Your Fat Cells Remember! Can You Heal the Metabolic Scar of Obesity?

New research in a top science journal has revealed how fat cells retain a memory of obesity after weight loss, and how this could impact your ability to maintain a healthy body composition. I want to show you what they found in this new paper, reveal what appears to be a pessimistic story, but ultimately leave you with some important takeaways that I hope you'll find empowering. Or at least useful. Now, the paper in question was just published in Nature and is entitled "Adipose tissue retains an epigenetic memory of obesity after weight loss." Adipose tissue refers to body fat, and epigenetic memory, well, if you don't know what that is, I'll explain that momentarily with an analogy. But first, let me provide you with a framework, a background for this paper. You're probably aware of the yo-yo diet effect, whereby people who lose excess body fat are prone to gain it back. Think about The Biggest Loser, where people lose a ton of weight quickly, but typically if you follow them up, you'll find that their metabolism's slow and they end up gaining most, if not all, of the weight back, which is a real bummer. But is this weight regain phenomenon a purely behavioral phenomenon, Or are there deeper metabolic mechanisms at play? This new research argues the latter. In this study, researchers took cell samples from human patients who were always lean versus those who had a history of obesity but who had lost weight after bariatric surgery, and they measured gene expression profiles from their fat cells. The controls,, and also those with obesity at the time of surgery and 2 years later after substantial weight loss, at least a quarter of their body weight. And they found significant changes in fat cell adipocyte, as well as fat cell precursor, and also other cell type gene expression patterns. Overall, what the researchers found is that fat cells from individuals with a history of obesity, even after weight loss, showed downregulation —so less gene expression—related to metabolic functions, and upregulation—more gene expression—of genes related to inflammatory functions and inflammation. Thus, in the author's own words, they conclude that these results indicate that obesity induces cellular and transcriptional obesogenic changes in fat cells which are not resolved following significant weight loss. The fat cells retain a memory of having been fat. Fat cells from people who had previously had obesity were less metabolically healthy and generally more inflammatory. That was the big picture finding. Now, before I get into some more of the results, I want to do a quick nerd aside, nerd alert, a quick tangent. You can skip forward in the video a little bit if you don't want the details, but I actually did want to dig into the technique they used to measure gene expression profiles in case you're interested. So what they did, it's called single nucleus RNA sequencing, where the nucleus is kind of the conductor of the cell. And what they do is they take cells and they break them up, and then they separate out the nuclei via centrifugation, and then you can actually sort types of cells or cell nuclei with something called Fluorescence Activated Cell Sorting, or FACS, where fluorescently labeled antibodies are used to tag different nuclei from different cell types, and that permits them to be identified and sorted with a literal laser based on their fluorescent properties, which is freaking cool. It's actually just really cool that this even works. Anyway, that was the nerdy aside. Back to what matters for you. To get more granular in this study, the researchers did then experiments on mice where they fattened some mice with a high-sugar, high-fat obesogenic diet and then normalized the weight of those mice through dietary restriction on a normal chow diet and compared the mice who had obesity but recovered to those mice who never had obesity in the first place. And they found, consistent with the human data we already reviewed, that there was persistent expression patterns whereby genes that were downregulated during obesity with respect to metabolic pathways remained downregulated, things like fatty acid oxidation and mitochondrial signaling. And obesity also left an epigenetic memory in terms of increasing inflammatory pathways. So just like in the humans, metabolic pathways tend to be downregulated, inflammatory pathways tend to be upregulated. But now I want to get to how does all of this work? And I want to use an analogy. The analogy is this: your genetic code, your DNA, is kind of like a book. And even though all the cells in your body contain your full genetic code, they are different. Your eye cell is different than a bone cell is different than a skin cell. Why? Because different cells read different pages in the book. Some pages are open, some pages are shut, depending on the cell type. What's more, cells can bookmark or dog-ear various pages for easy access as they read through the book. In the cell, this is kind of like an epigenetic change, where tags are put on DNA or the protein complexes around which DNA is wound, and this makes it easier or harder to gain access to certain pages in your genetic code which changes the gene expression profiles in those cells. Hopefully that makes sense. And that's how cells develop a memory of past events, including the memory in fat cells of, "Oh, I was once an obese fat cell." If it's not too dark to say, and to mix in another analogy, it's kind of like PTSD for fat cells. Now, another really important question: are these changes functionally or clinically meaningful? And it would appear so. Human observational and clinical data suggest that those who have lost weight are more prone to put that weight back on. And although, of course, in free-living humans it's really hard to disentangle the effects of behavioral and constitutional inborn differences from those imposed from true epigenetic changes brought about by a history of obesity, you can do parallel carefully controlled mouse experiments, which they did in this study, and which should generalize to humans given that these pathways are pretty conserved. And this all does indeed strongly suggest that a history of obesity does predispose fat cells to take up more sugar readily—this was shown in the paper—build up fat stores more in response to insulin, and also things like develop fatty liver more easily. The history of obesity does leave a memory, a metabolic fingerprint on the body. Now, those are the main findings of the paper, and it's a bit of a dark story, I'll admit, because it suggests that having had obesity is kind of like a "screw you" from biology. No fair, right? Well, I have a different take and a few concluding thoughts that I want to share with you. First, It's true that a history of obesity, even if one is now lean, may put a person behind the metabolic 8-ball. However, this might not be permanent because bear in mind, those who had obesity in this study and then recovered from obesity had a relatively short time frame of being newly not obese as compared to the time course over which they initially developed the obesity, which presumably took decades. So what we don't know, but what I suspect, is that if someone is able to maintain a lean, healthy weight for a long enough time, the epigenetic memory may fade. Thus, it's possible, although not proven, that the longer you can maintain a healthy, lean weight, the easier it becomes. And I think that's an uplifting thought. Also, I'd maintain that your present lifestyle choices today, and tomorrow, and going on to the future, still have the dominant effect. Even if your metabolic road might be rockier, it doesn't mean you shouldn't or can't traverse it. These data do not say that one can't maintain a lean, healthy weight after having had obesity. They just kind of acknowledge that biology can be a jerk sometimes, and it can. Biology isn't always fair. All right, two, the epigenetic memory is not specific to fat cells. There were also changes, for example, in endothelial cells, that line your blood vessels. Thus, a history of obesity could predispose individuals to diseases like cardiovascular disease. Furthermore, and as pointed out by the authors, there are many cell types that remain to be assessed, like neurons and other brain cells. We've barely seen the tip of the iceberg with respect to how different past metabolic and environmental exposures can impact gene expression across the body over time. And then 3, knowledge is power. It truly is. Understanding these mechanisms is the first step to developing therapies and/or protocols to change our epigenome and engineer our advantage over what nature seems to have planned for us. Or to put it another way, Learning about these metabolic mechanisms teaches us how to best take advantage of our evolutionary priming to work with, rather than against, nature's sometimes confusing design. Now, I want to ask you, how do you feel about these data? Do they bring you down, or do they empower you? Do they take the wind out of your sails, or do they motivate you because you better understand what's going on in your body? I think any of these reactions is fair, but I also know for a fact that if you're watching this video up until this point, it means that you're metabolically curious. And in the arsenal of tools that you have to achieve excellent metabolic health, metabolic curiosity has to be at the top of the list. So good on you, and stay curious. I hope you found this interesting.