July 14, 2020

If you happened to catch my podcast episode “Joel Greene Podcast Part 1: How To Reboot The Gut, Eat Cheesecake Without Gaining Weight, Amplify Any Fasting Protocol & Maximize Fat Loss” last week, then you're already familiar with health and nutrition legend Joel Greene. 

This man is the future of real-world health and nutrition, today, and his new book, The Immunity Code, was one of the most nitty-gritty deep dives into “rebooting your body” that I've ever read. Shedding light on an entirely new way to think about caring for your body, Joel describes how to learn to control your immunity, health, and aging using cutting edge science-based techniques (or hacks, if you will) to steer immunity for health and to slow, or even reverse, aging. ​

Part 2 of that epic podcast series is coming this week, but in the meantime, in today's article, a guest post by Joel himself, you'll discover how immune-centric health works (the idea that immunity, and the mechanisms that govern it, are at the center of every major system in the body) as well as how your immune system and fat cells are deeply connected and intertwined with one another. Nearly everything you've been taught about body fat will be questioned as it leaves the purview of weight loss and fitness and becomes a crucial part of a much bigger, more comprehensive umbrella. You'll learn how body fat is a major control mechanism over whole-body immunity and how it is connected with your immune system, aging, and even cancer.

Fat Cells 101

You, and most others out there, have been “hypnotized” to believe that fat loss is the key to optimized health—that once you get your body fat down to an ideal percentage, your health problems will magically disappear.

However, this is simply not true. The process of losing fat puts your fat cells under tremendous stress, and this stress leads to a whole host of issues for your immune system. It can even cause you to become more susceptible to gaining weight in the future. 

To understand this, let's begin with the emerging scientific view that cells are controlled from the “outside in.” In other words, signals from outside your cells affect the inner workings and inner state of those cells. These signals can be biochemical (proteins, lipids, ions, and gases) or mechanical (forces exerted on or produced by the cell). Mechanobiology tells us that mechanical loads on cells act as pivotal signals, a term known as mechanotransduction. Mechanotransduction describes how physical tensioning forces are central to the programming of cells in various ways. For example, when fat cells shrink, a number of mechanical forces come into play, and the net of these forces enact a series of events—all of which converge around immunity.

See, when a fat cell shrinks, the cell gets injured in a number of ways because fat cells are super vulnerable and very easy to damage. Look at the diagram below, and notice where the nucleus is located for each cell. 

While most cells have a nucleus in the center, fully protected by the surrounding cytoplasm, fat cells are different. The interior is taken up mostly by fat, and the nucleus is pushed up against the cell wall, making the entire cell far more vulnerable. Because it takes only a small amount of mechanical stress to damage a fat cell, body fat has what amounts to an exoskeleton, called the extracellular matrix (ECM), to protect the cell.

The ECM surrounding your body fat is extremely complex. In response to mechanical stress, the ECM can become stiffer, and stiffness in and around fat cells has a lot to do with the storage and burning of fat. 

To illustrate, think of brown fat, or brown adipose tissue (BAT), which contains mitochondria and is involved in cold weather adaption and thermogenesis. You're probably familiar with the mechanisms behind brown fat from Ben's previous articles, but the actual mechanism that allows brown fat to begin uncoupling fatty acids is mechanical tension. Filaments within brown fat cells change the tension of those cells, similar to the way that tensing your muscles up uses more energy. It is the stiffness within and between the ECM that actually controls the process of burning fat. A lot of back and forth “programming” takes place between the ECM and the cell. Mechanical stress on the ECM can reprogram fat cells; and, in return, fat cells can program the ECM to become stiffer over time. 

This is an important concept to understand before diving into what is really true about what happens when fat cells shrink.

How Losing Fat Injures Your Fat Cells

Think of a home with brick and mortar walls. Now imagine one day the bricks shrink. The shrinking bricks cause a “misfit” between the brick and mortar, meaning the mortar no longer fits snugly around the bricks. The misfit would cause a transfer of mechanical forces, the weight of the wall would shift, and the walls of the home would become severely damaged.

This is what's known as mechanical sheering stress, which is a stress caused by a transfer of mechanical forces. This is the same exact same thing that happens to your fat cells when you lose fat.

Now think of your fat cells as the bricks and the ECM surrounding those fat cells as the mortar. When you lose body fat, the misfit that is created between your ECM and your fat cells produces mechanical forces that reprogram both your ECM and fat cells and—this is important to remember—injure your fat mass.

Mechanical sheering stress is not the only physical force that can injure your fat cells, there's also traction stress. I hope you liked my first analogy because here comes another one to explain traction stress (or pulling stress). Imagine a flash flood has hit your home, your entire house gets moved 30 feet off of its foundation, and a repair crew attaches a steel cable to your home to pull the house back onto the foundation. Moving your entire house from a single point will create a lot of damage—walls get cracked, the water heater gets knocked around, etc.

Something very similar happens to your fat cells from fat loss. Traction Stress is stress that occurs when you move an object by a single point, which can be very damaging. See, muscles move using special fibers called actin filaments. Fat also uses actin filaments, but fat does not work like muscle and is not as easily movable. Fat is anchored to the ECM by actin filaments, and when fat cells shrink the actin filaments are stretched or broken, creating stress fibers in response. These stress fibers then work to pull your fat cells back and re-anchor them to the ECM. In the process, critical components of the cell, such as the nucleus, get kicked out of place and the cell becomes injured.

How Injured Fat Cells Become A Problem

After a fat cell shrinks, heat shock proteins are produced to fix the cellular damage. Heat shock proteins are also a mechanism that drives inflammatory signals, and they tend to stick around a long time.

New science has shown that after you lose fat, lingering inflammatory signals from heat shock proteins can provoke weight regain. This is just one immune mechanism, I will introduce several more.

While your top priority after fat loss is to keep the fat off, your fat mass's top priority is to repair the micro-cellular injury. A prominent researcher at Maastricht University in the Netherlands, E.C.M. Mariman, has studied the effect of mechanical forces on the ECM extensively. No, that's not a misprint, he and extracellular matrix share the same acronym. His work has shown the mechanical stress on the ECM from fat loss must be resolved to avoid further injury to the fat mass as a whole. How is the stress resolved? It's resolved by the fat cells refilling with fat. In other words, weight regain is inherent to the injury repair process caused by mechanical forces of fat loss. Biology wins. Your priorities lose.

In several papers, Dr. Mariman has shown the body has two options to repair injury from shrinking fat cells:

1. Refill the fat cells with fat. 
2. Reshape, or remodel, the ECM.  

Reshaping the ECM takes a lot of energy, and during fat loss, the energy needed to reshape the ECM may not be available. So what happens? Option 1 (refill the fat cells with fat) happens, because it’s easier for your body to just refill your fat cells than to reshape the ECM. In the brick and mortar analogy, if the mortar has to be redone, its major reconstruction. The same goes for your body—reshaping the ECM after fat loss a major remodel.  

The high cost of reshaping the ECM is well known with obesity. If you push your hand against a steel mesh fence, your hand quickly gets red and inflamed. Something similar happens in obesity: Fat cells push against the ECM, thereby creating chronic inflammation. To compensate, the ECM reprograms obese fat cells to make stiffer collagen fibers.

The stiffer fibers load into the ECM to hold the expanding fat together; and the stiffer the ECM becomes, you guessed it, the harder it is to lose fat.

A stiffer ECM also drives many health complications. The stiffer collagen fibers work like signal beacons and drive higher populations of inflammatory immune cells into your fat, looking something like this:

Stiffer ECM=> More inflammatory immune cells => Altered immune status => Harder to lose weight => Health issues

As you can see, the membrane that surrounds your fat exerts vast control over your immunity. People with metabolic disease, i.e., body fat problems, are more susceptible to viruses because when the health of one's body fat is compromised, it drives whole-body immunity in the wrong direction via populations of inflammatory immune cells, thereby affecting whole-body health.

There's a key type of stiff collagen that's seen in obesity, which is collagen 6. Collagen 6 stiffens up the ECM and drives cancer and inflammation. It also drives “crown-like structures” in your fat. These are areas where swarms of inflammatory immune cells surround dead fat cells in the shape of a crown. Several surprising studies have shown that the reshaping of the ECM from fat loss can induce similar characteristics of the ECM that are found in obese individuals!

• A 2010 study in the Journal of Cell and Molecular Life Sciences first postulated that characteristics of the ECM seen in obesity could be replicated by fat loss.
• In 2015, Dr. Gabriel Martinez-Santibañez and a team of researchers at Harvard Medical School demonstrated that fat loss could replicate the characteristics of inflamed fat found in obesity. The researchers found the culprit to be the remodeling of the ECM. The act of fat cells shrinking drove stiffer collagen fibers into the ECM, and the stiffer fibers resulted in inflamed fat.

The pioneering Harvard study by Dr. Martinez-Santibañez found something else very surprising. Paraphrasing from the research, “…weight loss significantly increases stiff collagen fibers in the ECM, which promotes long term metabolic problems despite losing weight.” With studies like these, a new view of what happens from fat loss is emerging. The problem seems to lie with the repeated remodeling of the ECM.

In other words, the direction of the remodeling of the ECM—outward from weight gain, or inward from fat loss—may be less important than the frequency of repeatedly reshaping the ECM. 

Stiffer, more resilient types of collagen fibers can deposit into the ECM during ECM remodeling. These fibers then emit signals that direct and control immune cell populations. In turn, these populations of inflammatory immune cells can control whole-body health. Here are just a few things collagen fibers can do:

• Direct baby fat cells to mature into other types of cells like macrophages.
• Direct fat cells to make stiffer fibers for the ECM. 
• Promote cancer onset.

Fat cells and cancer cells are closely related in many respects, including their capacity for growth. Unlike virtually any other tissue, they share a nearly identical ability to continuously expand as well as similar metabolic mechanisms. Cancer cells utilize what is known as the Warburg effect, meaning they have a high reliance on glycolysis (a cellular biochemical reaction that splits glucose, glycogen, or other carbohydrates into pyruvic, or lactic, acid) to grow. Similarly, fat cells utilize a “Warburg-like effect” to fuel growth, with the key difference being that fat cells are activated not only by growth (weight gain), but shockingly, this “Warburg-like effect” is also activated by fat loss during the reshaping of the ECM. After losing body fat, it takes a lot of energy to reshape the ECM. To do this, fat cells need enormous amounts of glucose. This drives the Warburg-like effect in fat cells. This Warburg-like effect in fat cells can actually feed cancer cells and is seen a lot in breast cancer, with a key player in breast cancer progression being cancer-adjacent adipocyte cells. These are fat cells that feed cancer cells the energy they need to grow and can develop as a result of ECM signals. 

ECM Stress => Warburg-Like Effect => ECM remodeling => Inflammatory Immune Signaling => Cancer

Fat is not simply fat, but something more like a mothership. It is a system, with multiple configurations, used for harboring many kinds of immune cells—including macrophages, eosinophils, innate lymphoid cells (ILCs), T cells, and B cells, which regulate immune homeostasis and inflammation.

Macrophages are your body's front line defense for innate immunity. You have different types of macrophages, some of which promote inflammation and some that reduce inflammation. In addition, fat also harbors stem cells that can become not only new fat cells, but also many other kinds of cells, including new immune cells. All of these things—fat cells, stem cells, immune cells, collagen fibers, and the ECM—all work together and are a vital component of your immune system. In fact, all of the major functions governing fat storage are controlled by macrophages. This is what I meant by configurations earlier—the specific mix of immune cells, genes, fat cells, collagen fibers, and stem cell fates. This all brings me to the main takeaway of this article:

As you age, gain weight, or chronically cycle your weight by gaining and losing body fat, your body fat takes on “aged configuration,” meaning your fat can become dominated by inflammatory macrophages, t-cells, and other kinds of inflammatory immune cells. When fat becomes immune-compromised, as in the case of obesity, old age, or cancer, your fat essentially acts like a giant immune cell factory, manufacturing inflammatory immune cells and signals that can literally control the immune status of your entire body. In fact, obesity is principally characterized as an immune disorder where fat mass becomes infiltrated with inflammatory macrophages. 

So What Can You Do About All Of This?

First, don't throw in the towel because now you think any weight you lose will automatically come back. Yes, weight regain is the inherent response to shrinking fat cells, but the good news is that this natural process can be offset with regular activity.

It's only when you remain sedentary that the natural cycle of the cell plays out.

So, stay active, but also take time to learn effective strategies for losing fat that'll steer you clear of the dangerous, neverending cycle of yo-yo dieting. Ben covers many such strategies, including one that actually induces your fat cells to die, in this article he published last week: “Why You’re Not Losing Fat, How To Turn Your Body Into A Fat Burning Machine, The Biggest Fat Loss Mistakes & Why Your Fat Loss May Have Come To A Screeching Halt.”

Additionally, I've prepared 3 easy fat loss hacks for you today that you can put into practice right away. These 3 techniques will allow your body to utilize immune mechanisms to control not only your body fat, but also the immune cell populations in your fat.

1. Visceral Fat Hack

• WHAT: Low-calorie gelatin to decrease visceral fat.
• WHEN: Before bed.
• HOW: Consume one serving of gelatin approximately one half hour to one hour before bedtime. I use good old fashioned Jell-O, but as a Ben Greenfield Fitness subscriber, I imagine this grass-fed, pasture-raised gelatin may be more up your alley.  (Note from Ben: I like to mix up some gelatin with a little bit of hot water, add in some coconut milk or kefir, then a little bit of stevia, put it in the fridge, let it set until firm, and then I'll have this giant pan of jello I can cut a small square from every night. It's an amazingly quick way to satiate your appetite and heal your body while you sleep. 

Gelatin is loaded with glycine, and ingestion of glycine has been shown to modulate the inflammatory status of visceral fat, the most dangerous kind of body fat—and reduce visceral fat by as much as 50 percent! Other benefits may include:

• Glutathione boost
• Reduction in oxidative stress
• Improved insulin function.

Glycine via low-calorie gelatin at night is a nice way to end the day and in the long term may have an impact on visceral fat. We have used this hack for nearly a decade at my company VEEP Nutrition.

2. Cold Fat Browning Hack

• WHAT: Ice, topical menthol, and (optional) a doorway or pull up rack.
• WHEN: Before bed, and upon waking in the morning before eating.
• HOW: Apply topical menthol to your problem fat areas. Then, lay a t-shirt (this is important to prevent burning!) across the same area and ice it for ten to twenty minutes. Finally, continue on to ab or core exercises of your choice for around 5 minutes. A Cool Fat Burner (use code BEN10CFB to save 10%) works great for something like this, but ice packs can also be used.

Cold induction helps to shift populations of immune cells. With this technique, you can change your fat from the kind that stores energy to the kind that burns energy. You will feel a cool supercharged sensation from both the ice and the menthol—both trigger brown fat production. You are literally changing the signal state of your fat, and it works immediately. This is powerful mechanobiology in real-time. Note: Do not do this for more than 7 days straight. Your body fat rapidly adapts to cold induction.

3. Senescent Fat Hack

• WHAT: Fisetin supplementation.
• WHEN: During morning fasting.
• HOW: With cold induction.

A nice way to give an added kick to cold induction in your fat is to add a Fisetin supplement to your morning routine. Fisetin, a phenol like quercetin, flushes senolytic non-dividing cells in your fat to magnify anti-inflammatory signals. It is one of the ways we remove old fat from the body. Fisetin has even been shown to enhance longevity. Ben goes more into fisetin for lowering inflammation, minimizing molecular dysfunction within cells, and enhancing cell function in chapter 19 of Boundless.

Summary

The modern era of weight loss and fitness can trace its roots back nearly seventy years. The underlying idea (a wonderfully simple, and very seductive idea) all this time has remained the same; body fat is simply stored energy, and all you have to do is lose it to be healthy.

Nearly every fat-loss program, routine, strategy, supplement, and diet you can think of has been based upon this foundation.  Ironically, none of these things have ever been based on what you just learned, what actually happens when fat cells shrink.

In the immune centric paradigm, control over macrophages becomes as important as diet or exercise. While we have just scratched the surface here, my hope in this article was to ground you in what is, and always has been, really true about how body fat really works. At the heart of how body fat works are immune mechanisms. Learning what they are and how to control them will take you into a new approach to your body—an immune-centric approach.

For more on immune centric health, you can pick up my book, The Immunity Code: The New Paradigm for Real Health & Radical Anti-Aging, here. Also, be sure to check out Part 1 of my podcast with Ben, “Joel Greene Podcast Part 1: How To Reboot The Gut, Eat Cheesecake Without Gaining Weight, Amplify Any Fasting Protocol & Maximize Fat Loss.“, and stay tuned for Part 2, which will go live this Thursday here.

Leave any thoughts, comments, or questions you have below, and I'll be sure to get back to you!