Shrinking Fat Cells’ Role In Weight Re-Gain, Health, Immunity, & More.


Today’s article is a guest post by Joel Greene, aka “the future of real-world health and nutrition, today.” Joel is a three-time repeat podcast guest of mine who first appeared in the episodesHow To Reboot The Gut, Eat Cheesecake Without Gaining Weight, Amplify Any Fasting Protocol & Maximize Fat Loss.” and “Joel Greene Podcast Part 2: How To Reshape Fat Cells, Enhance Repair During Sleep, Target Your “Circaseptan Rhythms,” Build Young Muscle & Get Rid Of Old Muscle.,” and most recently in “Carnivore Diet, Raw Beans, Lectin Myths, Pre-Sleep Gelatin, Apple Peels & More – Q&A Episode With Joel Greene!,“.

Joel also authored “Your Body Fat Is Your Immune System’s Mothership: The Mysterious Relationship Between Fat Cells & Immunity,” a recent guest post on my blog that I highly recommend you check out as a precursor to this article.

You can click here for Joel’s full bio.


Recently, I was approached by a physique competitor wanting my help with losing body fat. One look at this person and the last thing one would think is they needed help losing body fat. A veteran of many fitness competitions, they had the ultra-lean appearance most people only dream of. I responded by saying I don’t do pre-contest conditioning, it’s not my focus, and there are others who would do a better job than me at that kind of thing. They replied back explaining they didn’t want help for contest conditioning. Instead, they explained that after years of cycling body fat for shows, now in their late forties, they just can’t get lean anymore and wanted help overcoming the problem.

I bring this transaction up because it is no small thing. It represents something much larger than the transaction itself. It represents a tale of two paradigms.

It’s one thing for average people to have issues dropping body fat over time. Most people are not solution providers for body fat. It’s another thing entirely when a person who embodies a paradigm and an ethos about losing body fat—after many years getting and staying lean—has those same problems. It tells us something very important.

In one sense, this transaction highlights the end of an old paradigm and the beginning of a new one that is more pervasive and encompassing. The old paradigm says body fat is simply stored energy and all you have to do is lose it. And yet, even for a person who embodies that paradigm—a physique competitor with many years of experience getting in shape—the reality of how fat really works, and what really happens when fat cells shrink over time, is knocking at the door. Heralding that knock at the door is a more accurate and encompassing view of body fat. In this emerging view, immune mechanisms (immune cells, immune signals, genes, and proteins) exert vast control over not only body fat, but also aging. In this new paradigm where immune mechanisms dominate body fat, our approach to how we handle body fat needs to be immune centric.

The example of the physique competitor provides an insight into a reality in which many people are currently living. Over time, a number of immune mechanisms controlling body fat reach a critical mass. The net of this critical mass is that fat cells become very difficult to shrink. This is simply the reality of what happens to most people over time: The more seasons spent getting in shape, the worse the problem gets.

You have probably been coached to think the act of losing fat solves the problem. The truth, however, is very often the opposite. In many ways, shrinking fat cells begets a long-term problem that is only now beginning to be understood.

Hang on to this idea. We will return to it shortly.

In my previous article for Ben Greenfield Fitness, I made the rather shocking case that the act of shrinking fat cells is actually an injury. Since amelioration of injury is governed by your immune system, I further went on to say that fat loss is, you guessed it, controlled by immune mechanisms.

In today’s article, I want to close the loop and give you a foundation for a more accurate and more encompassing view of body fat. It’s going to change a lot of things. It will change how you think about losing body fat and your approach to losing body fat in the future.


How Immune Mechanisms Control Body Fat

To understand why an immune centric approach to body fat is necessary, you need to understand how immune mechanisms impact and control body fat. So, the first place to start is actually not your body fat.

See, with an immune centric approach, an understanding of body fat begins not in your fat, but in your gut.

It all begins with the body fat/gut lining axis. Here’s how it works: macrophages (types of white blood cells) are your body’s front line of defense for innate immunity. From the Greek words “makrós” (large) and “phagein” (to eat), these “large eaters” engulf and digest cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have the type of proteins specific to healthy body cells. The largest concentration of macrophages in your body resides in the lining of your gut, just below the cells that line the gut—the lamina propria.

When your gut lining is worn down—from, say, not enough fiber or too much fat or sugar in your diet—cell wall fragments of bacteria called lipopolysaccharides (LPS) penetrate into the lamina propria. (This is where the macrophages reside.) When the outer world penetrates into the macrophage defense layer, it’s an injury. You may not feel it, but it is an injury nonetheless. This injury, like all injuries, causes an immune reaction. Interleukin 6 (IL-6)—an endogenous chemical produced by your body wherever there is inflammation—becomes hyper-activated, causing a shift in macrophage populations. Think of this shift as having 50 soldiers on each side of a battlefield when suddenly, some of them switch sides. Interleukin 6 causes a change in macrophage metabolism that changes the signal output they produce. In turn, immune signals shift towards the kinds that make you susceptible to disease. After penetrating the gut lining, LPS and other bad bacteria can enter your bloodstream.

Once in the blood, LPS has an affinity for your body fat; and once in your body fat, LPS has a profound effect on macrophages that reside in your fat. LPS activates oxidative metabolism in macrophages. In other words, it makes them burn sugar. This causes them to polarize and flip to an inflammatory type. (In my book, The Immunity Code, I call this type “the Red Team.”) Imbalanced populations of Red Team macrophages in your body fat cause all sorts of problems.

The first, and the least of your problems when this happens, is weight gain. On a more serious level, the polarization of macrophages in your body fat influences a cascade of immune signals such as Interleukin-1B (which exacerbates damage during chronic disease and acute tissue injury) and the activation of the inflammasome (part of your immune system responsible for the activation of inflammatory responses). Activation of the inflammasome can have consequences across your entire body ranging from a high risk of metabolic disease to aging and even cancer. This is why LPS-mediated inflammation of fat is a key player in obesity.

As you can see, an immune centric approach to body fat begins in your gut, not your fat. Hopefully, you’re beginning to understand how this immune centric approach is far more encompassing—going beyond just body fat and involving other organs, immune cells, and immune signals. But, what about beyond the case of obesity? For example, the simple act of shrinking a fat cell. How do immune mechanisms work when your fat cells shrink?


When Fat Cells Shrink: What Really Happens

When your fat cells shrink, your fat mass remodels itself in a process known as extracellular matrix (ECM) remodeling. Check out my previous article here on Ben’s site to learn more about how ECM remodeling in your fat cells works.

In a nutshell, shrinking fat cells drive tissue remodeling of the ECM as well as the fat cells themselves. This can drive stiffer collagen fibers into the ECM, and stiffness in and around fat cells can drive inflammation and make it nearly impossible to lose fat.

The key idea to understand here is that inflammation is central to tissue remodeling. Post fat loss, one of the mechanisms that mediates inflammatory signals in your fat is heat shock proteins. Heat shock proteins are protein chaperones. Think of them as maintenance machines: When proteins get bent out of shape, heat shock proteins re-fold them.

It was once thought that heat shock proteins responded only to cellular stress from heat and that heat shock proteins are only good, but they can actually be both good and bad. A more refined view is heat shock proteins are highly involved in immunoregulation, meaning they can influence immune signals and processes. One of the hallmarks of shrunken fat cells is the presence of heat shock protein 60 (HSP60). In 2016, an article published in the British Journal of Nutrition was able to show the release of HSP60 in fat cells is driven by inflammatory stress from tissue remodeling. People who regain weight seem to have more HSP60 post fat loss. More HSP60 post fat loss provokes an inflammatory cascade as a result of your fat mass having to remodel. The net of this inflammatory cascade when HSP60 increases is weight regain. The important takeaway here is that this is what will happen to most people who lose body fat—the inevitable regain.

But this is only the start.


A Tale of Two Paradigms

In the old paradigm—the one where body fat is just stored energy—if you get your fat cells to shrink, success! Selfie time. This is the end of the story.

In the new paradigm, the one where body fat is governed by immune mechanisms, this is just the beginning of a story that will play out over many years and decades.

The process of regaining weight post fat loss has its own set immune centric dynamics. The act of regaining weight extracts a cost on your fat mass. Regaining lost body fat correlates to an increase in fat cell turnover and death. See, the act of shrinking fat cells is highly stressful on your fat mass. Fat cells are very easy to damage, there is a lot of tissue remodeling, and not every cell makes it through the remodeling process intact. It is this increase in dead fat cells, post fat loss, that has a very specific immunomodulatory effect. More dead fat cells drive higher populations of Red Team macrophages, and these altered Red Team ratios set off an innate immunity response.

A 2018 paper in the International Journal of Obesity was able to demonstrate the act of regaining weight, mediated by an increase in the Red Team macrophages, leads to the activation and proliferation of T-cells in your fat mass. The result is an activation of immune centric signals in your fat, and the net of these signals is to promote inflammation. Historically, the belief has been that this response is merely confined to obesity. An emerging view, however, is this process can happen in degrees mediated by weight cycling of body fat apart from obesity.

In other words, the same inflammatory dynamics created by shifting populations of immune cells seen in obesity can also happen in lean people simply by repeatedly losing and regaining weight. Also known as weight cycling, or “yo-yo dieting,” this practice is common in so-called “healthy, fit” individuals—especially people like wrestlers, UFC fighters, figure competitors, bodybuilders, endurance athletes, and any other exercise enthusiast who is attempting to “weigh-in” or optimize their power:weight ratio for a specific competition.

For a deeper dive into how immune mechanisms drive an inevitable outcome of shrinking and reinflating fat cells, you need to understand the impact of mechanical stress, mechanobiology, and mechanotransduction on fat cells, which I go over in this article.


The Secretory Associated Phenotype (SASP)

As you age, continue to gain and drop weight, and your fat is continuously remodeled, the immune centric makeup of your fat—now made up of stiffer collagen fibers, shifting populations of macrophages and t-cells, and immune signal cascades—begins to pass a critical mass.

It’s like a drumbeat that starts small and beats louder and louder as the years go by.

With age and the cycling of body fat, your fat mass takes on a Secretory Associated Phenotype (SASP) configuration, which refers to a configuration related to secretions from fat. In SASP mode, your body fat secretes inflammatory signals on a megaphone level: Immune signals and hormones from your fat promote the activation of several sets of genes—weakening immunity, driving inflammation, and speeding up the aging process.

Relevant to the current times we’re living in, once you understand how SASP mode ignites the fire of weakened immunity and aging, it becomes easy to see how obesity, old age, and inflamed fat correlate to greater susceptibility to viruses, including COVID-19.

SASP mode accelerates the progression of senescent (non-dividing) cells in your body; signals from fat then jump from organ to organ; your internal organs become inflamed; then, these same signals infiltrate your blood. Once in your blood, signals generated by the SASP mode of body fat ignite system-wide inflammation.

Fat actually renews itself from stem cells. When young and healthy, fat has a balanced mix of newly mature fat cells together with older fat cells. This gives your body flexibility to store fat or burn fat. Essentially, there is an equilibrium function with adipocytes, where the mix of young and old is maintained by selective apoptosis of old fat cells. When this equilibrium is thrown off, you’re left with more old cells and dead cells, which drive inflammation.

In other words, as you age, the process of stem cells maturing to new fat cells short circuits. Stem cells stop becoming new fat cells, and—as too many old fat cells accumulate and not enough young ones form—your body fat becomes imbalanced.

To make matters worse, stem cells can even change course. Stem cells in your fat can mature into immune cells, leaving you with an imbalance of Red Team macrophages! Your fat becomes a giant factory that produces inflammatory immune cells. This loss of fat cell renewal combined with increasing Red Team populations in your fat work together to jumpstart SASP mode, which, in turn, impairs whole-body immunity. It also accelerates the aging process. These changes then affect whole-body metabolism. Your fat neither stores fat nor burns it. Fat begins to get stored in places it should not go, such as organs and muscles.


Summary

We started with a simple idea: The ethos of the old paradigm—that body fat is simply stored energy, and all you have to do to lose fat is burn it off—is pure myth.

You’re now armed with the truth that…

  • The act of shrinking fat cells injures your cells,
  • Cellular stress mediated by mechanobiology drives a set of immune centric responses to repair and remodel your body fat,
  • Immune mechanisms kick in to mediate the fat loss injury, 
  • Heat shock proteins, stiffer collagen fibers, key sets of genes, macrophages, T-cells, and immune signals (including the inflammasome) all play an important role in a story that does not end when you lose body fat…

…and that this story is just beginning, culminating later in life when one day you realize that it’s nearly impossible to lose fat—all because you bought into something that was never true to begin with.

Additionally, this whole problem can become even more aggravated due to fat cell hyperplasia vs. fat cell hypertrophy from compounds such as linoleic acid.

For example, take two obese people who appear to be equal in size. Person A’s fat is the result of hyperplasia, which means they have more fat cells, but these fat cells never really grow in size substantially. This person, whose health from an outward perspective would appear to be on par with Person B’s health, is actually better off healthwise. Person B’s obesity is the result of hypertrophy, which means that their fat cell numbers are set, but the fat cells are increasing in size. The hypertrophic fat cell has a sort of “survival mechanism” which allows it to continue to pull in, and store more fat, and consequently leak not only fat, but also proinflammatory proteins. Fat cell hypertrophy leads to a wide variety of metabolic dysfunction, a concept discussed in Paul Saladino’s interview with Ben Bikman here at timestamp 1:34:53 and also referenced in this tweeted study by Paul.

The time for a new, immune centric, approach is far overdue.

In The Immunity Code, I make the case for a new order of operations. It has taken me nearly 8,000 words—in my first article “Your Body Fat Is Your Immune System’s Mothership: The Mysterious Relationship Between Fat Cells & Immunity.” and this one—to make the case that immune mechanisms dominate and control body fat.

So, while the minutiae of the solution are beyond the scope of a few articles, I want to leave you with what amounts to a new order of operations for body fat. From now on, consider the following framework your master list of steps to take for handling body fat. This framework surpasses the seventy-year-old paradigm of fitness, dieting, and weight loss. Fat loss can finally come into the 21st century under the umbrella of whole-body immunity, real health, and anti-aging.

  1. Restore the Gut Lining – The gut mucus layer is constantly renewing itself. In fact, it has a rate of outward growth that can even be measured, a “mucus growth rate.” In a healthy gut, the net effect is to push the gut bacteria away from the surface of the gut. When the rate of outward growth of the mucin layer slows, toxins like LPS can penetrate into the body and inflame fat. The first step is to restore the healthy growth rate of mucus. In The Immunity Code, I outline a general sequence of steps to do this that involve adding specialized carbohydrates, called human milk oligosaccharides (HMO), to help jumpstart a key mucin-producing bacteria called akkermansia. If you have read Ben’s book Boundless he has a host of additional solutions for fixing the gut in the “How To Fix Your Gut” section of chapter 13 of that book, including gut-nourishing compounds such as colostrum, glutamine, and bone broth.
  2. Recolonize the Gut – This step involves recolonizing your gut with commensal bacteria. Commensal bacteria are bacteria that confer benefits upon the host. For example, certain species of bacteria in the gut play a key part in helping your body to get and stay lean. One of the mechanisms is fasting-induced adipose factor (FIAF), a key protein that inhibits lipoprotein lipase in your fat mass. Certain bacteria increase circulating levels of FIAF and, in turn, help your body to better use fats for energy versus storing them. One of the easy-to-do steps at this phase is to add in apple pectin from apple skins and red phenol powder. Together, this combination provides the substrate, or food, needed by commensal bacteria to multiply.
  3. Spin Down Inflammation – One of the barriers to losing body fat is insulin resistance in fat cells mediated by immune cells like macrophages and T-cells. One of the ways you can spin down inflammation that I mention in The Immunity Code is to use a combination of cold induction, fisetin, and niacin. Fisetin is a flavonoid like quercetin. It helps to flush non-dividing senescent cells from your fat mass. Niacin has the effect of helping to flip macrophages from the inflammatory kind to the anti-inflammatory kind. Cold induction can also have a modulating effect on macrophages. By utilizing all three of these things in the morning prior to doing fat loss, it helps spin down immune cell-mediated insulin resistance in your body fat.
  4. Reduce Body Fat – I suggest reading part 1 of this article “Your Body Fat Is Your Immune System’s Mothership: The Mysterious Relationship Between Fat Cells & Immunity.” where I outline simple ways to reduce body fat that don’t involve dieting or killing yourself with cardio—namely, using low-calorie gelatin before bed to decrease visceral fat and a combination of topical menthol and cold to address your problem fat areas.
  5. Offset Mechanisms Opposing Fat Loss – We use the words “fat loss” and “weight loss” to describe the act of shrinking fat cells. For virtually all of human history, the act of shrinking fat cells coincided with starvation. Your body has numerous mechanisms to defend against starvation. One of those I detailed in The Immunity Code is lowered leptin levels, which coincide with shrinking fat cells. Lowered serum leptin post-fat loss drives long-term increases in eating behavior. Post-fat loss, one way to offset the mechanistic changes from fat loss is via very strategic eating to drive leptin but not add fat. For example, your body’s greatest capacity for thermogenesis is in the early morning. What this means is food is more likely to convert energy than fat. Research has shown that strategic breakfasts very high in protein and carbs can mitigate weight regain during active fat loss.
  6. Apply Anti-aging Protocols to Obtain Young Fat – You are not doomed to the SASP phenotype. There are a number of simple to-dos that are not time intensive that can be practiced on a daily basis as you age which will enable your fat to maintain a younger profile. For example, as dead fat cells begin to increase with age, this can lead to the formation of macrophage clusters called crown-like structures, which drive the inflamed aging phenotype. One way you can clear these structures is by activating estrogen receptor B (ERb). Silibinin is a natural flavonoid derived from milk thistle. Among its numerous properties, it works as a natural ERb agonist.

If you want to learn more, Ben and I dive quite deep into these steps in the podcast we recently recorded titled, “Carnivore Diet, Raw Beans, Lectin Myths, Pre-Sleep Gelatin, Apple Peels & More – Q&A Episode With Joel Greene!

Ultimately, the new umbrella for body fat is based on how fat has always really worked—what really happens when fat cells shrink. This connects the gut, immunity, body fat, and aging. The reality is all of these things have always been connected.

Additionally, each of these steps has a sub-order of operations. For example, with the gut, the protocols involving HMOs and red phenols are just the first steps in an order.

The first order of business in the new paradigm of body fat is not fat loss. That alone is a major shift. Instead, the first step is to seal and heal the gut lining. Without sealing the gut, you are not addressing the health of your body fat. To recap, step 1 in losing body fat:

  • Seal and heal the gut; In Ben’s book, Boundless, chapter 13 provides a comprehensive outline for this, including how to address:
    • Gluten, gliadin, and FODMAP sensitivities and food allergies…
    • Insufficient gut bacteria, stomach acid, and digestive enzymes (and low enzyme activity)…
    • Too much gut bacteria…
    • Yeast, fungus, and parasites…
    • Mold and mycotoxin exposure…
    • And more.
  • Once you’ve sealed and healed your gut, you can then move on to flipping the gut macrophage state from inflammatory to anti-inflammatory.

Notice that none of this involves doing any of the old things you’d normally do: count calories, hit the treadmill, diet strictly, etc. This is not a conversation that will go away any time soon, and once you understand and begin implementing what you’ve just learned, you’ll be lightyears ahead of everyone else in the game.

To learn more, be sure to check out “Part 1” of this article, “Your Body Fat Is Your Immune System’s Mothership: The Mysterious Relationship Between Fat Cells & Immunity.,” my recent podcast with Ben, “Carnivore Diet, Raw Beans, Lectin Myths, Pre-Sleep Gelatin, Apple Peels & More – Q&A Episode With Joel Greene!,” my first two podcasts with Ben, “How To Reboot The Gut, Eat Cheesecake Without Gaining Weight, Amplify Any Fasting Protocol & Maximize Fat Loss.” and “Joel Greene Podcast Part 2: How To Reshape Fat Cells, Enhance Repair During Sleep, Target Your “Circaseptan Rhythms,” Build Young Muscle & Get Rid Of Old Muscle.,” and—if you really want to dive into this stuff—my book, The Immunity Code.

What about you? Do you struggle with “yo-yo dieting” or finding it increasingly difficult to lose fat as you age? Leave your questions, comments, and thoughts below, and I’ll respond.


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