are doing a risky science experiment on themselves. Please be careful out there.
Of course, with ANY "diet", when you go off it and back to bad habits, you regain weight. I mean, if you go on a low fat diet for a year, then go back to a high fat, high carb diet, you'll regain the wait also. Keto is no different.
Keto has to be looked at as a lifestyle change, not a temporary "diet". Really any of them. I come from a family of short, fat Italians. I'm battling genetics. Keto is the only thing that has stabilized my weight over the long term. If I want to maintain a healthy weight, my body requires me to eat a ketogenic "diet". It's just what I've been dealt and it's up to me to live that way, or eat whatever I want and be overweight.
"microbiome uses to tell the body that it is sated (namely the production of short chain fatty acids SCFA from soluble fiber in the colon"
Except that's obviously not the full story. Try to overeat on just steak. It's really hard. The satiety index of just meat is crazy high.
Which is why the weight just melts off people doing carnivore diets (which doesn't mean those diets are optimum for health, but they do help you lose weight like crazy)
I love these fast deep dives, like Scott Alexander for people who don’t want to read the actual papers.
I agree this is informative and fast, though it is more of a survey than a deep dive.
Really interesting article, Derek! A secondary issue is how the GLP-1 variations on the market (like Zepbound, for example) pan out with respect to the proposed benefits. I think the proposed explanation that these artificial agonists work by reducing metabolic inflammation wherever they land is a good one - it is very well known that cellular inflammation is VERY bad for every part and parcel of the body that is subjected to it.
Having studied metabolism and neurophysiology in a former life, I can say with absolute certainty that the intricacies of the workings of many systems of the human body are mind-blowing - are true miracles - and we are just at the edges of beginning to understand how the systems work and interact with each other. As a student and then a researcher I can tell you without reservation that the more you learn about how your body operates, the more amazed you are at the processes, and the wilder it is to you that, for the most part, every single second of every single hour of every day all those myriad, intricate operations proceed successfully.
I’ve been on a GLP-1 for sleep apnea for about 10 weeks. I’ve lost 5% of my body weight and my migraines have improved. The sleep apnea is still there, but maybe it’ll get better when I get up to the therapeutic dose. I’m still on the lowest dose.
Why not titrate up? The low dose isn’t considered therapeutic, although some people do respond to it.
Curious why you omitted any mention of the muscle loss, which is a larger magnitude of the general loss of weight than is typical for weight loss programs?
https://www.thelancet.com/journals/landia/article/PIIS2213-8587(24)00272-9/abstract
Seems to me this is a under-discussed piece to GLP-1 drugs which is why not just healthy, but specifically very fit people, will have hesitancy even with all the other benefits.
This muscle loss is due to a lack of exercise and inadequate amounts of protein as well as the speed of the weight loss, rather than an effect of GLP-1s directly.
Easily avoided if you do both but i guess you could say they wouldnt need the drug if they had the will power to do both consistently.
Probably not the case. Exercise and protein dont overcome a catabolic fuel partitioning state. Work with bodybuilders on a cut. Eat hundreds of grams of protein and train and you still lose as much muscle as fat once BF is under a certain amount, even with anabolic. Bodies are not dumb fat storage machines. Bodies are fuel partitioning algorithms.
Sure i agree that some muscle loss is inevitable when losing weight but Bill seems to be asserting that the GLP-1 directly catabolizes muscle(beyond what you’d expect from fast, large deficits, low protein, and no resistance training.) which hasn't been proven to be true.
High protein, resistance training and a controlled sensible weight loss rate wont completely eliminate muscle loss that comes along with weight loss but it will certainly help.
I've lived through a few miracle pharmaceutical interventions for obesity that didn't pan out in the long term so I'll wait and see. Its hard to this easily tamper with a complex system by interventions in one part. What we need to wonder to wonder is why almost nobody was fat when I was a kid in the 70s. People haven't gotten worse at being hungry and lean people arent just better at being hungry.
decline of smoking may partially account for it. tobacco also complements caffeine (both in their effects, and you metabolize caffeine faster so it doesn't disturb sleep as much). it's too bad that the positive health effects of tobacco are outweighed by cardiovascular disease and lung cancer.
I don't think we need to wonder. Wide variety of tasty, often cheap, processed, high-calorie food. Americans making more money to eat in restaurants more often where they are generally optimizing for taste, not health. More sedentary lifestyle, both at work and in free time. All kinds of couch-based entertainment available, not the least of which is your phone, why go outside? And finally, probably because of our online malaise, people do seem worse at tackling challenges. Take all the griping there is now about Daylight Saving Time.
I dont think people overeat because food is tasty exactly (tastiness likely being a surface manifestation of deeper biochemical causation) - i think the food changes how we partition the energy we eat and hunger results. Of uour fat storage algorithm overprioritizes gat storage, more energy is taken from circulation resulting in hunger and low energy to replace what fat storage is taxing. I think fat people are as hungry when they are overeating as I am when staying lean. Its native biological differences and native susceptibility to biochemical changes caused by the food itself unmasked by a food environment. I'm pretty sure i find junky food as tasty as anyone else but I genuinely dont have the sensation of willpower being exercised to avoid it. Im pretty bad at sitting around hungry but I'm lean. My exercise mostly just makes me hungrier, which i dont white knuckle through.
Thank you for your writings on GLP-1s, Derek.
I fear the inevitable backlash. I lived through the backlash against Prozac and the like. "Everyone should suffer and just tough it out!" :-(
Many people are actively hoping for some disastrous outcome like the one for phen/fen in the 90s. The pent-up desire to say "I told you so" is depressing.
Scott Alexander has noted that there absolutely will be a backlash, because there *always* is. Some new drug has good results, people claim it cures everything; it doesn't cure everything, the media summarize that as "Drug is Huge Failure." Eventually it all balances out.
That is usually how it goes, there is no free lunch. But there are exceptions, like the birth control pill has some side effects, but obviously women overwhelmingly are willing to put up with them. Ditto antibiotics, etc.
Yes, but it's been 65 years since the bc pill was introduced! The dosage of contemporary pills is much lower now, too. If you're young, you have no memory of the screaming about bc pills and their physical effects in the beginning. Even in the late 1970s, people were still yelling about hormones interrupting your moon cycles and your syncronicity with the moon, or whatever the hell.
I don't want to "like" your comment, but it is spot-on. Depressing, yes.
PS: https://www.mattball.org/2025/07/we-have-found-magic-drug-and-another.html
Everyone I’ve talked to who’s described how they feel after starting GLP-1s just describes how I feel all the time. I can fast easily. Never feel hungry. Rarely feel thirsty. Wrestled throughout childhood and never struggled to cut 8-10 pounds as needed. I can’t wait for more research to come out about this. I’m convinced there’s a population whose base state is what others need these compounds to reach.
I suspect there's a population whose base state better matches the factory food society we live in. And I'm not talking about McDonald's. I mean the vast majority of the foods we eat are monoculture. Our bodies did not evolve in a monoculture. They evolved with variety and some thrive with one kind of food other side with another kind of food.
And then there's the amount of food we have available to us. In the West we are so crazy wealthy, especially regarding food. Hunter-gatherer societies and, I suspect, even farmers for most of the time we've been living with agriculture, did not have access to this much food.
*This much monoculture food.*
The fact that neither of these is what our bodies evolved to eat can't be healthy.
I guess we won't starve so we've got that going for us.
When I was talking with a research doctor about GLP-1s, he highlighted how many neurons we have in the stomach and intestine to begin with (I believe this is the enteric nervous system?) and that the "brain drug" effects may be more distributed than just the literal brain. Is that consistent with the effects you were describing here?
It made me wonder if that is a common root cause of all these other symptoms, that essentially something in modern life is pressing on the ENS and it's creating these diverse symptoms. So when that pressure is relieved, a bunch of seemingly unconnected symptoms resolve. It doesn't really fit with GLP-1s binding throughout the body, which strikes me as the most obvious candidate, but I hadn't seen anyone else highlight it as plausible pathway.
As someone who's on a compounded version (even still) and only knows other people still on a compounded version are your numbers accounting for that or just actual prescribed dosages? Cause that could change the math a LOT.
Recent crackdowns on compounding are a huge driver of usage as well.
Anglerfish of that size are all technically female (as males are tiny and turn into sperm sacs after mating) so 'handsome fella' isn't quite right.
I mean this in jest of course, great article!
Great article, Derek. Thanks as always. I've written about this topic a few times on my substack (for a more technical audience), but wanted to draw your attention to one post that specifically addresses GLP-1s for diseases of the brain and hits on some supplementary points to what your post holds: https://www.bigpharmasharma.com/p/0739ae62-98e6-4e81-a38d-6de618058a98
The biggest readout in this space is Novo's P3 Alzheimer study, which is supposed to readout some time this year. That will be a major inflection point for the future of this class. If positive, we could get an Alzheimer's label for GLP-1s within 9-12 months of that readout. Pretty monumental.
Regarding mechanism of action, my read of the literature suggests that all three of the theories you propose can co-exist, but a deeper understanding of which effects are direct or indirect (and for which molecules) is still being unveiled. For example, with the "it's a brain drug" theory, the quirk about the most popular versions of these molecules, notably tirzepitide and semaglutide, are that neither of these molecules are any good at penetrating the blood brain barrier. So if these are having central (brain) effects they are in large part operating through the gut-brain axis (is one theory).
Taking that one step further, when drug co's do design the next generation of GLP-1-based drugs that are more brain penetrant and can hit the GLP-1 receptors, which do exist even in deep brain regions where the current generation of drugs cannot penetrate, does this dial-up the brain health benefits of this class or are the indirect actions through the gut-brain axis enough? We will discover answers to this soon given the number of scientific minds, companies, and risk-on dollars flowing into this space.
You would love Dr. Chris Palmer’s book BRAIN ENERGY. Metabolic health is at the root of all human health - and although mitochondrial research is in its infancy - decades of scientific research supports these theories.
And as Dr. Georgia Ede says… “the brain IS part of the body”. Metabolic health is at the root of our health - including our mental health.
Enjoying the ongoing GLP-1 coverage! I excitedly brought the subject up for discussion with someone who’s medically adjacent and fairly well versed on that front. They tossed some cold water on the topic due to the ‘black box warning’ pointing to the risk of thyroid cancers. Citing the following article. Curious how serious that warning is intended to be taken, especially when this piece points out how GLP-1s are correlated with reduced cancer risk?
https://pubmed.ncbi.nlm.nih.gov/38045343/
Thank you Derek for this dive of a wonderful drug. The thing is, you have to stay on the drug for life. How do I know this you may question. After a year I went off it. Yea, I gained all my weight back. So I'm back on that train again to drop the lbs and stay on it to feel better. However I'm fond of spaghetti, so I have to monitor my pleasure with my favorite staple. 😎
And the dosage has to be increased over time as you build up a tolerance, right?
Right. However, you can reduce dosage in maintenance, which I will understand better this second time around.
Important avenue of inquiry, Derek, keep it coming. I am generally skeptical of taking any drug (especially for life) when a non-drug avenue exists, i.e. diet and exercise. That's great if GLP-1s reduce general inflammation, but what is the cause of that inflammation? Is it something that all humans are doomed to experience, or is it a product of the modern American diet and lifestyle? As with weight-loss surgeries, I would not feel good about resorting to such an intervention, knowing that if I changed my behavior without the surgery I would receive the same results. Also, there are benefits to diet and exercise beyond losing weight; I assume any doctor would recommend them over GLP-1s if their patients would stick to them.
“diet and exercise” at the scale required have tolerability so poor that if they were a drug they would never go to market. People Will Not Just.
You're right of course, at least these days. Didn't used to be a problem! This is why I am not opposed to weight loss drugs or weight loss surgery, even though I would never partake of them myself. As an individual I have agency, have been able to eat a healthy-ish diet and do some exercise, but for the population as a whole the forces of our current society and culture are very strong, pushing people to eat all manor of high-calorie processed foods and spend most of their day gazing at phones. As long as that condition exists, some sort of artificial remedy to our artificial problem is welcome.
Obviously it would also be good to address the root of the problem: our society and culture that leads us to these habits. Just a simple fact that the immediate pleasure from eating delicious high-calorie food while doomscolling on your phone is tangible, while the long-term ill effects on our bodies and sanity are not.
"Didn't used to be a problem"
Different food landscape. Also, just a lot less disposable income.
I hate your judgy comment.
I have eaten a very good diet for years and I get decent moderate exercise. Without changing anything, I’ve lost about 68 pounds in a year. A slightly smaller portion of food satisfies me. Previously, I ate larger portions of healthy food, and if I didn’t, I felt hungry. Nobody can sustain hunger for life unless they develop an eating disorder.
I hope to stay on these drugs forever.
I think, as you surmise, generalized metabolic inflammation is almost inescapable if one lives anywhere but 3d-world subsistence countries...the current diets in the US and Europe are chock-full of natural and synthetic molecules that our bodies were simply never evolutionarily developed to consume and therefore register as "alien" and cause inflammation...everywhere. Chronic inflammation is understood at this point to be absolutely anathema to the healthy functioning of the human body, and the greater the inflammation and the longer it is present works adversely on all genetic variations of people. So, although "diet and exercise" is vastly important in consideration of gradients of health (in the developed countries, at least) isn't going to have the effect you presume on weight and health in general. We have woven our environment with too many toxins and molecules that we ingest that our amazing bodies were never made to process. And those toxins and "foreign" molecules are, unfortunately, inescapable in modern life.
Some are inescapable (microplastics?) but clearly diet and exercise do work for losing weight and general health (see Derek's article "Why Exercise Is a Miracle Drug"). Nobody is forced to eat all that processed food. But can the average person resist all the temptations we've put in front of them and stick to a diet and exercise regimen? Perhaps not. We have made it harder and you see the results.
"but clearly diet and exercise do work for losing weight and general health"
On an individual level sure. On a population level obviously not. Otherwise the last 50 years of diet and exercise would beaten the obesity epidemic
I'm actually not sure diet and exercise does help much once you're already fat. I think it can keep you from getting fat, and I think the story has to be make sure you don't get fat. But once you have the fat, the body has a strong, strong predisposition to making sure you don't lose it. When it comes to weight, we are primed to not losing it like those one-way traffic spikes when driving out of a pay parking lot.
My granddaughter was born with Prader Willi Syndrome. PWS is known for hyperphagia, inability to feel sated, resulting in morbid obesity if diet is not controlled. Of course, the PWS community thought that GLP-1 drugs would be a game changer. Apparently not. GLP-1s have no effect on PWS cravings or obesity. But why? I don't understand!