How to Outsmart Your Obesity Genes

I got a comprehensive genetic test. The report was 144 pages long, and on page 105, I received the diagnosis of obesity. Here it is. Here's my report. You can see it for yourself. I have 3 separate genetic variants associated with an increased risk of obesity and no reported protective variants. And so my fate was sealed. Obviously, I'm poking fun at a rather serious matter. Because I've never struggled with being overweight. Despite eating as a kid a pretty standard junky diet, I was never a chunker. Now, before you go crazy in the comments about my use of a politically incorrect term here, chunker, I used that hurtful schoolyard slur intentionally to frame our discussion, provoke your emotions, frame our discussion between two apparently opposite beliefs that pervade in society. The one belief is that obesity is predestined, shaped by our genetics, or otherwise out of our control. In fact, this first belief has become such a cultural meme that I'm confident I can guess the image arising in your mind right now. And I'm going to show it to you. You ready? Think. Here it is. Was I right? Tell me in the comments. And if you've been living under a rock, here's that famous clip from Dr. Fatima Cody Stanford on 60 Minutes. The number one cause of obesity is genetics. Now, I know those 8 words don't represent the full nuance of her point of view, but I share them because the fact they've become themselves a cultural meme represents a social reality about our perspectives on obesity. And the second belief, too, is that obesity is a moral failure, a failure of willpower deserving of insult and shaming. Honestly, I think these two beliefs— obesity is genetic and predestined and obesity is a failure of willpower— are maliciously similar. They both, in my opinion, disempower and alienate those persons with elevated BMIs, or paraphrasing my dad, who struggled with obesity most of his adult life. He says, "I'm not overweight, I'm just undertall." But, as an aside, kudos to dad. Almost a decade ago, he dropped 50 pounds and has kept it off. And he'd be the first person to tell you, it is not a matter of sheer willpower. Although, I'll add, as a prior South African international rugby player, MD, PhD, MBA, surgeon-scientist, Rhodes Scholar, he's far from deficient in intelligence and grit. Actually, he, my dad, was the first proof to me growing up that willpower alone is insufficient to combat obesity. You need much more. So in the rest of this video, I want to challenge both narratives, challenge that obesity is genetic and challenge that it's a moral failing, an issue of willpower. And I'm also gonna give you what I hope is practical and actionable wisdom that will help you or a loved one better understand the problem of obesity and the ecosystem of solutions. I'll start with the obvious. Obesity is largely a modern disease. It was a relative rarity 50 years ago. So it's obvious that obesity is not just genetic. But, and I hope this is obvious as well, there is a matter of gene-environment interaction. Some people are predisposed to certain conditions, be that obesity or inflammatory bowel disease, but those vulnerabilities only transform into the clinical manifestations of the disease when environment permits. So to play on a famous phrase, genes load the gun, and the metaphorical Twinkie pulls the trigger. And yet, even that metaphor grossly oversimplifies things because obesity is not just one disease. There is no singular root cause of obesity. Let me be clear, obesity is not just about body size and shape. It's about metabolic health. You can have obesity with excellent blood markers, and you can also be lean with serious internal dysfunctions underneath the hood. To prove that point, take data from this study comparing lean people with a BMI of around 23 kg/m² on average to persons with obesity, either metabolically healthy obese subjects, MHO for short, or metabolically unhealthy obese subjects, MUO for short, each with BMIs on average of 39 kg/m². That's bordering on class 3 obesity. Now the lean and the metabolically healthy obese groups clearly match each other far, far more than the two obesity groups match each other. For example, take a look at intrahepatic triglycerides on this table. This is a fancy term for liver fat. It was 1.6% in the lean group and 2.5% in the metabolically healthy obese group, but 15.9% in the metabolically unhealthy obese group. So when you pop open the hood, the metabolically healthy obese individuals, despite having class 2 bordering on class 3 obesity, appear far more lean metabolically than their metabolically unhealthy counterparts. The BMI doesn't capture the whole picture. Again, point being, or the point I want to make, we are transitioning to a world where pounds, kilograms, and BMI take a back seat and more useful and informative metabolic markers step forward to inform our health. I think this is great. This is what should be happening as metabolic dysfunctions are the real problem. With obesity just being a symptom, a canary in the coal mine. Now, with that caveat placed up front, because it's important, I will say at a population level and for most people, excess body fat is still an issue and a manifestation of metabolic dysfunction. So let's now break down just a few of the different systems, metabolic systems and other systems that can lead to undesired and unhealthy fat gain. Mechanism in system 1: insulin resistance, which can impair fat burning and keep your body in fat-storing mode. In my opinion, insulin resistance is one of the strongest, if not the strongest driver of obesity. Insulin is a hormone that favors storage of fat. But wait, if you stop and think about it for a moment, wouldn't resistance to insulin Insulin resistance prevent fat gain if insulin promotes fat storage? What gives? Where's the logic trap? Well, there are two nuances here. First, not all cells, tissues, and organs become equally insulin resistant. Some are more insulin resistant than others, and others don't become insulin resistant at all. However, to compensate for insulin resistance, the body, the pancreas, sends out more insulin. This is called hyperinsulinemia, meaning high insulin. But if some tissues and organs are more resistant than others, the result, the metabolic scenario you get is some don't get enough insulin signal, those that are really insulin resistant, and others get far too much insulin signal because of hyperinsulinemia. So as an example, a case in point, take the liver itself. Insulin should shut down the production of glucose and promote the storage of fat. But because these pathways are differentially insulin sensitive, the fat and the glucose, insulin does not put the brakes on glucose production enough, and insulin hits the gas too hard on making fat when you're insulin resistant. Mechanistically, this is tied to something called the bifurcation in the insulin signaling pathway. You can see this paper for more, very fascinating. And this leads to metabolic Dahab, where both glucose and fat—triglycerides—are high in the bloodstream. These are two hallmarks of metabolic syndrome that go hand in hand with metabolically unhealthy obesity. Now, the second nuance is that insulin resistance at fat cells does in fact kind of protect them from growing further, but this protective mechanism only kicks in once the fat cells are packed —past a certain threshold, which varies person to person. So some people can store more healthy subcutaneous fat than others. There's a lot of individual variation. So different people will have different threshold BMIs at which they become metabolically unhealthy. Okay, moving on. 2. Leptin resistance. This disrupts hunger and fullness signals, leading you to be more hungry more often. Leptin is a hormone primarily released from fat cells that signals to the brain to decrease feeding and increase energy output. But in metabolically unhealthy obesity, there's leptin resistance, which is intermingled with insulin resistance but distinct. And we are now beginning to understand better how leptin resistance works in the brain. But admittedly, because the brain is so hard to study in humans, serious actionable insights for improving leptin resistance with precision targeting those pathways are likely at least a few years away. But, as a heuristic that I'd offer you, that which improves insulin resistance will likely improve leptin resistance as well, leading to less hunger and more energy expenditure. Alright, moving on. 3. A disrupted circadian rhythm. This messes with hunger hormones and messes with cravings. There are a lot of data that shift workers and overall disruption of circadian rhythm and sleep deprivation can lead to weight gain and metabolic dysfunction. There are many mechanisms at play, but just to give you an intellectual handhold, one mechanism at play is likely changes in the hunger hormone, ghrelin. More ghrelin equals more hunger. For example, one study found that just one night of poor sleep can increase ghrelin levels in parallel with increases in self-reported hunger. In this study, they also noted a dose-response effect whereby even less sleep The less sleep a person got, below 7 hours, the higher their ghrelin levels got. So you couple these surges in an anti-satiety, pro-hunger hormone with the food options usually available late at night, say at 2 AM, and sleep deprivation is a recipe for adiposity. All right, moving on. Emotional eating and trauma. Food as coping, not as fuel. This is biological truly as much as it is psychological. Multiple studies have shown that trauma, like adverse childhood experiences, abbreviated ACE in the literature, can become biologically embedded, leaving a lasting metabolic signature on multiple body systems, and that the presence of elevated adverse childhood experience scores predicts obesity in adulthood. And while we don't know all the biological mechanisms, we do know that chronic stress can negatively impact overall health, likely contribute to metabolic dysfunction and obesity, and that mental health and metabolic health cannot be separated. Gut microbiome changes. These can affect cravings and calorie extraction from food. Now, to double-click on this for a moment because it's fascinating, I want to go through 3 examples drawn from the primary scientific literature. First, research shows that ketogenic diets, very low-carb, high-fat diets, can change the microbiome to increase the fecal excretion of calories. In other words, keto may make you poop more calories. And as I know there will be a subgroup of the audience that says, "See, it all comes down to calories," here's my response: I'll let you have that imagined win, provided you shovel your feces into a bomb calorimeter so you can measure your true calorie deficit in the future. Now moving on to the second study, there are data showing that even just 1 week of artificial sweetener intake can cause insulin resistance in some people linked to the microbiome. And as we reviewed, insulin resistance can lead to the development of obesity. Finally, the third study— there are now data showing that viruses, in particular bacteriophages that infect bacteria in the gut, can change the microbiome and microbiome function, leading to worse food addiction symptoms, cravings, changes in brain activity in humans, and can cause food addiction-like behavior in animal models where they do fecal transplants. But back to the main point. There are many paths to obesity, just as diverse as there are solutions. None of these solutions we're about to review are alone sufficient, but all have potential as part of a solution ecosystem to help. So let's run through some, categorized by the problems they're meant to address. Okay, one, if insulin resistance is driving your weight gain, the goal should be to eat fewer refined carbs and sugars. A lower glycemic load diet overall. Focus on proteins and whole foods. And also try time-restricted eating or very low-carb diets. Indeed, there are actually data showing that some people are predisposed to secrete more insulin in response to carbohydrates, which can lead to more fat storage. In fact, there are even Mendelian randomization, a type of genetic study, suggesting those with inborn tendencies to secrete more insulin in response to sugar and carbs tend to carry more weight. And so these people might do better, even better with low-carb diets. They get extra bang for the buck from carbohydrate restriction. Remember, the gene loads the gun and the metaphorical Twinkie or bowl of pasta pulls the trigger. So make smart choices, informed choices given your genetic predispositions. 2. If stress and emotional eating are your issue, really focus on prioritizing sleep. You can think of sleep as kind of like a willpower boost. Consider therapy or journaling and try habit stacking. More on that in a moment. And also, this is critical, remove junk food from your environment, especially during vulnerable moments. It's about constructing an environment that will support your success. And 3, if habits and environment are the issue, try meal prepping to reduce the convenience barrier to access healthy foods. Preparation is key. And also use this habit stacking technique to create healthier defaults. So what is that? I mentioned it now twice. Habit stacking. It's one of the most practical and powerful behavior change tools you can use for long-term weight loss and sustainable health improvements overall. Habit stacking means pairing a new habit with an existing one so the current habit acts as a trigger or anchor for the new behavior you want to adopt. Instead of relying on motivation or willpower alone, you stack the desired behavior on top of something automatic that you already do. So you create a contract with yourself. The formula is basically after current habit, say brushing your teeth, I will new habit, say doing 10 push-ups. The reason it works is it reduces friction. You don't need to remember to do the new behavior once you've made this contract with yourself. You've tied it to something you already do. And also it leverages automaticity. The more automatic the base habit, say brushing your teeth, the more likely the new habit will become automatic too. And also, it builds identity. It generates small wins that compound over time. Habit stacking changes your self-perception. You start to think, "I'm the kind of person who takes care of my body or does push-ups after I brush my teeth." It just becomes automatic and you become proud of yourself, and that really matters. It can push you forward, you being your own cheerleader. And now changing gears a little bit, Of course, this video includes an obligatory commentary on GLP-1 medications like Ozempic and Wegovy. The fact is they aren't magic, and they come with risks like any powerful pharmacotherapy, any powerful medication. But my concise two cents on the matter is this: they can be powerful catalysts for behavior change. We now better understand how GLP-1 receptor agonists quiet food noise in the brain, creating space for people to make more thoughtful, conscious choices in a world that's honestly beset with dietary landmines and booby traps and food pushers. So while I absolutely do not think we can afford to lose sight of the forest for the trees— obesity is a lifestyle disease— we also need to recognize that environmental conditions are so far from ideal that tools in many different forms, including pharmacologic tools, can and should be used in a targeted and responsible manner. GLP-1 medications aren't alone the answer, but that doesn't invalidate them as a tool that, in their best form, again, are catalysts or can be catalysts for behavior change. For more, if you're interested in this topic, I've assembled a series of videos on GLP-1 medications, mostly focusing on the interesting metabolic mechanisms. Here it is, you can check out this video, It's pretty long, it's a 1-hour long composite just to warn you, but you'll definitely learn a lot from it if you take a watch. So now, wrapping up, let's return to that 144-page genetic report. Page 105 told me I have obesity. Genetically, at least. It listed 3 separate variants that predicted I was high risk. That page delivered a verdict of sorts. And yet, here I am. I've never struggled with obesity, because whether by luck or learned behavior, and I think it's 99% luck, quite honestly, my environment aligned with the entirety of my biology. That's the real point. Genetic risk is not destiny. That report was incomplete. It told me what might happen, not what would happen. And that distinction is where power lives. The truth is we all have something like my page 105. Maybe it's a genetic predisposition. Maybe it's trauma, a difficult childhood, food insecurity, chronic stress. Whatever your page 105 says, it does not write your chapters. No matter what's in your genes, you still have agency. You can still change your habits. You can still change your environment. You can use tools that work for you. So yes, yes, genes matter. Life isn't fair. Genetics aren't fair. Biology isn't fair. But your choices matter as much or more. And the best choices are the ones made with understanding, compassion, intention, and information. You write the story, and that story isn't over yet.