The Birth, Care,
and Feeding of a Fat Cell
Kay is a seven-year-old girl who was born at a normal weight. She first visited the clinic at age two, when she was 45 pounds (twice normal size) and her BMI was 30 (double the normal BMI for her age). Her mother and sister are both rail-thin. Lab testing showed massive insulin release, similar to that in the brain tumor children. Kay’s mother kept her from all problem foods and promoted exercise as much as she could, but without effect. Over the next five years, Kay tried diet and exercise, and various weight-loss medications. Nothing seemed to slow down her weight gain. At age seven, she weighed 140 pounds, and she had a fatty liver, lipid problems, and hypertension. As a last resort, she had a lap-band procedure, to reduce her stomach’s capacity. She was our youngest patient to undergo bariatric surgery at the time. Within six months post-op she had lost 30 pounds, and her face was now separate from her neck. All her labs improved. Her mother was ecstatic, in no small part because Kay could now wipe her own behind.
Your Fat, Your Fate?
In a nutshell, your body fat is your biggest long-term risk for infirmity. Nothing correlates with diabetes, heart disease, and cancer better than your fat. So is your fat your fate? Everyone says, “Lose the fat to extend and improve your life,” but virtually no one can do it. So how do you lose the fat? Better yet, how do you prevent it from arriving in the first place, and preferably leave your muscle mass in place? In order to answer these questions a little more knowledge is required about what causes fat accumulation.
Each of us starts out as a single cell, the product of the fertilization of a sperm and an egg. As an adult, we end up having a total of between 5 and 10 trillion cells, with more than 250 cell types in our bodies. Where did the fat cells come from and why are they there in the first place? How do you make an adipocyte (fat cell)? What drives its proliferation? Can you make fewer, and would you even want to? Once a fat cell is made, how do you fill it? Finally, for all the marbles, once a fat cell is filled, how do you empty it?
These are the questions that drive scientists and the pharmaceutical industry in their quest to relegate obesity to the dustbin of medical oddities (and make a bundle in the process). The sad thing is, here we are, thirty years into the obesity pandemic, and we haven’t yet harnessed the science to help us.
How Do You Make a Fat Cell?
The size of your fat tissue depot depends on two properties: fat cell number and size. In reality, the number of fat cells you have dictates your ultimate fate after they have been created. Once made, fat cells want to be filled. Think of a fat cell as a balloon. When empty, it is pretty small and many can be stored in a bag without taking up much space. The fat content is what blows the balloon up; when many are put together, they can fill an entire room. So to control obesity, you need only control your fat cell number. Alas, this is easier said than done. How and when do fat cells get born? In the early 1970s, Jules Hirsch, at Rockefeller University, demonstrated that your fat cell number is determined by age two. More recently, research has confirmed that while there is a constant low-level turnover, the majority of fat cells are formed very early in life.1
Why do we even need fat cells? The flippant answer is that without them, girls would look like boys. The evolutionary answer is that fat cells are repositories of energy and are necessary for survival of the species, especially in times of famine. Fat cells are protective; they provide cushioning of vital organs. In addition, specialized fat cells provide heat after you’re born, to keep you from succumbing to the elements. Fat cells are not just storage devices. They are active participants in, and are necessary for, your metabolic health. As you will see in chapter 8, you need your fat cells. Fat cells are the difference between being the picture of health and suffering a miserable, lingering death.
What makes one person fatter than the next? How is it that Kay and her sister—children raised in identical environments with the same parents, values, and meals—can be so physically different from each other? Why does one child dream of nothing but soccer while the other obsesses over doughnuts? Everyone thinks they are in control, but the reality is they aren’t. No one is. So please, people, give up on this idea that you are in control of your fat cells. They were laid down a long time ago. Control over your fat is an illusion promulgated by the weight-loss and fashion industry to keep you in tow, paying big bucks. Your mother was more likely in control before you were born, and she didn’t even know it. (Another reason to blame Mom at the therapist’s office, as if you needed one.)
Over the last twenty-five years, birth weight has increased worldwide by as much as 200 grams (half a pound), coincident with the obesity pandemic.2 Is this conferring the risk for obesity on the newborn? It is likely that maternal weight gain is translated into fetal body fat; the more weight mothers gain during their pregnancy, the greater the birth weight of the newborn;3 and the more fat cells early on, the greater the health risk later on.4 Mom can bestow a blessing or a curse; what she does and eats during her pregnancy can result in an altered destiny—either way, for better or for worse.
Your fat cell number is determined before you’re born and is dictated through four separate physiological pathways, none of which can you alter now.
1. Genetics. When we talk about genetics, we mean a change in the sequence of our DNA. Scientists routinely say that obesity is 50 percent genetics (nature) and 50 percent environment (nurture). We do know of a few genetic mutations in the energy balance pathway that clearly predetermine your risk, which accounts for about 2 percent of morbid obesity. However, despite exhaustive searches, not that many people have genetic mutations to account for their obesity. Researchers worldwide have scanned the human genome and have identified thirty-two genes that are associated with obesity in the general population.5 Altogether, these genes explain a total of 9 percent of obesity. And even if one person had every single bad gene variation, it would account for only about 22 pounds—hardly enough to explain our current obesity pandemic. Lastly, the genetic pool doesn’t change that fast, so the gene argument can’t explain the last thirty years. All these investigations show that we need to look past genetics as a cause of obesity.
2. Epigenetics. Epigenetics is different from genetics. It refers to changes in the areas around our genes that can cause them to be turned on or off, usually inappropriately, and that over time can result in the development of various diseases. Think of epigenetics as the On-Off switch attached to the dimmer of your living room chandelier. The gene is the light bulb; the epigene is the light switch. If the light bulb is defective or the switch is frozen in the Off position, the dimmer function is useless as it is, as it is constantly giving off low light and you are unable to read. Likewise, epigenes control the extent to which the gene turns on.
Epigenetics has become a very hot area of investigation. Here are four reasons why you should care. First, an epigenetic alteration can cause as much havoc as a genetic alteration, but the actual DNA sequence remains unchanged, so even with a full genome analysis, you can have defective epigenetics without knowing it. Second, epigenetic changes usually occur after conception but before birth. You are not just the product of your genes; you are equally the product of your epigenes. Third, changes in maternal nutrition or altered physical stress to the mother are felt by the fetus through the placenta. They can modify gene expression and function, affecting the child for the rest of his life. Fourth, and the most ominous fact of all: once your epigenetic pattern has changed, there’s a better-than-even-money chance that you will transmit this same epigenetic change to your offspring, and they to theirs, ad infinitum. A recent study demonstrated that the epigenetic marks that babies harbor in their DNA at birth predict their degree of fat accumulation at age nine years,6 suggesting that what the fetus experiences through the placenta has a huge impact on future risk of obesity.
3. Developmental programming. A relatively new field in medicine is known as developmental origins of health and disease (DOHaD), or developmental programming. We now assume that a hostile intrauterine environment (undernutrition, overnutrition, or maternal stress) transmits some signal to the fetus, which conveys information about future threat: It’s a tough world out there, kid; best be ready for it. This drives the infant to store extra energy and increase its fat after birth when there is no need to do so, to the ultimate detriment of health later on. Such a baby’s intrauterine and postnatal environment are mismatched. The child is “programmed” for survival at the expense of longevity.
David Barker first postulated that prenatal biological influences could affect postnatal outcomes for obesity. He observed that maternal nutrition affected the fetus. Small-for-gestational-age (SGA) infants (very small at birth) were at an increased risk for future obesity, diabetes, and heart disease.7 This finding was corroborated by the Dutch Famine Study.8 At the end of World War II, for a four-month period, the official daily rations in the Netherlands were between 400 and 800 calories per person. Those who were undernourished as fetuses developed obesity and metabolic syndrome (see chapter 9) in middle age.
Several studies of SGA newborns demonstrate that they exhibit rapid catch-up growth in the early postnatal period and develop obesity, persistent insulin resistance, and metabolic syndrome in childhood. An analysis of newborns born in Pune, India, versus those born in London demonstrated that, despite the fact that those born in India weighed 700 grams less at birth, their insulin levels were markedly elevated. After adjustment for birth weight, the India-born babies demonstrated increased adiposity, four times higher insulin, and two times higher leptin levels than their London-born counterparts.9 Because these babies were already insulin and leptin resistant at birth, they were predestined to develop obesity and metabolic syndrome.
Worse yet, premature babies also manifest insulin resistance.10 It’s assumed that some aspect of prematurity leads to alteration in developmental programming. This is often compounded by well-meaning pediatricians, who prescribe high-calorie formula to rapidly increase the baby’s weight gain. The infant is then at enormously high risk for metabolic syndrome in childhood or in adulthood.
But the converse is also true. Babies born large for gestational age (LGA) also end up with obesity and metabolic syndrome in later life.11 They’re also hyperinsulinemic and insulin resistant, but for a different reason. Most babies are LGA due to gestational diabetes mellitus (GDM), a type of diabetes that occurs in approximately 5 percent of pregnant women. The high blood glucose of the mother leads to high blood glucose of the fetus, and high insulin levels, which drive fat cells to grow. These GDM babies have three times the chance for obesity and diabetes in later life. In general, the “vertical” transmission of diabetes from mother to child has been documented in studies of the Pima, a Native American tribe in Arizona. Clearly, this is the “gift that keeps on giving.”
However, GDM isn’t required to produce obesity. LGA babies without GDM also have double the chance of insulin resistance and metabolic syndrome. Animal studies show that both fetal undernutrition and overnutrition can change epigenetics, making it less likely that beta-cells (cells in the pancreas that make insulin) will keep dividing. LGA children have a limited insulin reserve. As they gain weight over their lives, diabetes will be the final outcome. But this can be prevented: obese women who underwent bariatric surgery between their first and second child reduced both the chance of LGA in the second child and the second child’s future risk for obesity. Fix the mother, fix the offspring.
Why does this happen? Generally, as the fetal brain develops, the hormone leptin (coming from the fetal fat cells) tells the hypothalamus to develop normally, defending against obesity. However, either lack of leptin (as in the undernourished SGA baby) or insulin antagonism of leptin action (seen in SGA, GDM, LGA, and premature babies) may prevent normal hypothalamic development and generate a baby whose brain never gets the right signal. His brain always sees starvation! The infant will eat more and exercise less right from birth, which will predispose him to obesity in later life, especially given our current overabundant food supply.12
4. Environmental toxins. Lastly, there is the possibility that toxins in our environment are programming increased fetal adipose tissue development. Numerous compounds in our environment, called obesogens, can act on three molecular switches to turn on fat cell differentiation. Early fetal exposure may increase the “adipocyte load,” fostering future obesity, even if the exposure is short-lived (see chapter 15).
What these four lines of reasoning tell us is that the major determinant for your disease risk is the development of your fat cells before you were even born. You had no say in the matter. This can happen due to problems in the fetal liver (insulin resistance), fetal brain (leptin signaling), or the developing fat cell itself, increasing your fat cell number and storage capacity. So does this mean it’s a done deal? Do all children like Kay need surgery to lose weight? Are we completely powerless to control our fate? Should you stop reading this book and live on French fries with ice cream because you are doomed anyway? Not quite.
How Do You Fill a Fat Cell?
So our number of fat cells is predetermined, but what about filling them? This is the crux of the book and the pivot on which your long-term health can turn. We could easily put our blinders on and recite the old adage that “fat cells get bigger because we eat too much and exercise too little.” And, of course, we do. One recent report determined that increased caloric intake accounts for the entire U.S. obesity epidemic.13 Alternatively, less energy expenditure, due to increased screen time and decreased physical education in schools, has been directly correlated with both obesity and the prevalence of metabolic syndrome in adolescents. Aside from the obvious changes in the caloric and exercise milieu in which we find ourselves, numerous other processes have been proffered as examples of environmental change, such as sleep debt, changes in ambient temperature, and exposure to obesity-causing viruses. Even social networks have been implicated as causes of obesity.14
Would that it were that simple. All these are examples of correlation, not causation. The journey through obesity and chronic metabolic disease begins and ends with the hormone insulin, the energy-storage hormone (see chapter 4). There is no fat accumulation without insulin. Insulin shunts sugar to fat. It makes your fat cells grow. The more insulin, the more fat, period. While there are many causes of obesity, excess insulin (known as hyperinsulinemia) in some form is the “final common pathway” for the overwhelming majority of them. Block it, and the fat cells remain empty.
And we’re all making more insulin than we used to. Today’s adolescents have double the level of insulin secretion of their predecessors in 1975.15 High insulin is responsible for perhaps 75–80 percent of all obesity.
There are three different ways to increase your insulin:
1. If, in response to a meal, particularly one high in refined carbohydrates (see chapter 10), your pancreas makes extra insulin (called insulin hypersecretion), it will drive your fat cells to store energy.16 This happens when your brain sends a signal to the pancreas through the vagus, or “energy storage,” nerve.
2. If, because of the specific foods you eat (see chapters 9 and 11) you build up fat in your liver, this fat will make the liver sick (called insulin resistance). The pancreas has no choice but to make more insulin in order to force the liver to do its job. This raises insulin levels throughout the body, driving energy into fat cells everywhere, and making other organs sick as well.
3. If your stress hormone cortisol (which comes from your adrenal gland) increases, two things will happen. It will work on the liver and muscle to make them insulin resistant, raising your insulin and driving energy deposition into fat. It may also work on the brain to make you eat more (see chapter 6).
Of course, these three insulin problems are not mutually exclusive. One person could have more than one problem going on at a time, which makes it even harder to diagnose and treat.
There’s yet another way that our current society increases insulin and weight gain. Three classes of medicines (steroids to control inflammation, antipsychotics to stabilize mood, and oral hypoglycemic agents to treat diabetes) are notorious for driving insulin up and causing excessive weight gain. Bottom line, once a glucose molecule is in the bloodstream it has one of three fates: it can be burned (by exercise), it can be stored in fat (by insulin), or it can be excreted in the urine (which eventually kills your kidneys). It’s way better not to need these drugs in the first place—but usually they are the lesser of two evils.
Can You Get Your Fat Cells to Slim Down?
As you can imagine, these biochemical pathways are pretty darn powerful. Fat cells want to be downsized about as much as General Motors or AIG. And it doesn’t matter if you’re young or old—your fat is here to stay. Once the balloon is filled, it doesn’t want to be deflated. It’s because of insulin that weight loss is so difficult. Virtually every aspect of our modern society drives our insulin levels higher and higher. From an evolutionary perspective, our ancestors had to work hard in the face of famine to accumulate their fat. Their children needed to be prepared for this fate in utero to have a chance at survival. Once the fat is stored we don’t want to give it up, at least not without a fight. Because when fat cells get smaller, they stop making leptin. And when there’s no leptin, there’s no puberty, no pregnancy, no human race. To add insult to injury, our current drug armamentarium is only minimally effective in promoting fat loss (see chapter 19).
So, how do we slim down a fat cell? What options are left? One promising research tool is to deprive fat cells of their blood supply. Investigators are actively pursuing the possibility of using chemicals called angiogenesis inhibitors, which would cut off the blood supply to fat tissue. Animal experiments using these compounds demonstrate melting away of the fat tissue. But it will be years before we are ready for trials in humans. Other compounds are in development, but likewise it will be a long time before they’re ready to use. In fact, many drug companies have left the obesity research business, despite the promise of the pot of gold at the end of the rainbow (see chapter 19).
So, at least today, there’s only one hope: Reverse the biochemistry. Stop the energy storage. Fix the leptin resistance. Lowering the insulin works on both counts. But there are two problems with this strategy: First, not everyone has the same insulin problem. So giving general guidelines is not going to work for everybody. We need some version of “personalized obesity medicine.” Second, changes in the environment are what drive the biochemistry. If you want to fix the biochemistry, you have to fix the environment. And that’s not easily done. Parts 5 and 6 will provide some guidance.