By Devaki Lindsey Berkson, DC

Fat cells have a bad rap. Understandable, as too many of us battle excess adiposity. Thus, we often regard fat cells as ugly, dangerous nuisances, keeping us out of tight-fitting designer jeans—upping our risk of heart disease, fatty liver, type 2 diabetes, and cancer. Or promoting inflammatory “angry” and cognitively dull thinking.

But deep “scientific dives” into fat physiology reveal that we can’t live without fat cells, as much as it seems frustrating to live with them. Fat cells, biology unveils, are a huge part of living healthfully, permitting humans to evolve and build cultures, as long as the fat cells themselves stay on a healthy “fat fate trajectory.”

Fat cells, as it turns out, are quite the gooey, complex populace. Since fat is complex, the more accurate term for fat is adipocyte tissue. I refer to these cells as both “fat cells” and “adipocyte tissue.”

A recent article published in the New England Journal of Medicine¹ plunged into the science of the “unappreciated adipose cell.” It got me thinking.

I used to be a speaker for weight loss clinics in California. I spoke across that big state on the topic of “no-fair fat.” The focus was partly on the explanation of the hidden mechanisms as to why certain persons struggle with excess fat cells more than others and how to minimize this fat handicap. I pointed accusing fingers at hidden food hypersensitivities as well as undiagnosed subclinical hypothyroidism and more.

Since that time, the galaxy of adiposity has enlarged. But even though science knows more and more, the planet is getting fatter and fatter. The rapidly growing global obesity epidemic,² its co-morbidity role in today’s Covid pandemic,³ its evolving role in promoting a growing epidemic of bone loss,⁴ the role of too many unhealthy fat cells in driving major debilitating diseases from diabetes to heart disease in both young and old are all wakeup calls: it’s time to understand fat physiology and translate this science into action so we can slow down this tsunami of adiposity, disease, and vulnerability.

So far, not many efforts are really working. And our chaotic politically correct culture isn’t allowing health experts to shout out the need to lose weight for fear of fat-shaming. Perhaps diving into fat physiology will hold some clinically effective answers to tame our fat cells to work “with” us rather than “against” us.

Mother Earth is all of one thing. Every single thing matters.

Even the lowly fat cell.

First off, fat cells are dynamic. They can enlarge and shrink. No other cell can enlarge or shrink like white adipose tissue (WAT). White adipocytes can swell from a diameter of 30-40 μm to more than 100 μm, an increase in volume by a factor of more than ten. Thus, fat cells are capable of more than doubling in mass and can then return to their fat cell baseline. You might experience this by losing twenty pounds, only to gain that fat right back again, or even more.

Fat cells are “plastic.” Over the last three decades, laboratories have collected a large body of evidence documenting and replicating that fully differentiated adipocytes have the physiological ability to “transdifferentiate.” In other words, they can morph in and out of each other.^5,6 Mature adipocytes undergo genome reprogramming and can turn into different cell types, serving different physiological roles. White fat can morph into brown fat. Or beige fat. Or back again. This has huge implications for your overall health and even the health of your individual organs, such as the liver and brain. This is one reason that the environment, how we eat, how regularly we exercise and what type of exercise we do, the chemicals we are exposed to, and the nutraceuticals we swallow from pre-conception as well as from womb to tomb can all influence “stem” cells, which give “birth” to fat cells, nudging fat cell fate.

Fat stem cells. Stem cells are cells with the potential to develop into different types of cells in the body. There are two main types of stem cells: embryonic stem cells and adult stem cells. They serve as both “birthing” and “repair” systems for the body’s cell populations. The “fat stem cell” microenvironment greatly contributes to terminal fat (or bone) cell fate. Fat and bone stem cells are in constant flux with each other, a fact that is also growing in appreciation, especially for its clinical implications. Unhealthy fat stem cells drive both the obesity and the growing osteoporosis epidemic.

Fat stem cells influence

• Whether white fat become brite or brown.⁷
  • How fat cells behave.
  • How fat cells can be lysed (broken down or destroyed) for you to be able to lose weight… or not.
  • How bone stem cells behave.
  • Adipose-derived stem cells (ADSCs)—repair and reboot tissues, via exosomes. used in regenerative medicine.⁸

Fat Cell Types

Fat cells aren’t simple. There are many types. Fat is a “polychromatic” organ, meaning it comes in varying colors secondary to their distinct physiologies and functions.  

White fat (White Adipose Tissue, WAT). This fat has a white, yellowish appearance. WAT protects organs. WAT stores energy as triglycerides, which are lipids. Stored energy allows us to interact with life without constantly needing to eat. When needed, free fatty acids are released during fasting periods. Stored calories allow humans to devote body, mind, and spirit toward building lives. If we eat too often, let alone too much, we store energy instead of using it, and those excess stored calories are a driving force of the obesity epidemic and why you are not fitting into those jeans.

Brown fat (Brown Adipose Tissue, BAT). Brown fat consumes energy and warms us by burning glucose and lipids to maintain thermal homeostasis. To do so, BAT is flush with mitochondria that are rich in iron-containing heme co-factors found in mitochondrial enzymes (cytochrome oxidases). Iron is brownish-red, giving brown fat its tone. WAT contains some mitochondria, but not enough to affect its color. These iron-rich brown mitochondrial enzymes enable BAT to convert chemical energy into heat, a process called adaptive thermogenesis. Brown fat requires “numerous” and “functional” mitochondria to perform adaptive thermogenesis.

When healthy, BAT⁹ is supposed to keep us from getting obese. Healthy thermogenesis helps us stay thinner rather than fatter. Many pathological states are linked to dysfunctional mitochondria—such as chronic fatigue syndrome, fatty liver, type 2 diabetes, and even sleep apnea—which can make an ill patient more overweight and more fatigued. The potential list is long and ever growing.

Dysfunctional BAT¹⁰ is a major contributor driving today’s obesity epidemic. The formation of BAT is called brown adipogenesis (making more fat cells). If we can turn on more brown adipogenesis, we may help treat obesity and metabolic disorders. As WAT gets more respect for its complexity and it is seen that WAT can be induced or coaxed into becoming brown adipocytes, there has been a surge of research into adipocyte biology to try to turn the Titanic of humanity away from global morbid obesity.

Beige/brite fat is made in the muscles. WAT can be “browned”¹¹ into BAT or brite adipose tissue^12,13 when you exercise regularly; genetics, healthy biomes, and specific nutrients also play a role.

Pink fat is made in breast tissue from white fat mixed with glandular tissue, giving this fat its color. Pink fat helps produce milk for lactation. “Excessive pinking”¹⁴ of breast fat may contribute to breast cancer.¹⁵

Bone marrow fat is inside bones. Bone marrow fat is an endocrine organ that secretes hormones. Its balance affects fat and bone stem cell function.

Dermis fat lies underneath the skin. Dermis fat (subcutaneous fat underneath the skin) contributes to bodily protection and shape.

White Fat Facts (WAT)

WAT exists as both visceral fat and subcutaneous fat. Subcutaneous fat isjust under the skin and is normally harmless. It may even protect against some diseases. Visceral fat is fat that wraps around your abdominal organs deep inside your body. You can’t always feel it or see it. In fact, you may have a flat tummy and still have visceral fat, called “thin fat.”

Fat’s number one job is the storage, use, and maintenance of energy. WAT stores energy as triglycerides, the main constituent of fat. When WAT enlarges with excess triglycerides, especially in dangerous locations like the torso, WAT becomes a nasty organ, capable of secreting pro-inflammatory molecules. We are learning that many diseases arise from excess inflammation (inflammation out of control).

Upper-body subcutaneous adipose tissue accounts for most of the systemic free fatty acids in the bloodstream. When fat cells break open or lyse (process of lipolysis) and release stored fatty acids, where the fat cells first came from (belly vs. thigh) affects where these fatty acids go into the rest of the body.

Belly vs Thigh Fat Dynamics

The first adipocytic environment that matters most is where fat cells are “birthed.” In other words, the location of fat matters.Excess visceral¹⁶ fat in the wrong locations (as they say in real-estate, “location, location, location”) can contribute to disease by pumping out pro-inflammatory cytokines that can travel far and wide throughout the body. White fat on the thighs is different from white fat on the belly. Belly fat cells expand, and larger fat cells are harder to break open (lipolysis) to lose weight. Larger fat cells store more pollutants. Some pollutants make fat stem cells birth larger and nastier-acting fat cells.

Belly fat creates insulin resistance.¹⁷ Accumulation of visceral belly fat over five years was found to be an independent predictor of the future development of type 2 diabetes,¹⁸ independent of baseline adiposity levels. In comparison, fat cells on the thighs are smaller fat cells. They are better acting and easier to lose. They don’t harbor pollutants or give off pro-inflammatory substances.

These fat cell differences are reflected in gaining extra weight.

• Weight gain in the upper body (abdomen/torso) comes mostly from expanded fat cells—large, potentially nastier-acting fat cells.
• Weight gain on the hips and thighs is in the form of new fat cells. Small. Less nasty acting.

Visceral fat lipolysis contributes a modest portion of free fatty acids in the bloodstream. Most visceral fat breakdown shunts much of these fatty acids to the liver. Excess belly fat is thus implicated as a major driving force in the sadly expanding fatty liver epidemic. Abdominal visceral fat drives insulin resistance, obesity, and other types of health issues far more than thigh fat.

An increase in visceral adiposity predicts diminished insulin sensitivity over ten years of follow-up,¹⁹ independent of the size of this adipose depot at baseline. Also, belly visceral fat plays a huge role in releasing pro-inflammatory molecules that can travel far and wide. They can cross the blood-brain barrier and inflame and shrink brain tissue. In essence, the bigger the belly visceral fat, the more shrinkage of precious brain tissue.²⁰

This sad scenario hits lower body muscle mass, too. The larger the belly, the more thigh muscle is lost (thigh sarcopenia).²¹ Thigh muscle helps prevent falls as we age. You don’t want to allow your waistline to expand more and more. This shrinks your brain tissue, your thigh muscles, and makes your insulin receptors less sensitive to their major food, glucose.

Over the last two years, while much of the world has been isolating, I have been flying around the country lecturing. What I see is scary: too many Americans are letting their torso fat threaten their overall health. Especially their brain health!20 This is part of the consequence of letting body fat get the better of you. To protect the rest of you, getting rid of excess belly/torso fat should be a goal of your daily workout, along with your diet and nutraceutical strategies.

Brown Fat Facts (BAT)

Brown fat begins to form in the fetus during the late second trimester of pregnancy. BAT protects newborns from cold while they develop the ability to shiver (thermogenesis). Then BAT keeps us warm and thinner throughout life. The distribution of adult human BAT is found in specific anatomical areas: the neck, shoulders, posterior thorax, and abdomen. These BAT depots drain directly into the systemic circulation, leading to rapid distribution of “warmed blood” to the rest of the body. That’s how BAT is supposed to keep us warm.

But I have patients that are on plenty of thyroid medication with normal thyroid labs, or endogenously healthy thyroid, but are still freezing. This can occur secondary to dysfunctional BAT. Since BAT is so flush with mitochondria, dysfunctional BAT can arise secondarily from mitochondrial dysfunction.²²

BAT contributes to more than keeping us warm. Long-term activation of BAT contributes to a range of health benefits that positively influence multiple systems¹⁰: gastrointestinal, cardiovascular, and musculoskeletal systems.

Regular exercise “browns” white fat, called adipocyte browning.²³ As lifestyle choices become less healthy, and pollutants mess with fat stem cells, brown fat can shrink and/or become dysfunctional. Exercise, regular exercise and not just strolling along, helps make more brown fat out of white fat. Recruiting of muscles releases myokines (PGC1-α-dependent) that drive WAT browning into BAT.²⁴

Humans have proportionally less BAT than smaller mammals, but contemporary humans may have even less BAT than is required to support their physiological and metabolic needs. Why? From too little exercise, too much eating unhealthy foods, and too much eating with too little time off for “fasting” and “food resting.” Exercise, through a wide range of mechanisms, induces a phenotypic “switch” in adipose tissue from WAT to thermogenic beige/brite and brown adipocytes. This brown fat activation lowers the risk of heart disease. It can force-feed skeletal muscle cells to consume glucose and lipids, rather than have white fat store them. (Human muscle cells marbled with WAT become less healthy-functioning muscles).

BAT in adults appears to have a substantial clinical “weight homeostasis effect,” as retrospective and prospective studies show an inverse association between BAT activity and BMI.

• The more BAT our bodies have, the less we have metabolic diseases.
• Brown fat releases substances (exosomal microRNAs) that can regulate gene expression. Not just in fat stem cells, but in other cells, such as some organ cells like the liver.  BAT can release exosomes that are health promoting, such as reducing metabolic syndrome (shown in a rodent model²⁵) and reducing inflammation.²⁶ Conversely, once cancer is present, WAT can morph into releasing tumor-promoting properties.²⁷ This may be one way that WAT contributes to worsening cancer dynamics. This may suggest that fat stem cell therapies may be contraindicated in some cases of cancer.

Stress, poor diet, mitochondrial unwellness, insufficient exercise, and even aging (less so if on HRT, in my opinion) promotes BAT atrophy. Too much white adipose tissue plus brown adipose atrophy and/or more “dysfunctional” BAT are driving the obesity crisis, along with endocrine-disrupting chemicals (EDCs) adversely affecting fat stem cells to birth nastier-acting fat cells (and potentially adversely affect bone stem cells).

Fat Cell Compartments       

Fat cells are not an island unto themselves. Microscopic anatomical analysis has shown fat cells also contain “non-fat cells” that co-exist along with fat cells, but in different cellular compartments. These other cells have their own diverse functions. Many of these cells “cross-talk” with other tissues and organs, far-and-wide throughout the body.

What is stored in fat gets mixed and merged with our blood and, thus, the rest of our tissues. For example, a stromal vascular fraction of fat cells is made up of cells, such as fibroblasts, blood and blood vessels, macrophages, and other immune cells, and nerve tissue. Since  fat cells are in constant communication with our blood, whatever endocrine-disrupting pollutants that fat cells may “horde,” like lead for example, are in constant communication with the rest of the bloodstream. These pollutants can be carried far and wide to other tissues, like your brain. Yes, lead does cross the sacred-blood brain barrier. (The ability of lead to pass through the blood-brain barrier is due in large part to its ability to substitute for calcium ions.²⁸)

This also means that fat cells are in communication with our nervous and immune systems. For example, both WAT and BAT participate in immunomodulation, the suppression and activation of the immune system, and each fat tissue releases distinct mediators of the complement system.

WAT, and more recently BAT, have been identified as integral and regulatable components of lipoprotein and bile acid metabolism. This means that our fat stores affect digestion. White and brown fat get in on nutrient bioavailability. They both give off signals to liver and skeletal muscle that affect and help coordinate how these tissues use nutrients to fulfill their job descriptions. Digestion is not just about digestive enzymes or probiotics!

It’s very clear that fat is not a lumpy island. We are one of a thing. Common sense says that all of our body communicates with all of our body. Inside our human body suit, we are made up of many things that all work communally together. At least we hope they are working together rather than the divide-and-conquer we are sadly seeing culturally today.

Brite Fat Facts

            Beige/brite fats are results of white fat cell plasticity²⁹ and distinct thermogenic adipocytes that have features of both white and brown adipocytes. These “brown-in-white” (brite) or beige cells emerge in the white adipose depots in response to cold temperature,³⁰ a broad spectrum of pharmacological substances, and thank god, by exercise. Exercise promotes beige/brite fat as well as brown fat. Thus, brite fat is also known as “inducible brown adipocytes.”

I have suspected for a long time that low-dose naltrexone³¹ induces brown and brite fat in this manner, too, as so many patients lose those last several pounds on it. So much so that they have tried giving it for smoking cessation to avoid extra weight gain, but that has not shown great promise.

Activation/inducing of brite adipocytes (along with brown) promotes “fat burning” over “fat storing,” making it less challenging to maintain a healthier weight. Brite fat cell induction (along with brown) also reduces diverse metabolic disease incidence.

Brite fat was first recognized in rodents. Lab animals were found to contain two populations of Ucp1-expressing adipocytes, with well-characterized thermogenic functions, or burning fat off as heat/calories. These were found in the classical interscapular brown adipocytes and in brite/beige adipocytes. Anatomical localization, gene expression profiling, and functional characterization of Ucp1-expressing fat cells indicate that brite and brown adipocytes also co-exist in human beings. Such adaptability of adipocytes is regulated by epigenetic mechanisms. This is why Dr. Bruce Blumberg found that exposure to certain endocrine-disrupting chemicals in the womb can affect epigenetics for the next several generations, making fat cells less able to have browning or beiging and keeping the animals fatter, even in fasting states. This is one way pollution exposure is partly driving today’s obesity epidemic as much as or more than what we eat or how much we eat.

Some folks make brite fat much more easily than others and have an easier time staying slimmer. Some folks are exposed in the womb to chemicals that keep them fatter. DES—a synthetic estrogen, fifty times more powerful than our endogenous estrogen—is the model chemical for endocrine disruption. Exposure to this in the womb (from prenatal vitamins³² containing it or from being prescribed it for a threatened miscarriage) alters the phenotype of the DES daughter,³³ making her epigenetically fatter.

Future generations get our genes. But these genes can be morphed especially while in the womb. Especially vulnerable are genes to fat and bone cells.

Methylation activates or represses gene expression depending on which residue is methylated. Histone methylation is an epigenetic marker for what nudges gene expression. mediates cellular memory to induce and maintain beige adipocyte characteristics. Enzymes that catalyze regulators of gene expression of brown adipocyte biogenesis can be tracked.³⁴ This tracking has demonstrated that fat cells have cellular memory, which can be nudged by environmental stimuli. The more you exercise, the more your fat cellular memory serves you well. But exposure to adverse stimuli, like environmental pollutants, can nudge fat cell memory in pro-fattening ways.

Exposure to endocrine disruptors that disrupt fat stem cells at the epigenetic level — which Dr. Bruce Blumberg calls obesogens³⁵—can upset this histone cart. The functional response of the adipose organ to a range of metabolic and environmental challenges highlights its extraordinary plasticity³⁶ while also highlighting that today’s dirty planet can morph our fat cells to act more nastily.

Stress does not help.

This illustrates that how we live affects how our fat cells live.

There is a “bi-directional”³⁷ ability of WAT to go to brite fat, but also, poor lifestyle choices and certain pollutants can reverse brite back to WAT. You are how you choose!

Pink Fat Facts

Emerging evidence suggests that pink fat is made from subcutaneous white fat, or WAT. In other words, pink fat comes from the trans-differentiation of subcutaneous white adipocytes. The “pink” component develops in subcutaneous depots during pregnancy. It is made from WAT and again demonstrates the plasticity of fat. Pink adipocytes are mammary gland alveolar epithelial cells whose role is to produce and secrete milk. Pink fat allows us to nurse the next generation. The pink adipocyte has recently been characterized in mouse subcutaneous fat depots during pregnancy and lactation.

Excessive “pinking” of breast fat may be a contributing factor to breast cancer. This remains to be explored but has been suggested by research from several labs.³⁸ The female breast is rich in adipose tissue. Adipose tissue has significant roles in the dynamics of breast changes throughout the life span of a female breast from puberty through pregnancy, lactation, and involution. There is a constant interaction between breast adipose tissue and surrounding cancer cells and vice-versa. Pollutants contained in breast fat can promote tumor microenvironment in favor of cancer.

Bone Marrow Adipoyctes (BMA)

Bone marrow fat is distinct from white, brown, and beige adipocytes, indicating that the bone marrow is its own “unique” adipose depot. Adipocyte tissue was first identified in human bone marrow more than a century ago, but we didn’t understand much about it. Human arrogance thought it had little functional significance. When did Mother Nature ever invent anything without a purpose?

Bone marrow adipocytes³⁹ are the most abundant component of the bone marrow microenvironment. Recently, BMA was found to serve as an “endocrine organ” that secretes adipokines, cytokines, chemokines, and even growth factors.

Bone marrow fat cells, and even the total mass of bone marrow fat cells, have critical function and influence. Bone marrow fat mass needs to be in a state of Goldilocks “just right” balance—not too much and not too little—to keep physiology humming. When bone marrow fat increases in response to certain pathological signals coming from a variety of sources, fat stems cells and even bone stem cells can take a serious hit.

Dr. Bruce Blumberg, whom I met at a Cooper conference and interviewed for my breakthrough book on endocrine disruption (Hormone Deception,⁴⁰ McGraw-Hill 2000) and on my podcast (Dr. Berkson’s Best Health radio #133) has demonstrated that when bone marrow fat mass excessively increases, fat stem cells go rogue.

What can cause bone marrow fat to excessively increase? Endocrine-disrupting pollutants commonly found in food, air, water, and personal care products. Even exposure in the womb (in-utero) matters. When bone marrow fat mass increases beyond the balance point, this can upset the balance of bone stem cells.⁴¹ Fat stem cells and bone stem cells are in a constant dance. When mass of bone marrow fat cells goes too high, nastier-acting fat cells are birthed that are much more resistant to weight loss measures, making it much harder to lose weight in 2022 than it was in 1952 (when we had much less endocrine disrupting chemicals inside our environment and bodies). Also, when the mass of bone marrow fat cells enlarges excessively, bone stem cells mass can pathologically lessen.

The Intimate Link Between Fat and Bone

Bone formation is complex and tightly regulated. We learn in school that we build bone with osteoblasts. and break down bone with osteoclasts. Throughout life, bone is in dynamic balance, constantly building up and breaking down. This harmony involves a complex coordination of multiple bone marrow cell types.

• Osteoblasts birth from a common archival cell, a cousin to adipocytes. Herein lies some of the intimacy. Osteoblasts come from marrow mesenchymal stem cells (MSCs).
• Osteoclasts come from hematopoietic stem cell precursors (HSCs) along the myeloid differentiation lineage.

Bone formation by osteoblasts and resorption by osteoclasts is responsible for continuous bone “remodeling.” Imbalance between bone formation and bone resorption is a risk factor for a variety of health issues and pathologies, from bone issues such as osteopetrosis, osteopenia, and osteoporosis⁴² to autoimmunity and even to cancer and obesity.

This balance between bone breakdown and buildup depends upon the tightly controlled commitment of MSCs⁴³ to ensure that bone will keep up with the body’s demands, continually manufacturing when the body needs more bone. Thus, MSCs have a lot to do with bone homeostasis and indirectly with many downstream potential health issues.

Although a variety of cell types can be derived from MSCs, the “commitment” of MSCs to either adipocytes or osteoblasts has been specially implicated in certain diseases. If MSCs commit to making less new bone, then bone marrow fat content is increased, which increases the risk of osteoporosis. What tweaks MSCs to make less new bone? Aging, obesity, excessive inflammation, and certain blood cancers. With less bone stem cells and more bone marrow fat, the risk of metastatic cancer increases. Remember, bone marrow fat gives off growth factors. The more bone marrow fat, the more growth factors. These can encourage cancer cells to travel and kill. BMAs may function as a pivotal modulator of bone metastasis of breast cancer.⁴⁴

It’s All About Balance

There is a “yoga” to be maintained between bone stem cells and fat stem cells that affects bone health as well as fat cell health. If either goes rogue or behaves in an aberrant manner, they can adversely affect each other.

If fat stem cells nudge aberrant skeletal stem cells (SSCs), this reduces osteoblastic, or bone building, which in turn reduces bone mass while increasing marrow adipose tissue. Bones get thinner. You get fatter. Numerous in vitro investigations have demonstrated that fat-induction factors inhibit osteogenesis and, conversely, bone-induction factors hinder adipogenesis.

Disharmony between the delicate balance of adipo-osteogenic differentiation of MSCs creates excess fat at the expense of bone.

What’s a growing trigger? Endocrine disruptors. Specifically, endocrine-disrupting compounds (EDCs) that specifically act on fat stem cells to make them commit to aberrant fates.

Dr. Bruce Blumberg and EDC Obesogens⁴⁵

Dr. Bruce Blumberg has demonstrated that specific endocrine disruptors can hasten the morphing of increased fat stem cells at the expense of bone stem cells. He showed that tributyltin—the now banned chemical that was painted on the bottom of boats for many decades to prevent the buildup of barnacles, etc.—when given to pregnant rodents, epigenetically altered the fat stem cells of the next several generations, even without further exposure. They became fatter, and the fatness resisted weight loss measures. Even fasting didn’t make the next generation of animals lose weight. And this was demonstrated by exposure to only ONE endocrine-disrupting chemical. We now live in a soup of many thousands of endocrine disrupting chemicals.

The peroxisome-proliferator-activated receptor γ coactivator 1-α (PGC-1α) is a critical “switch” of cell fate decisions whose expression decreases with aging and from exposure to endocrine disruptors. Loss of PGC-1α promoted nastier fat archetypal cells being made instead of skeletal ones—promoting obesity and at the same time, loss of bone density. Deletion of PGC-1α in SSCs impaired bone formation and indirectly promoted bone resorption while enhancing bone marrow fat accumulation.

Conversely, induction of PGC-1α blocked osteoporotic bone loss and MAT accumulation. How does PGC-1α do this? Mechanistically, PGC-1α maintains bone and fat balance by inducing TAZ,⁴⁶ a transcriptional co-regulator. TAZ⁴⁷ is a main regulator of bone organ growth and biology.

How we live effects TAZ. Excess sugar ingestion, excess processed foods, and/or excess stress hormones, as well as excessive production of the pro-inflammatory cAMP pathway (often inversely related to release of sufficient melatonin during a sufficiently “dark” night), increases loss of PGC-1α.

This may go to show that a worse diet, with more stress (anyone living outside this pandemic?) along with too much light at night (hey, that’s the whole Western hemisphere), exposed to an endocrine-disrupting chemical soup, may be at risk of worse bones and worse fat cells, starting at the marrow level.

But there is hope. We are not born with all the fat cells we will ever have. We make new fats cells all throughout life.

If the “obesogen hypothesis” by Dr. Blumberg is accurate, then the more contemporary fat cells we are living with are more resistant to normal and proper behavior. However, the hope comes from the fact that normal fat cells have a “turnover” rate of eight percent a year. This means fat cells are recreated every fifteen years throughout our lives. This fat cell turnover is faster than many other cells, such as that of the heart cardiomyocytes, and similar to bone osteocytes. This means that there is hope about endocrine disruptors and fat cell fate. If we detox. Eat well. Eat less. Eat more plant foods. And exercise. That is one reason I recently formulated and designed two new products to help clear toxins and keep physiology humming (Receptor Detox and Hormone Balance & Protect available at https://drlindseyberkson.estorerx.com/).

This “renewal” of fat cells is done through “pre-adipocytes,” which can be nastily tweaked by endocrine disruptors to act less normally and more frustratingly. But they can also be tweaked to act more normal and help you battle excess adiposity by detoxing, decreasing pollution exposure, and lifestyle choices in multiple life domains.

At the cell level, plasticity of the fat cell[xlviii] is provided not only by stem cell proliferation and differentiation but also by direct trans-differentiation⁴⁹ of fully differentiated adipocytes via stimuli that induce genetic expression reprogramming—such as the chemicals you may be exposed to while eating fish flesh, or standing in an unfiltered shower, or through various exposures to diverse plastics. 

Chronic exposure to some endocrine-disrupting pollutants—obesogens—can act on mature WAT and tweak them genetically to be more “problematic” fat!

If nothing else can encourage us to go more “green,” perhaps the promise of less frustrating fat and the hope of thinner waistlines might. What a great motivation to go green.

When I was a distinguished scholar at the Center for Bioenvironmental Research at Tulane University, the last e.hormone conference we held was all about effective remediation. There are many scientific and lifestyle ways to turn the Titanic away from the global obesity and bone loss epidemics.

The Hormone Family and Fat

Hormones are a family of proteins that are the most powerful signaling molecules in the body. Like Rodney Dangerfield, they often “don’t get no respect.” But another underappreciated feature of hormones is that they function and dysfunction together. If one hormone, far off, is having issues, such as resistant leptin or too little testosterone, this can affect other hormones. Like thyroid. Or estrogen. Or adiponectin. If there is too much of one, it can diminish another. This is because they can often “sit” and “signal” on each other’s receptors. Hormones are powerful. But potentially promiscuous. Fat cells, by producing hormones, get in on all these incestuous politics. Just saying….

Leptin keeps us in a normal-size body suit. It’s a hormone made by adipose cells and enterocytes (gut wall cells) in the small intestine that regulate energy balance. Leptin keeps us from overeating by inhibiting hunger, which in turn diminishes fat storage in adipocytes. Some people suffering with obesity have “leptin resistance.” Detoxing their receptors may be helpful in reversing this.

Adiponectin⁵⁰—fat cells, muscles, and the brain make this hormone, which regulates glucose and fatty acid metabolism. But it’s mainly made inside fat cells. It sensitizes insulin receptors. Of course, the brain mainly consumes oxygen and glucose most of the time. So does much of our body. So, adiponectin drives physiology on a huge scale. Adiponectin also helps the liver do many of its jobs more appropriately. The production of adiponectin increases following regular exercise! This is yet another way exercise improves energy and glucose metabolism. Low levels of adiponectin are associated with obesity, Type 2 diabetes, fatty liver, atherosclerosis and probably more.

Adipokines. Beyond these hormones, adipocytes and the other resident cell types produce dozens of other “adipokines” that affect local and distant physiology, good and bad. For example, adipokines can promote nasty pro-inflammatory molecules, such as proinflammatory tumor necrosis factor α (TNF-α) and monocyte chemotactic protein 1.

Estrogen. WAT produces the sex hormone estrogen in both genders. More WAT promotes more estrogen, but in the form of estrone, the more “pro-carcinogenic” form of estrogen. It signals “growth” via the first estrogen receptor (ER alpha) more than estradiol and estriol. Excess WAT makes lots more estrogen, which can lead to early puberty in young girls. In this way, fat cells can alter hard-wired biologic milestones of reproduction. Men who are overweight, sit too much, drink too much alcohol, and eat foods with high microplastic content can make excessive estrone that can lead to breast development in males, called gynecomastia, which is presently treated by surgery. This is on the rise. Lowering the WAT burden, cleaning up lifestyle factors, and sometimes replacing testosterone can get at cause rather than just the effect.

You can have too little WAT. Too little white fat stores occur in anorexia nervosa, some cases of amenorrhea, and lipodystrophies, all of which can interrupt menstruation. Too little WAT can halt menstruation as estrogen levels go way too low.

Fat Cells as Hoarders That Crosstalk

Fat cells are not totally separate from the rest of the body. About five percent of fat cells are in constant communication with our bloodstream 24/7. Whatever is stored inside fat cells slowly releases into the bloodstream from this five percent of the fat cell in communication with our blood. This has been known for a few decades (I wrote about this in Hormone Deception a number of years back). Thus, whatever is sequestered in fat cells over a lifetime merges with every cellular nook and cranny inside you. This is a fundamental unappreciated action of adipose tissue.

This is partially what the concept of detoxification is about. Once we realized that fat (and other cells, like bone for example) can “sequester” pollutants, heavy metals, pesticides, etc. which, over a lifetime, slowly leak out and mingle and merge with all of our cellular real estate, that underscores the need for “cellular housecleaning”—detoxification. This also gives us some understanding as to why sudden and severe weight loss, over a relatively short period of time, can cause toxic exposure to the body (and brain). It sometimes results in such gallbladder pathology that the person—now happy to be suddenly thinner—unhappily learns they may need to have their gallbladder removed.

Fat cells chit-chat far and wide. Adipose tissue contains various cell subtypes that play critical roles in not only regulating adipogenesis and thermogenesis, but get this, “inter-organ communication!”

Adipose cells also contain proteoglycans inside an extracellular matrix. Proteoglycans⁵¹ give fat physicochemical capabilities that allow fat to enlarge and shrink dynamically. Proteoglycans allow fat cells to withstand “pressure,” and provide hydration and swelling pressure to the adipocytes, enabling them to withstand compressional forces. This allows fat to “protect” what it surrounds. Like organs. But proteoglycans can get glycosylated in “good” ways, as in enzymatic reactions, or in “bad” ways, because of dietary choices that drive unhealthy glycosylation.⁵² The more processed foods, sugar, and high fructose corn syrup that you eat, the less compliant of a protective job your fat cells afford your organs. Diet affects everything!

Obesity

Obesity is a world-wide epidemic, but especially in the US. Obesity is the number one co-morbidity that drives severe Covid. One of my colleagues, an ICU doc in Idaho, confided that most of what she sees in the ICU are obese patients.

What drives obesity? Let me count the possible ways:

• Excessive triglyceride storage (which is why tracking triglyceride levels in patients is critical, and you don’t want to go much higher than 150).
• Excess WAT
• Dysfunctional BAT
• Dysfunctional hypothalamus/body crosstalk (Animal studies suggest it may have something to do with the hypothalamus/hormone/body crosstalk going haywire, and we already know that obesity itself, besides extra WAT, also disrupts the ability of the hypothalamus to stimulate BAT energy expenditure in a normal way.)
• Dysfunctional hunger hormones
• Dysfunctional sex steroid hormones
• Dysfunctional thyroid
• Gut illness/infections that contribute to BAT and hypothalamic/whole body cross talk miscommunication

Starting in early adulthood, lean Americans are mostly headed toward a chubbier future. Lean younger US adults tend to gain an average of 1.1 pounds per year, which challenges the morphing quality of fat cells. They meet this challenge by enlarging.

• The larger the WAT cells, the more dysfunctional BAT and its mitochondria become.
• Increased pro-inflammatory signals are sent to organs far and wide.
• More health-damaging pollutants are stored and become in constant contact with our blood supply that reaches tissues and organs far and wide.

If children, teens, and young adults start out overweight or obese, their weight gain in mid-life can increase substantially. Covid and lockdown have not helped. When many patients come back into the office now, the first thing they say with a defeated smile is, “I gained that darn Covid 15.”

By the fifth and sixth decades of life, a large increase in WAT stores more triglycerides and tamps down much of the protective effect of healthy fat cells. More WAT, less healthy functional BAT.

            Ultimately, hypertrophic WAT keep growing and expanding. Getting more alien-like. Waxing WAT and waning BAT restrict the ability of oxygen to diffuse from the capillaries into the adipocytes. This hypoxia constitutes a biologic red alert for the cells, altering over 1,000 genes to express in unhealthy ways. More resistance to local insulin. More resistance to all adrenal hormones. More inflammation. More cellular damage.

            When the WAT can no longer expand, then a flood of triglycerides rages throughout the body. Once the serum levels of triglycerides start to rise about 150, this is starting to occur.

            Triglycerides accumulate in skeletal muscle. enter the liver, and worsen insulin resistance. Any attempt at losing WAT becomes near impossible with a fatty liver and the insulin resistance it imprints onto local tissues. Fatty liver is rising in epidemic fashion, even in children.

            Obesity is a risk factor for fatty liver, but so is unhealthy ergonomics. Obesity works by putting pressure on musculature in the back of the throat from the extra weight. But so does unhealthy posture. Children who are raised on screens (phones and tablets) jut their chin forward and, in a manner, push their musculature similar to that of holding extra weight.

            Fatty liver creates insulin resistance and makes it almost impossible to lose weight. If one has fatty liver, this must be identified and fixed in order to lose more weight, and to have the liver available to perform so many of its myriad other functions.

            P.S. You might identify some cases of fatty liver by a below normal, high-density lipoprotein (HDL) blood level, as HDL is only manufactured in the liver. Ultrasounds of the liver can identify fatty liver, but the new liver elastography (FibroScan) is much more sensitive to fat deposits and to fibrosis and scarring.

            Excess triglycerides hiding away in organs and creating havoc is called “lipid toxicity,” which drives all metabolic diseases and the potentially worse outcomes of Covid. Why? Because lipid toxicity damages immune responses. That’s why obesity is also associated with an increased risk of many types of cancer, including cancer of the breast, uterus, ovary, esophagus, stomach, colon, or rectum, liver, gallbladder, pancreas, kidney, thyroid, and meninges, as well as multiple myeloma.

Nutrients and Hormones That May Help Lessen the Obesity Epidemic

The main function of brown adipose tissue (BAT) is to burn off energy as heat. This is a process mediated by “uncoupling protein 1″ (UCP1), which is located in the inner mitochondrial membrane. This protein releases ATP, which uncouples oxidative phosphorylation so energy can be turned into heat. White adipose tissue can be “nudged” into expressing UCP1 cells. This is the back-copy of what is happening with the “browning” of WAT to BAT. The browning of WAT into BAT helps keep us warmer, healthier, and not too overweight.

            The UCP1-mediated browning of WAT can be enhanced by specific nutrients—butyrate,⁵³ a short-chain fatty acid, and resveratrol,⁵⁴ a plant compound found in some foods and skins of grapes and some nuts. And fermented foods.

Butyrate. Short-chain fatty acids (SCFAs) play an important role in the host system. Among SCFAs, butyrate has received particular attention for a robust effect on host immunity, particularly in supplying energy to enterocytes, the single layer of cells that make up the gut wall, as well as help producing local gut immune cells.⁵⁵

Butyrate also is an inflammation controller to help control human host homeostasis. How can butyrate control inflammation? Let me count the ways.

Butyrate enters the cells through the Solute Carrier Family 5 Member 8 (SLC5A8) transporters, then works as a histone deacetylase inhibitor (HDAC) that inhibits the activation of nuclear factor-dB (NF-κB), which “down-regulates” the expression of IL-1β, IL-6, TNF-α. This means that butyrate tamps down inflammation. In this way, butyrate is famous in functional medicine circles as an anti-inflammatory and immune modulatory55 tool for the gut wall.

Meanwhile, butyrate also acts as a ligand to activate G protein-coupled receptors GPR41, GPR43, and GPR109, promoting the expression of anti-inflammatory factors.

Further, it can also suppress the expression of pro-inflammatory chemokines to reduce inflammation. By the way, it also suppresses excessive appetite!⁵⁶

Butyrate is not only a gatekeeper of the gut wall and of taming excessive inflammation; it also helps us avoid getting obese. Let me count these ways, too. Butyrate has been shown to prevent diet-induced obesity, hyper-insulinemia,⁵⁷ hyper-triglyceridaemia and fatty liver (hepatic steatosis). Butyrate does this through several mechanisms.

Butyrate helps maintain healthy “gut-brain neural circuitry.”⁵⁶ This has input into our energy intake, portion control, and enhances burning off fat by fat oxidation. Butyrate also improves insulin sensitivity and increases energy expenditure in mice and most likely does this in humans, too.

Where butyrate especially shines in helping with weight loss, as well as healthier levels of triglycerides and insulin, is by boosting browning of WAT to BAT.

How do we consume butyrate? Butyrate is found in resistant potato starch, raw green organic banana flour, lentils, white beans, and cooked and cooled potatoes and rice. Foods rich in butyrate are ghee, organic cow’s milk, butter, goat’s milk, breast milk, and parmesan cheese. When celiac disease was not well understood, one of the first doctors to save failure-to-thrive infants, accomplished this by giving them raw green bananas. The resistant starch helped heal their gut and keep them alive. This was the first use of resistant food starch as medicine.

Resveratrol. Resveratrol⁵⁸ is a polyphenol, the micronutrients inside plants, and there are about 8,000 identified so far. Resveratrol also helps brown WAT into fat-burning BAT through quite a number of routes. Resveratrol and its derivative pterostilbene⁵⁹ activate BAT from white fat by promoting the browning action, by promoting the mitochondria that make brown fat brown, and by protecting activity against glycation, which protects the inner membranes of mitochondria, especially in brown fat.

Both resveratrol and pterostilbene induce thermogenic capacity in interscapular BAT by increasing mitochondriogenesis, as well as enhancing fatty acid oxidation and glucose disposal. This says that patients with mitochondrial dysfunction ought to make sure they eat and supplement robustly with resveratrol. It’s a mitochondrial “Adam,” birthing more mitochondria so your brown fat can serve you better.

Resveratrol promotes browning of BAT by another platform—by upregulating an insulin receptor, the peroxisome proliferator-activated receptor (PPAR). This underscores resveratrol as an “insulin sensitizer.” Resveratrol also induces brown fat-like phenotype by activating peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). It also reduces lipid accumulation inside fat cells (WAT), possibly by activation of mammalian target of rapamycin (mTOR). Resveratrol has yet another trick up its “browning” sleeve: it promotes biome diversity and healthy biome infrastructure, which also nudges WAT toward BAT. It is so influential in this that there is an axis named the Gut Microbiota-Adipose Tissue Axis.⁶⁰

Resveratrol is found in grape skins, peanut skins, pistachio skins, micro-greens, tomatoes, cocoa, and blueberries, bilberries, cranberries…and wine. The more resveratrol on hand, the healthier calorie-burning BAT. That is one reason to eat less “junk processed food” and consume more plant food.

Resveratrol is not easily absorbed. To get tissues rife with this protective flavonoid, plant foods and/or supplementation need to be taken regularly for months, if not years. Slowly, through healthy choices over time, our tissues accumulate healthy levels of resveratrol. If you do supplement, consider companies that have, in safe ways, “processed” their resveratrol to enhance its bioavailability. It is so poorly absorbed that it takes a lot of exposure, over lots of time, to make sure your piggy bank reserves are full enough. It is fat soluble, so it is better absorbed when consumed with a high fat meal.

Fermented foods for better fat metabolism. Foods that are fermented have been naturally processed to create healthy substances, such as lactic acids that boost weight loss and healthier biomes. An international team of scientists from Japan found that fermented soybeans improve fat metabolism and help block some effects of diet-induced obesity and possibly pollution. They showed that mice on a high fat diet, supplemented with fermented veggies, gained less body mass and had lower levels of fat and cholesterol after three weeks as compared to mice on the same diet but not fed any fermented food (they used fermented okra,⁶¹ but also miso from soy in some other peer-reviewed studies). Mice fed fermented soy also had less visceral and subcutaneous fat than mice on a high-fat diet without any fermented food.

Why? Fermentation creates Aspergillus oryzae and Aspergillus sojae, which are typical aspergillus fungi used to produce soy sauce and miso, and okra. They do the magic. But you would have to consume the fermented food regularly—at least five days a week over a few months—to get the benefit.

There are many types of fermented foods: kimchi, yogurt, kefir, fermented pickles, fermented string beans, umeboshi plum paste (1/2 to 1 tsp/d makes it very easy to get this), and on and on. I love a cup of miso in the evening and add 1 tsp. of fermented gluten-free soy sauce and some granulated garlic to give it more nutritional and taste bang for my buck. Fermented soy has more protein and a higher total phenolic content—an indication of higher antioxidant properties—but due to the fermentation process, folks who are reactive or allergic to soy can often handle it better without adverse issues, than soy foods that are not fermented.

Nitric oxide. In a rodent model, sustained nitric oxide was given as well as a high-fat diet. This boosted the hormone lipase (which my new product Hormone Balance & Protect also does); and compared to control rats, there was loss of fat, increased browning of white fat, no loss of muscle, a reduction in the size of fat cells in epididymal white adipose tissue, improved glucose tolerance, and decreases in fasting serum insulin and leptin levels as well as protection against non-alcoholic fatty liver disease.⁶²

Aging, Hormones, FSH. Most of us think as we age, we inevitably get fatter. And the battle gets harder. What drives this? Hormone loss. But it turns out it is not just hormone loss, as also an elevation of FSH.  FSH rises in both females and males as we age. This turns out to be part of the “gaining weight as we age” issue.

FSH helps younger males produce testosterone. In women, it stimulates the growth and recruitment of immature follicles in the ovary, essential for female fertility. It oversees reproduction on both males and females.

But like most things, FSH has a lot more actions than just reproductive. (Just as we are learning that all sex steroid hormones have a lot more actions than reproductive).  A younger, lower level of FSH, is part of staying lean and more youthful. For example, “lower” FSH levels help protect bones in both sexes. While high FSH, independent of sex hormones, stimulates bone destruction.

Although conflicting, studies in rodents and humans during the last decade have provided genetic, pharmacological, and physiological evidence that “elevated” FSH levels that occur in the face of normal or declining estrogen and/or testosterone levels directly regulate bone mass—and adiposity.⁶³ Keeping FSH lower, in hormonally replaced patients, not only helps how they “feel,” but also one’s mass. Or…torso size.

Recently, an efficacious blocking polyclonal FSHβ antibody was developed that inhibited ovariectomy-induced bone loss and triggered white-to-brown fat conversion accompanied by mitochondrial biogenesis in mice. Moreover, additional nongonadal targets of FSH action have been identified, and these include the female reproductive tract (endometrium and myometrium), the placenta, hepatocytes, and blood vessels. Thus, FSH elevations are endothelial unfriendly—another reason to monitor this in your replaced patients. Both genders.

PS: This info comes from prestigious groups (Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Division of Reproductive Endocrinology & Infertility, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado).

Turns out that there are a number of extragonadal actions of FSH.⁶⁴; FSH is now being shown, by the group above, to have “input” into mitochondria of fat cells as well as angiogenic activity on blood vessels.⁶⁵

We know that when women and males get onto HRT, the plasma levels of estradiol and testosterone increase. FSH decreases.

Elevated FSH is being linked to age-related weight gain, bone loss, and even cognitive decline.⁶⁶ Pharmaceutical companies are competitively looking for FSH humanized antibodies to follicle-stimulating hormone (FSH) to promote weight loss, bone health, and cognition improvement. This is a very hot area of research. But of course, hormone replacement is the easier and, in my opinion, more natural approach.

Meal Timing. Brigham and Women’s Hospital is the second largest teaching hospital of Harvard Medical School. In one of their recent studies,⁶⁷ their researchers demonstratedexperimental evidence that late eating causes decreased energy expenditure, increased hunger, and epigenetic changes in fat tissue that combined, keeps “love handles” on, no matter your weight loss efforts.  Moral of this new research story, avoid regular late-night nibbles while Netflix binging. Late night eating alters fat cells to work against your weight loss efforts.

De-stressing is critical, too. It’s not just what we eat, but how much we eat.Excessive caloric intake is thought to be sensed by the brain, which then activates thermogenesis as a means of preventing obesity. But if BAT is dysfunctional, this protection mechanism gets thwarted.

            Stress does not help. The sympathetic nervous system, through the beta-adrenergic receptor (betaAR)^68,69 action on target tissues, is the efferent arm of this homeostatic mechanism. If the sympathetic nervous system is on overload, it blocks healthy BAT and thermogenesis. You are stressed, you overeat, but you can’t induce adequate thermogenesis to right plump wrongs.

            A healthy balance between sympathetic and parasympathetic nervous systems is needed to achieve thermogenesis post overeating. Thus, stress plus excessive eating and snacking sets up chubbier and more unhealthy fates.

How to Heal Our Fat Selves

We may need to exercise harder and live smarter to outwit our WAT and the contemporary nasty fat stem cell. I think it’s worth it. By the way, when you perform moderately active aerobic exercise, your muscles secrete a fat-fighting hormone called irisin, which fights fat with a one-two punch. First, irisin appears to activate genes and a protein that transforms calorie-storing white fat cells into brown fat cells, which continue to burn energy after you finish exercising. Second, irisin appears to inhibit the formation of fatty tissue. So, keep moving. It’s the fat-taming mantra.

• Keep moving.
• Detox. Detox. Detox.
• Consume fermented foods daily.
• Take butyrate and resveratrol. Daily.
• Over 40 years of age, consider nitric oxide boosters.
• Consider Receptor Detox and Hormone Balance and Protect.
• Identify subclinical hypothyroidism and treat.
• Get your hormones tested and balanced by hormone replacement if need be.

Test, track FSH. Wow, huh?

Remember, the human body is really all of one thing. Everything affects everything else. We are our own planet.

Mother Earth is all of one thing. Every single thing matters. Even the lowly fat cell.

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Dr. DL Berkson is considered a thought leader in functional medicine. Dr. Berkson has been lecturing for CMEs to MDs, pharmacists, DCS, NDs, and nutritionists for more decades than her ego wants to admit.

Dr Berkson wrote one of the breakthrough books on endocrine disruption. Based on this book, Hormone Deception (McGraw-Hill 2000 Awakened Medicine Press 2016) she was invited to be a distinguished scholar at an estrogen think tank at Tulane University (Center for Bioenvironmental Research) where she studied with the scientists that discovered the first two estrogen receptors and launched the EDC field.

Her book Healthy Digestion the Natural Way (Wiley 2002) was the first gut, nutrition, spirituality digestion book and a long-time best seller. Its sequel is a breakthrough book creating a new field — Nutritional Gastroenterology. Her latest book, Sexy Brain, warns of environmental castration and how sex steroid hormones rule the brain.

Dr. B presently works at the Naples’ Center for Functional Medicine (Dr. David Perlmutter’s old clinic) where she initiated the first functional renal program and adjunctive nutritional/pharmaceutical/hormonal support program for breast cancer survivors. 

Berkson hosts the Dr. Berkson Best Health Radio Show (soon to be called Agile Answers), and launched a membership for practitioners – Smart + Heart  during the pandemic. She writes for substacks.com under Agile Thinking.