The dominant female (estrogens) and male (androgens) sex hormones play important roles in determining the amount and location of body fat throughout much of our adult lives. Your age and hormonal stage in life (for instance, a twenty-something versus a sixty-something) largely determine how and when these hormones get produced. The ovaries make the highest amount of estrogens, mostly estradiol, in women of childbearing age. These compounds induce monthly ovulation during an active menstrual cycle. In fact, the word “estrogen” is defined as any chemical that makes the uterine lining proliferate (grow). Young women produce large amounts of estradiol in their ovaries, while young men produce high levels of androgens, such as testosterone, in their testes; levels of both hormones decrease as we age. In men, and in postmenopausal women, estrogens do not come principally from the sex glands. Instead, fat and a variety of other types of cells produce estrogens, which mostly act where they are made rather than being secreted in large amounts into the blood.65 The natural shifts in these sex hormone levels during the aging process are associated with changes in body fat distribution.
Changes in growth hormone production as we age also affect body fat. Growth hormone helps stimulate cell growth and division, is pumped out by the pituitary, and is essential during our younger years when we are developing rapidly—growing taller and building bone and muscle. Levels of growth hormone naturally begin to wane as we age, and this slows down our metabolism. Growth hormone supplementation is becoming popular for its “antiaging powers” (that is, to spur weight loss, improve the appearance of skin, and increase muscle mass more easily), but such use is controversial and may be associated with a heightened risk for cancer and an earlier death.66
Simplistically, you might think that restoring hormone levels to what they were when we were young is a good idea; perhaps you have seen pictures of a certain seventy-something doctor who looks like a young bodybuilder in advertisements on the Internet. Searching for the hormonal “fountain of youth” is a big business; however, it should be viewed in this light and not as a pursuit of good health. What is good for young people is not necessarily good for older adults. In reality, the same hormones may have different effects across the life span and result in different outcomes on health and disease. This is an important concept to understand because it relates directly to how substances such as obesogens and EDCs can have different effects across the life span. As you are probably aware, after menopause women tend to gain weight. This shows that loss of estrogens promotes weight gain and, therefore, that estrogens prevent weight gain. However, as I will explain, estrogens play a different role earlier in life. Exposure to excess estrogens before birth or during early life promotes obesity later in life. So the way an estrogen-like substance affects a prepubescent girl will be different from how that same substance affects a grown woman. This will become very important in our discussion of endocrine disruption later in the book.
Fat in your body serves many functions beyond keeping you warm, insulated, and cushioned. But remember, location matters. You might want to melt away the unsightly fat under your arms and on your thighs, but you would probably be better off worrying about the fat you do not see because it is wrapped snugly around your internal organs. People who outwardly do not appear to be obese can have high levels of harmful but hidden visceral fat that puts them at a much higher risk for diseases than people who appear fatter because they carry their weight as rolls of the unsightly subcutaneous fat most of us want to be rid of.
What is it about visceral fat that strongly links it to disease risk? Although scientists are still working out all the details, there are plenty of clues pointing us toward some answers. But to understand these clues, you must first understand the different types of body fat and how location dictates their impact on the body.
Broadly speaking, body fat can be split into two fundamental categories: essential fat and storage fat. Essential fat is necessary for normal, healthy functioning and is found in relatively small amounts in your bone marrow, organs, central nervous system, and muscles, among other places. Men do not need as much essential fat as women (about 3 percent versus 12 percent of body weight) because essential fat in women includes fat in their breasts, pelvis, hips, and thighs that is critical for normal reproductive function. It follows, then, that reducing your body fat to near or below these levels, no matter how much you like your new appearance, will have negative health consequences. This could explain why some elite female athletes lose their monthly periods and why underweight women often suffer from infertility. Storage fat, on the other hand, accumulates beneath your skin (subcutaneous fat), in your muscles, and in specific areas inside your body. Overall, women generally have a higher percentage of body fat than men for childbearing reasons; they need that extra fat to meet the demands of pregnancy and lactation.
There are other ways to categorize body fat. The above categories of fat depots relate mostly to white body fat. New research in the past few years has revealed other distinctly colored fat types—from brown to beige in addition to white.67,68 Each of these different types of fat comes with unique molecular properties and health implications.
Brown fat is thermogenic—it uncouples metabolism from the formation of energy, which causes heat to be produced for the body (that is, it “burns” calories to produce heat). For example, human infants have quite a bit of brown fat (up to 5 percent of their body mass), which functions to keep them warm. Unlike white fat, which stores energy and produces hormones that are secreted into the bloodstream, brown fat tissue has many blood vessels. Brown fat acts more like a muscle in its ability to burn triglycerides to produce heat. In fact, brown fat cells and muscle cells are derived from the same precursor cell type. Although it was originally thought that only babies had brown fat, in 2009 researchers found small amounts of brown fat in adults. It is thought that an adult of normal weight will carry about two to three ounces of brown fat.
Beige fat, which was just discovered in 2012,69 is an additional type of “good” body fat, although we know less about this fat and how it works. Beige fat is another form of thermogenic fat that has properties of both brown and white fat. Beige fat develops in areas of white fat in response to various activators, such as exposure to cold. Relatively little is known about the origins of beige fat. One school of thought holds that beige fat is derived from white fat, whereas others have shown that beige fat is produced in response to cold from a type of stem cell located around blood vessels in fat.70 The activities of both brown and beige fat cells reduce metabolic disease, including obesity, in mice and are associated with leanness in humans. Induction of beige fat is being explored as a promising new therapy for type 2 diabetes.
In distinct contrast to the relatively small amounts of brown and beige fat found in our bodies, white fat is the plentiful energy-storing type of fat found throughout, particularly in the hips, thighs, and belly and under the skin. White fat is intended to store energy in the form of triglycerides, and the most benign place for fat to be stored is subcutaneously. Excess visceral (internal) white fat storage is unhealthy; you will often see having too much of this fat referred to as abdominal, central, or android obesity (they all refer to the same thing). Visceral white fat is metabolically different from subcutaneous white fat. Visceral fat actively releases fatty acids,i inflammatory compounds, and hormones that can ultimately lead to higher low-density lipoprotein (LDL, or bad) cholesterol, elevated triglycerides, increased blood pressure, and insensitivity to insulin, which often leads to type 2 diabetes.
One long-established explanation for the toxicity of visceral fat has been its relationship to an overactive stress response in the body. Increased stress leads to higher production of glucocorticoids (such as cortisol), which raise blood pressure, elevate blood glucose levels, and increase the risk of cardiovascular disease. These are definitely important factors, but we also need to consider the role of the liver and the concept of lipotoxicity—a metabolic problem that results from the accumulation of fat molecules in tissues and organs where they do not belong.
Unlike other types of body fat, visceral fat cells are unique in that they release their metabolic products directly into the portal circulation—the system of veins that carries blood from your intestines to the liver through the portal vein. Consequently, visceral fat cells that are enlarged and full of excess triglycerides dump free fatty acids straight into the liver. Many of these are converted by the liver back into triglycerides, some of which are stored. However, some of these fatty acids are not easily bound to glycerol by the liver and are released into the general circulation. This allows them to collect in places that are not intended to store fat, such as the pancreas, heart, and other organs. This can lead to organ dysfunction and, in turn, dysregulation of insulin, blood sugar balance, and cholesterol. All of this activity fuels biological pathways that can result in increased and widespread inflammation, which is not a good thing for overall health.
Large fat cells leak fat that attracts immune cells such as macrophages, which try to pick up this excess fat. Leaky fat cells also produce proteins that induce local inflammation, attracting other immune cells, leading to sustained inflammation. Inflammation per se is not necessarily destructive; inflammation is an important first step in healing from an injury. Inflammation is necessary for survival and serves as an indication that the body is trying to defend itself against something likely to be harmful. Without inflammation, we would not be able to combat foreign invaders such as pathogenic bacteria, viruses, toxins (natural poisons), and toxicants (man-made poisons). Inflammation kicks off the natural healing mechanisms in our bodies, temporarily revving up the immune system to take care of, say, a sprained ankle or cold virus. Inflammation is intended to be a temporary response that stops when the healing process is under way.
But what happens when the process is always “on” and the immune system is permanently keyed up? The biological substances (hormones, lymphokines, free radicals, prostaglandins, nitric oxide) produced during the inflammatory process harm cells throughout the body when they are continuously present. This type of inflammation is systemic—a slow-boil full-body disturbance that is usually not confined to one particular area. The bloodstream allows it to spread throughout the body; hence, we have the ability to detect this kind of widespread inflammation through blood tests. A classic marker that your doctor may measure in blood tests is C-reactive protein (CRP), which indicates an ongoing inflammatory process. One of the most important discoveries in modern medicine has been recognition that chronic (systemic) inflammation underlies many, if not most, chronic illnesses, including obesity.
Levels of inflammation may, in fact, help explain the difference between people who are obese yet apparently remain metabolically healthy and people who are obese and metabolically unhealthy. In general, obesity is linked to a higher risk of diabetes and heart disease, but some obese people do not develop high blood pressure and unhealthy cholesterol levels—factors that increase the risk of metabolic disorders. This phenomenon makes up as much as 35 percent of the obese population. A 2013 study showed that metabolically healthy people—both obese and non-obese—had lower levels of several markers of inflammation, such as CRP, in their blood. No matter what their body mass index was, people with favorable inflammatory profiles also tended to have healthy metabolic profiles.71
Study after study shows that there is a strong relationship between visceral fat and high levels of inflammation. In addition to visceral fat powering up inflammation, it can become inflamed itself, thereby generating a vicious cycle. Researchers from the Mayo Clinic showed in 2015 just how bad excess abdominal fat can be, irrespective of overall weight. Analysis of fourteen years’ worth of follow-up data collected from 15,184 people who participated in the NHANES III survey (Third National Health and Nutrition Examination Survey) found that people considered to be “normal” weight but who had flabby midsections (central obesity) were twice as likely to die from heart disease as those considered obese but whose fat was distributed throughout their bodies.72
These findings further point to the adverse effects visceral fat has on the body compared with subcutaneous fat. We also know that the increased mortality risk accompanying higher ratios of visceral fat is likely due, at least in part, to increased insulin resistance. When you are insulin resistant, your cells do not respond to the hormone insulin, which is key to their ability to use glucose from the blood for fuel. In turn, this causes the insulin-producing beta cells of the pancreas to synthesize and secrete more insulin. Insulin resistance almost always leads to type 2 diabetes because the beta cells will eventually become incapable of producing enough insulin to meet the demand. Diabetics have high blood glucose levels because their bodies cannot transport glucose into cells, where it can be safely stored for energy. Instead, this excess blood glucose has pathological effects on the pancreatic beta cells and on vascular endothelial cells (the cells lining blood vessels). Most of the negative consequences of type 2 diabetes involve defects in circulation, particularly in the small vessels in the eyes and kidneys and near nerves. About 80 percent of type 2 diabetics are overweight or obese, establishing a strong link between fat and diabetes.
In humans, fat tissue can first be observed by the fourteenth week of gestation, the time when the fetus is about the size of a lemon. This is followed by a second period of increased fat cell proliferation that continues after birth and lasts through adolescence. Fat cells are replaced at a rate of about 10 percent per year in adulthood; thus the tissue is not static. The contents of a fat cell change over time, and fat (and chemicals contained in this fat) stored in a cell that is recycled must necessarily be liberated in the process. Fat cells are derived from mesenchymal stem cells (MSCs), which are a special type of precursor cell found in the bone marrow and around blood vessels in fat tissue that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells), and adipocytes (fat cells), depending on the signals they receive from surrounding cells and tissue. Once formed, fat tissue, as you know by now, is dynamic. Fat cells are capable of growing to fifteen times their original size.73
We don’t know exactly what triggers the body to generate more fat cells and to maintain its set number of fat cells. It is recognized that by about the end of adolescence, our bodies “know” how many fat cells they will have, but how this happens remains a mystery. It was previously believed that once the number of fat cells is set, this number does not change and that these cells last for a lifetime. In a clever 2009 study that changed this thinking, Kirsty Spalding and Erik Arner, working at the Karolinska Institute in Sweden, used a by-product of atmospheric nuclear testing (radioactive carbon, or 14C) to show that fat cells are actually continually replenished throughout life. The average fat cell lives about ten years, and around 8.4 percent of human white adipocytes turn over every year.60 What still remains largely unknown is how the body knows the correct number of cells to regenerate. Developmental biology is providing some answers about the developmental origins of fat cells as well as information about what types of signals trigger the formation of new fat cells from local stem cells.73 One thing is for sure, no matter what underlies the process: more fat cells—and bigger fat cells—means more weight.
Have you ever wondered what happens after eating a meal? How does food become part of your fat if you overindulge? It is important to understand how this process works because it sheds light on how erroneous many of the generalizations made by fad diets are. Here is a very simplified overview.
Digestion starts in your mouth. Saliva contains enzymes that break down starches in the food to simple sugars. The food then moves to the stomach along with any fat and water. Once there, the food gets churned up and transformed with the help of enzymes such as pepsin, which digests protein, and hydrochloric acid. These chemicals further break down the food and turn it into a mixture of gastric juices and partially digested food called chyme, which then enters the first part of the small intestine called the duodenum. This is where bile, secreted from the liver and stored in the gallbladder, mixes with the chyme to emulsify the fat, permitting it to be digested. A variety of enzymes made in the pancreas also join the party to further break down the carbohydrates, fat, and protein. This process ultimately thins out the mixture into a fluid form so nutrients can be more easily absorbed through the lining of the small intestine. Here the paths of fats, carbohydrates, and proteins diverge. Fats and fat-soluble molecules travel readily across the cell membranes. Nutrients, proteins, and carbohydrates require specific transporter proteins that move them either actively or passively across the cell membrane. If the cell does not need to expend energy, the process is said to be passive, whereas transport that requires energy is active.
Once carbohydrates have been broken down into simple sugars such as glucose and fructose, they can be moved into the bloodstream for delivery to cells and tissues. Some carbohydrates become stored in the liver as glycogen, and whatever is left is converted to fat and cached in fat cells. The fats also go into the bloodstream, but they are destined for the liver, which burns some of the fat and converts some to other substances, such as cholesterol. The remainder is destined for storage in fat cells.
Proteins are broken down into smaller fragments known as peptides, which are further dismantled to become amino acids that can then be transported across the lining of the small intestine to enter the bloodstream for transport to cells. From here, some amino acids are used to build new proteins. Superfluous amino acids can end up in fat cells, albeit in a roundabout way. When protein is first metabolized into amino acids, some types of these amino acids can be converted into glucose, which your body also uses for energy, through a process called gluconeogenesis. If your cells have enough glucose, and glycogen stores in the muscles and liver are full, the excess glucose is converted into fat and stored. Other types of excess amino acids are converted by the liver into “ketone bodies,” which are much beloved by Atkins and Paleo devotees. Ketone bodies can be used to produce energy in most cell types. So technically speaking, even extra protein can eventually become part of fat tissue. Thus, the commonly held idea that eating lots of protein and avoiding carbohydrates will only “put muscle on your bones” is false. Excess of any type of food will end up in fat cells.
I should also note that how your intestines absorb nutrients depends on the health and function of the trillions of bacterial cells that collaborate with your digestion and influence how many calories in the form of nutrients your body takes in. Depending on the exact types of bacteria in their intestines, some people absorb more calories than others and thus have a higher risk of overweight and obesity. Scientific research is also under way to understand the role of metabolites produced by the gut bacteria that may contribute to body weight and disease. Some types of these bacteria and the small molecules they produce (that also end up being absorbed into the circulation) have been implicated in obesity and diabetes, whereas others have protective benefits against weight gain and metabolic disorders. We will talk more about this in chapter 5.
To understand how fat cells fill up and empty out, it helps to know a little bit about lipoproteins. Fats (lipids) do not dissolve in water like other food items we consume. They must first be broken down to be absorbed and circulated. The fats you eat and the fats your liver can create from carbohydrates are bound to protein molecules for transport throughout the blood. In fact, all sorts of non-water-soluble molecules (fats, steroid hormones, some vitamins) must be bound to proteins for transport through the blood. Lipoproteins (lipids bound to proteins) are specific proteins that are recognized by receptors on the surface of the cells that are destined to process them. Different lipoproteins are charged with specific responsibilities depending on which cellular receptors they can bind to. For example, low-density lipoprotein (LDL) receptors on the surface of many types of cells recognize cholesterol-rich LDL from the blood so the cells can extract cholesterol. LDL transports lipids to the cells for use in important cellular processes such as making cell membranes, making the myelin sheath that surrounds nerves, and synthesizing cholesterol derivatives such as steroid hormones, bile acids, and vitamin D3. LDL also transports excess fat to fat cells for storage, but some of it may end up in the liver and in arterial walls, where it gets stuck in plaque-forming foam cells that can eventually cause blocking of the arteries. In contrast, high-density lipoproteins (HDL) are recognized by HDL receptors on the liver cells that are responsible for recycling “used” cholesterol and removing fat from the body. The amount of HDL a person has is inversely correlated with risk of heart attack—that is, more HDL is associated with a decreased risk of heart disease.
Although fat cells are storage depots for fat, their “doors” cannot accommodate large molecules. Triglycerides are too big to easily pass through the membrane of a fat cell without breaking up a little bit first into smaller pieces. The individual fatty acids that make up the triglyceride must be released and then travel across the cell membrane. The major enzymes responsible for stripping down triglycerides into their component fatty acids and glycerol are called lipases. One of the most important enzymes in allowing fat to enter fat cells is lipoprotein lipase, or LPL. The glycerol molecule remains outside.
Fat cells do more than just shelter fatty acids supplied from outside. With the help of glucose from the blood, they also build their own triglycerides. So fat storage involves two key ingredients: LPL to liberate free fatty acids from LDL, and glucose to generate triglycerides inside the cell from these fatty acids and glycerol. All of this activity is coordinated to a large extent by insulin, which regulates how much glucose gets from the bloodstream into muscle, fat, and liver cells. More insulin, either from high sugar intake or from being insulin resistant, means that there will be more LPL and more glucose to transport into the fat cell, ultimately producing more fat storage.
LPL is not exclusively bad; it does not exist solely to load up fat cells. For example, the LDL receptor will move fat into a muscle cell, where it can be chopped up by LPL and burned for fuel. LPL helps to haul fat from the bloodstream into whatever cell happens to have an LDL receptor. In the absence of insulin, an enzyme called hormone-sensitive lipase, or HSL, conducts business in the other direction. HSL frees fatty acids from stored triglycerides so they can go into circulation and be used for energy. This is how your fat gets “burned.” When there is less insulin around and more HSL activity, fat is more easily tapped for fuel. But when insulin levels are high, LPL takes control and moves fat into storage.74
This well-defined series of events by which these two metabolic processes balance each other out helps explain why we find that overconsuming carbohydrates precipitates much of obesity. When we eat carbs, that rapidly raise blood sugar, such as simple, refined carbs insulin levels also rise rapidly, especially when this activity is not countered with physical activity to burn the glucose. This creates the conditions for fat storage and fat retention by the processes described earlier. High insulin levels favor fat storage by inducing the expression of LPL. About the worst thing you can do for your body fat is to consume high levels of fat and simple sugars together. Unfortunately, this is known as “the Western Diet,” the predominant diet in the United States (also referred to as the Standard American Diet or, appropriately, SAD).
While we all know that eating a large excess of anything—fat, protein, or carbs—can lead to obesity, we often forget that the body is in many ways self-regulating. It has numerous automatic feedback mechanisms to maintain balance (“homeostasis”). We have evolved to be physiologically resilient over a wide range of potentially harmful conditions. Our bodies are designed to store enough energy to survive between meals and even during periods of starvation without compromising vital organ systems or our physical performance. These feedback mechanisms involve not just the metabolic system, but also the endocrine, nervous, and digestive systems. I have hardly mentioned the role of the brain in all this, but it is also part of the picture. Without the brain, your body could not produce many hormonal signals at all, much less listen to the messages and perform certain functions, from the simple, such as overseeing digestion to the complex, such as coordinating communications, so you know when you are full.
My reason for emphasizing the complexity of the human body is to underscore the point that obesity is rarely a condition that is “natural” to develop if you possess a healthy body whose functions are all working properly. To become obese typically requires enough glitches somewhere in this elaborate system to perpetuate circumstances that favor unhealthy fat cell proliferation. For example, a small percentage of people in the world are born with a genetic defect that prevents them from producing enough of the satiety hormone leptin, which is made by white fat cells and signals to the brain that you have sufficient fat stores, so stop eating. Luckily, these individuals can be treated with leptin to reverse their rare condition. But it is becoming common today that persistently high insulin levels coupled with low sensitivity to the leptin not only favor weight gain, but also disrupt our metabolic health. We become more prone to conditions such as type 2 diabetes, non-alcoholic fatty liver disease, high blood pressure, and abnormal cholesterol levels.
Carbohydrates are now considered the main culprit when it comes to obesity, and for good reason. Not only do they abound in refined form in our modern diets, but many trigger dramatic increases in insulin levels. This makes lots of glucose available for triglyceride storage. In a well-balanced system, insulin should simultaneously work toward suppressing appetite and move glucose into cells, but excessively high insulin levels move too much glucose into the cells. The brain then detects low levels of glucose in the blood and takes action to stimulate eating. It is as if the brain is tricked by the effects of the insulin spike and may think starvation is imminent. The brain needs a certain level of blood glucose to ensure its own proper functioning, so it activates signals that urge you to eat more, leading you to gravitate toward those carbs and perpetuate a vicious cycle. (Gary Taubes describes this unfortunate sequence of events in detail, and the basics of fat metabolism, in his book Why We Get Fat.75) Eating a balance of macronutrients—complex carbohydrates, healthy fats, and proteins—is ideal, as it promotes metabolic homeostasis. How so? It prevents dangerous insulin surges that create an imbalance in bodily hormone regulation. Proper energy levels in the blood can be maintained, and your preprogrammed system for controlling appetite and managing hunger can operate normally.
But we all know that many people do, in fact, rather easily become obese. Something has gone wrong with the system. If body fat is expertly regulated, then the obesity epidemic cannot be explained entirely by lack of restraint, gluttony, and sloth. Indeed, the obesity disorder is about abnormal growth of fat tissue, but the story rarely includes a look at the hormones and enzymes that manage that growth to begin with. And rarely does it consider the impact of obesogens.
In early 2003, I was at a meeting in Matsuyama, Japan, that was about endocrine disrupting chemicals (EDCs), a subject area in which I was increasingly working that we will discuss more shortly. Here I heard a talk by Professor Shinsuke Tanabe from Ehime University about tributyltin (TBT), a compound used in antifouling paints to prevent invertebrate organisms from growing on ship hulls. My lab was collaborating with my Japanese friend and colleague Professor Taisen Iguchi to determine whether twenty priority EDCs of interest to the Japanese government, including TBT, could activate a nuclear hormone receptor I discovered when I was at the Salk Institute that we called the steroid and xenobiotic receptor (SXR). One major function of SXR is to regulate expression of enzymes that break down drugs and toxic chemicals (aka the xenobiotic response). Professor Tanabe’s presentation described how TBT could turn female fish into males, and I wondered what exactly TBT was up to. The most obvious way to cause such sex reversal was to alter the function of estrogen or androgen signaling pathways.
Curious about what receptor TBT might be targeting, I asked my team back home in California to test TBT on our entire collection of nuclear hormone receptors to determine which one(s) it activated. To our surprise, instead of activating or inhibiting a sex hormone receptor, we found that TBT and related chemicals activated PPARγ and its cellular partner, the retinoid X receptor (RXR). This receptor dimer is the master regulator of fat cell development.76 My team went on to show that TBT can spur fat cell precursors to become fat cells in vitro, that frog embryos exposed to TBT have their testes replaced by fat, and that mice exposed to TBT in utero have greater fat stores as adults. Six years later, we documented the most stunning finding of all: the offspring of exposed animals were also prone to store more fat. This proved how heritable chemical-induced obesity could be.