Where's that fat coming from that ends up in the liver? Yes. So this is, we were designed, right?
And we lived as humans, right? You know, our world has a history of what? 13 billion years, right? Our species has a history of hundreds of thousands of years.
Most of our history, we lived in societies of scarcity, not affluence. A lot of famine. Famine. So we are programmed.
to metabolize the calories we take in and store them. There were no refrigerators, no freezers at that point. So store them. And we are very efficient. And our societies of affluence are not making things easier.
We have high calorie dense foods. We have more fat and lipids in our diet. than we used to have throughout our history. And we exercise less, we have less demands, we don't burn as many calories as someone who is a farmer or a builder because machines are doing the work for us.
So the energy balance is against us. So if we don't watch what we eat and this takes time, our brain gets used to it and over time we are leptin tolerant and we develop more fat and after we exhaust our storage space it becomes ectopic fat and dangerous fat, right? What explains the difference between why one person can store more fat subcutaneously than the next person?
Presumably there's some type of genetic difference? Genetically and epigenetically, we have different adipose tissues, storage space. And this is differences between individuals, but also differences between ethnic backgrounds.
I told you earlier that BMI reflects overall obesity in Europeans or North Americans. But if you go to Southeast Asia, BMI has no relationship. People don't put a lot of fat in their subcutaneous tissue.
They just put it directly in the abdomen. So for a given... BMI, they'll store more weight around their belly.
Exactly. So for a given, say, percent fat or for a given amount of fat, kilograms or whatever, they put it in their abdomen, intra-abdominal, not elsewhere. Which is why they have a different BMI classification.
That's why. This is why we are leading now to having different classifications, because lower BMI is more dangerous for certain people. For certain people. So if we think through that evolutionary lens, for a moment here you spoke to the fact there that you know throughout evolution humans mostly have existed in an environment of food scarcity so it makes sense to be really well adapted to store body fat that helps you survive critically important to reach an age to procreate that's what evolution cares about right mostly but is there an evolutionary advantage for storing fat viscerally, perhaps? Do you think?
I don't think so. I don't think so. There is an extra fat, right?
The fat will have to be stored somewhere. But let me go, before we go into this, let me, you gave me an incentive to talk about some of our work, which is, this is close to our heart, about reproduction and fat, right? So, I think people out there realize that, say, college-age women or young women who exercise a lot, they have a lean physique. They cannot conceive. They have reproductive issues.
And if you push it all the way to anorexia nervosa... They get osteoporosis. Exactly.
So they may manifest, this may manifest as osteoporosis or even stress fractures, like small bones, they fracture as they exercise. And people say, well, I exercise, I'm an athlete. How come I have low bond density?
And how come... and then you go deeper, right? Their reproductive axis is shut off and they have hormonal abnormalities.
Thyroid is abnormal, IGF is abnormal, you name it. So when I was a medical student, we could not, I could not, we could not put all these together. And I created a certain line of research as a young investigator when we discovered leptin.
So leptin is the signal that goes from the fat, very simple, to the brain to notify how much energy we have stored in fat. So the idea was... If leptin levels are low, so we don't have a lot of energy in our body, what would our brain do? So our brain does not understand, the brain of someone who exercises a lot or has anorexia nervosa, does not realize that we have a freezer or a fridge to store calories.
Our brain realizes we cannot survive. We don't have enough fat. to survive, to live. So what goes first? What goes first, right?
It shuts off. Shuts reproduction off in order to survive. In order to survive. So it makes no sense for a woman, right, to become pregnant because she cannot bring a pregnancy to term. She needs to survive herself, right?
So the very first thing to go is the reproductive axis, right? And then it also makes sense for the thyroid hormones that regulate metabolism to go down. We have a slower metabolism because we conserve energy.
And then IGF-1, which is the insulin growth factor that grows our muscle, also goes down. Because this is not a priority to build muscle, here we have survive. And we have another system that we studied a lot, it's the activin-folistatin system, which is a beautiful system.
In the beginning, it was called activin because it activates the reproductive axis. But we realize now that in starvation states, actin goes down, so it's a second system to block the reproductive axis and make us survive, right? But at the same time, it also has effects on muscle mass, bone mass, and insulin resistance goes to the liver and make each and every drop of energy we have stored in the liver and fat available to us to survive.
And it's clearly, and we have proven this in animals and humans, the effect of leptin. So as leptin goes down, all these mechanisms are activated and if we give leptin back to people, we start restoring one by one all these mechanisms. So, which is beautiful physiology, right?
But also beautiful therapeutics, right? If you think about it, because we have not been there yet, but if you think about it, these two systems, if we give it back, the active foliostatin and the leptin, we can prevent fractures. We can treat fractures. And we have done proof of concept studies.
We gave leptin back, and we have shown this. Right. So is that… It's not indicated at this point.
So in medicine, the way that knowledge progresses is you start from animal models and in vitro, then you go to epidemiology. So you either confirm or refute your hypothesis, right? And then you go to phase one, phase two clinical trials.
Phase one is safety. First, do no harm, go back to Hippocrates like 2,500 years ago. First, do no harm.
So phase one, safe. Phase two is proof of concept. So clinical trials, you randomize. We randomized women who were strenuously exercising, women athletes, rowers and dancers and you give to half of them leptin and half of them placebo and you follow them for a year or two years and you see what happens to their hormones and bone mass and So, and we proved, right?
It's proof of concept. We proved that bone density goes up by 6-7% and you normalize all the hormones and everything. And then to get to the market, you need the company to come in and say, okay, I will do the phase three and phase four studies, right?
Phase three, you need at least two phase three studies to prove to the FDA that you can market it. and you need to face three studies from two independent groups and we can talk why but do you i want to come back to fatty liver but but just quickly to tie the knot in that do you get a similar increase in leptin and normalization of that other system with that person if they increase the amount of food they're eating and reduce their exercise yes Exactly. If you increase the food intake, right, energy intake and decrease energy expenditure, you will get to the same point, right? But it is as difficult as telling to an obese person, exercise more and reduce your food intake. This is mirror image.
So most obese people can decrease their food intake and exercise for a while. But predictably, right, after a few months, the system fails and they have to defend their original body weight. So they will go back.
You see in most diet interventions. short term you get some weight loss but from years two to five like most of the weights were gained yes yes so you're saying the similar thing happens in reverse to these people very much right these are people if you tell a woman with anorexia nervosa or strenuously exercising a woman athlete right or over or we have like five percent of college-age women boston is a college you know it's a college town right one of the first signs is the loss of period right Amenorrhea or irregularity. Exactly.
This is the first. And there is a hierarchy of responses. I mean, you're right on target. But most athletes don't think about it. It's convenient.
And if you're a student, you don't have to worry about it for exams and everything. They don't think about downstream effects. Yes, you are right.
Let's talk about it for a minute. So there is a hierarchy of responses. The very first thing that goes is reproduction.
This does not affect our own body, right? It's okay, prevents procreation. And then you have, as leptin goes lower, the thyroid, the IGF-1, and if you go very, very low, you're really hectic, your immune system is also affected.
We talked about immunology, inflammation in obesity. It's exactly the same. Th1, Th2 imbalance. So think about emaciated people in Africa who have all these infections and they die from infections.
Or people who die from tuberculosis, right? If they're extremely thin. So I diverge for a minute. But it's a mirror image.
So if you tell a woman who exercises a lot, right? Try to eat... More right and exercise less they will look at you Are you nuts?
What are you talking about? Sorry for the explain, but that's that's what they're telling you right? And even if they don't tell you They're not going to follow you The same is true for obesity as you said a few years ago We did a large study and we followed people for several years ten years 5,000 people 10,000 people with diabetes, randomized in two groups. One was 5,000 people, multi-center, you know, controlled trial.
Go home, lose weight, follow the advice of your primary care doctor. And the other one, follow toolbox approach. Everything that we could. See a dietician every two weeks.
Exercise physiologist. Take medications. Like, not the medications we have today, but the medications we had a few years ago.
And predictably, people would lose with the intensive intervention, about 9-10% year one, and then they would start regaining it. Why is the body fighting back despite having excessive body fat? It has excessive body fat and is used to it. Let's put it this way, right? It's like a new set point.
It's a new set point. It has to defend the original set point, which is crazy, right? But I can't remember the set point from before you were overweight. Exactly.
So it probably needs more time, more time than a year or two, right, to go back, right, or more progressive weight loss. Because that's probably how we are built, right? We are built to adjust.
So you gain weight, let's say you gain weight and you become 100 kilograms or 220 pounds, and you are at that weight for some time. Now your body essentially says, this is our new normal. This is my new normal.
And from that point, 100 kilograms, you go on a diet, you lose, let's say, 10 kilograms, you're at 90. Your body is confused and says, we need to get you back to 100. Yes. And I think that similar to each and every system, the faster you lose the weight, the more pronounced is the desire of your body to go back to baseline, right? You have to adapt to a new environment.
And our body needs time. To resensitize its systems. To resensitize, right.
So, for example, one of the questions, we did not talk about the new successful medications, right, for weight loss. But one of the questions that we have for people... with respect to the new medications.
Like Ozempic? Ozempic or, you know, I don't want, yeah, I don't mean to advertise one, but Ozempic-like medications. There are several medications, right? And now we are discovering even stronger medications that will be available like in a couple of years.
So I call them first generation, second generation, third generation. The first generation was what we had at our disposal before 2010, 2012. And we would be happy with 5% weight loss for most people. Second generation is what we had in the past decade, GLP-1 agonists, 10-15% weight loss.
What is coming now to the market, 2022-2030, 25% weight loss. And we are learning from... Sustained.
Sustained. Over like 12 months, 24 months? Well, at this point, we know a couple of years.
and most probably longer um and that's because it's it's acting on these regions of the brain that drive appetite or hunger yeah we we don't know everything that we need to know but we know the basics right so let's go back to the example i gave you earlier about uh bariatric surgery i told you about surgery for uh hypertension bariatric surgery right so people who um who undergo surgery to lose weight, they may lose 35-40%, 45% of their body weight. But we also know that there is certain changes of hormones in their bloodstream. So GLP-1 for example goes up, GLP-2 goes up. More recently we studied other hormones, soxintamodulin, you don't want to confuse people with names.
That's what we do, or pharmaceutical industry does, when they create the new medications. So they started with GLP-1, one medication. Now the next generation, third generation, is GLP-1 plus GIP, duals. And we are going to have triples or quadruples, cocktails.
So all the hormones that are changing after bariatric surgery. you put them into one medication. And instead of having surgery, you give this cocktail.
And so the idea, I just want to see if I'm hearing this right. So I gave that example of, say, someone that got 100 kilograms, 220 pounds, and they wanted to lose weight. And we said that the body, if they've been at that level for a long time, it's going to defend against that level. It's like a new set point. So presumably...
when we say set point we're saying that there is a hormonal profile or kind of milieu yeah that it's an established milieu that makes you that makes you maintain that makes you maintain weight or sort of create it affects your appetite in a way such that you stay at the same body weight exactly so now what you're saying is say i've got 70 kilograms so you need the tool let's put it this way you need the tool right to affect number one appetite And number two, so what happens when we eat, right? Without thinking about it, you eat a certain amount of food which is the appropriate amount for you, right? And then you feel full, right? What does this mean in practice, right?
In practice means that our GI tract slows down and tells you, you know, I'm stuffed, I'm full. And then there are centers in your brain, the appetite centers, that say, well, the appetite goes down. So with these medications, they act primarily, but not exclusively, they act in certain organs.
Primarily in two organs. One is the GI tract, and slows down the stomach of the GI tract, so you feel full earlier because you eat food that does not travel down the GI tract. And number two, and that's why some people have nausea and vomiting, if you don't go slowly, and it goes also to the brain and tells you, okay, you will have satiety faster and sooner.
So, if you add two or three medications, you have much more pronounced effect and that's why you lose weight longer. Now let me add one more sentence because I see your eyes, you get excited with that. If you have less fat, as we keep our body weight down longer.
you would expect to have less inflammation because you will need less macrophages and less inflammation. If this plays a role in the maintenance of body weight, you would expect that you may not need as much medication 2, 3, 5 years down the road when you reach a new steady state.