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What Makes Us Fat?

  What Makes Us Fat?

By Greg Critser • Illustration by Mark Sojka • Photography by Ann Johansson

Why are so many of us fat? Because we live sedentary lifestyles that neither demand nor encourage us to get up and move. It’s our diet: the fat in our food, high-fructose corn syrup in our super-sized drinks, too-many carbs, too-little fiber, insufficient protein. In many communities, the root cause may be more nuanced: poverty, food deserts and even federal agricultural policy. Walk into a large bookstore, and there are rows upon rows of hardcovers and paperbacks that expound on the subject. Go to a dinner party, and just about everyone at the table will have his or her own theory. And most all of them will be based on science.

This may be the current state of the discussion, but all of it is confusing to the public and does nothing to provide people with a rational approach to addressing weight, asserts David Heber, MD (RES ’77, ’79), PhD ’78, founding director of UCLA’s Center for Human Nutrition. “Everyone has their own idea of what we ‘know’ about obesity, and lots of non-scientists consider themselves to be nutrition experts simply because they eat,” he says. “But the fact is, the science of obesity has only become a respectable field of science since the late 1970s, and now we finally are making significant progress.”

Medicine beckons that science. Although the numbers have declined slightly, almost two-thirds of Americans are classified as overweight, with nearly one-third of them being obese — overweight enough to experience one or more chronic diseases. A growing number have type 2 diabetes (a condition Dr. Heber refers to as diabesity), sleep apnea, kidney disease and heart problems. Obesity also increasingly is thought to be driving an epidemic of nonalcoholic fatty liver disease, which in turn is leading to many more patients who are developing cirrhosis and in need of a lifesaving transplant.

What’s more, according to a study published by health-policy researchers at Cornell University in 2012, obesity and its associated complications cost the U.S. healthcare system upward of $190 billion annually and account for an astounding 20.6 percent of the nation’s healthcare costs. Weight-control drugs have failed and in some cases been found to themselves cause significant health damage. Public-health campaigns? They have yielded few measurable results. That’s left us with little firepower with which to battle an epidemic that, if the trend continues, could result by 2050 in a U.S. population in which most everyone is overweight or obese.

Is it a matter of individual responsibility? Environment or behavior? There simply is no one factor. At UCLA, investigators are looking at many promising avenues of research to better understand obesity and perhaps translate them into prevention and public-health strategies. Increasingly, many of these researchers believe the answers are buried deep within us, to be excavated by more forward-thinking science. As Dr. Heber says, “We can do a lot now as individuals, but the issue for science is pretty basic: We’ve got to understand the core mechanisms of weight gain, obesity and diet, and those are complex.”

Indeed they are. In fact, we can trace the core mechanisms of obesity back hundreds of thousands of years, to our origins as human beings. “Obesity is so complex,” Dr. Heber says, “because it is the end result of many different pathways that have been designed over the eons to maintain our bodies in the face of starvation.” At our beginning, food was a scarce and difficult-to-obtain resource, so our bodies learned to hoard the calories necessary to provide us with the energy we needed to survive. It is only within the past few hundred years or so that the food supply has become sufficiently available to provide secure and ample nutrition. “Our bodies haven’t had time to adapt to that change,” Dr. Heber says. “We still crave more food.”

So as we grapple with this complicated issue, there are many different avenues receiving scientific scrutiny. At one level, there is the seemingly simple calculus of energy in, energy out. Our forebears stored up calories from what food they were able to scrounge to carry them through lean periods, but they also expended calories in the daily hunt for sustenance. So what calories they consumed didn’t have time to hang around and turn into fat — they either were utilized by the body when food was scarce or they were burned up in the pursuit of something else to eat. Of course, that is not how most of us now live. “In this day and age, our bodies have few defenses against excess eating and a sedentary lifestyle,” Dr. Heber says.

What we eat is, of course, another significant contributor to the problem of obesity. But that, too, is complex. Consider the ongoing discussion about diet. For years, dietary wisdom held that fat was the main culprit underlying weight gain and that consumers should cut way down on fat and eat more carbohydrates. But that ignored the role of simple carbohydrates, hidden sugars and low-protein intake that drive the obesity epidemic. The evidence for this position keeps building. One of Dr. Heber’s colleagues in obesity research, George A. Bray, MD, at Louisiana State University’s Pennington Biomedical Research Center, has teased out some of the more exquisite details. Dr. Bray, a dean of modern obesity science, replicated weight gain by overfeeding adult volunteer subjects by the same number of calories. He broke the subjects into three groups, and each group was assigned a different percentage of protein in its meals. The members of one group got 5 percent of their calories from protein, another got 15 percent and the third group got 25 percent. The results were eyebrow-raising: After eight weeks, the participants in the low-protein group had a lower amount of the desired lean-body mass than they had pre-study; they also showed the largest increase in fat mass among the three groups. The medium-protein eaters gained both lean-body mass and body fat. But it was the members of the high-protein group who evidenced the biggest drop in fat mass and the most gain in lean-body mass. “Findings like that have pointed us all in a new direction,” Dr. Heber says.

  Dr. David Heber  
  “The issue for science is pretty basic,” says Dr. David Heber. “We’ve got to understand the core mechanisms of weight gain, obesity and diet, and those are complex.”

Now when Dr. Heber examines a new patient, he matches the amount of the patient’s lfean-body mass with the amount of protein in his or her diet at a rate of 1 gram of protein per pound of lean-body mass, which turns out to be about twice the amount originally suggested by the U.S. Department of Agriculture but well within the 2010 guidelines of the Institute of Medicine of the U.S. National Academy of Sciences. “We encourage patients to build protein consumption and lower their fat and refined-carbohydrate intake,” he says. “The combination tends to maintain lean-body mass during weight loss and control hunger. And if you control hunger with protein, you have a greater opportunity to make better food choices.”

If there’s one thing most everyone engaged in the obesity debate can agree on, it’s that environment matters. That extends beyond the usual environmental culprits of poverty, poor shopping alternatives, fast food on every corner (and much of the block in between) and recreation-poor neighborhoods.

Environment also means people — specifically, the people closest to you, your social network. In a 2007 study published in the New England Journal of Medicine of more than 12,000 people tracked between 1971 and 2003, researchers from Harvard Medical School’s Department of Health Care Policy found that a person’s chance of becoming obese increased by 57 percent if he or she had a friend who became obese in the same interval. The same is true of adult siblings; if your brother becomes obese, the chances that you also will be obese rise by 40 percent. If your spouse becomes obese, the risk increases by 37 percent. As Dr. Heber points out, “Obesity can be socially and psychologically contagious.”

IF ONE’S EXTERNAL ENVIRONMENT plays a big role in weight gain and obesity, so, too, does one’s internal environment, what the 19th-century French physiologist Claude Bernard dubbed the milieu intérieur. Most of us may have heard this termed as homeostasis, the state of physiological balance that our body struggles to maintain every day. It’s what happens when we take, for example, a blood-pressure medication to push unhealthy levels back to healthy ones. And it’s what happens when we eat breakfast, lunch or dinner, restoring our energy balance. This exquisite equilibrium is regulated, in large part, by hormones, which, in turn, are regulated by the brain.

The body gets many of those regulatory cues from three key neural structures: the hypothalamus and the pituitary and the adrenal glands — also known as the HPA axis. The HPA axis does a good job telling other organs when to rev up and when to downshift. When it comes to food intake and energy expenditure, the axis is often the critical factor governing weight gain, loss or maintenance. It’s how we maintain internal balance. One can easily imagine how modern life and its attendant daily stresses disrupt the axis and leave our bodies in perpetual imbalance. Scientists have known this for decades.

  Psychological and emotional distress on body weight/BMI set-point  
  A conceptual overview of the potential influence of psychological and emotional distress on body weight/BMI set-point. Once the number of internal distress factors accumulate, especially in relation to protective factors, BMI is likely to increase as energy homeostasis becomes increasingly disrupted by psychological and emotional overload.
Graphic: Dr. Erik Hemmingsson/Karolinska University Hospital. Published in Obesity Reviews, September 2014

But through the work of researchers like Yvette Taché, PhD, professor of digestive diseases and co-director of the UCLA Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, we now know something new about stress: The classic beneficial stress response — fight or flight — can be hijacked by other stressors. She cites a recent review by Erik Hemmingsson, PhD, of the Obesity Center of Karolinska University Hospital in Stockholm, Sweden, published in Obesity Reviews, that points out that ”psychological and emotional distress is a fundamental link between socioeconomic disadvantage and weight gain.” Among those socioeconomic disadvantages triggering stress responses are poverty, family distress, unemployment, low education, marital discord, work environment, poor self-esteem and depression. “The chronicity of these factors combines to disrupt our usual adaptive responses and adversely affects health,” Dr. Taché says. They can do it in almost cryptic ways that only now, under the light of modern technology, reveal themselves.

Consider stress and palatability — our taste for fatty, sugary foods, or what we often call comfort foods. The phenomenon is easy to observe: One gets upset, tears into a bag of cookies (or potato chips or a carton of ice cream) and feels better. At least momentarily. But why cookies and not an apple? Dr. Taché theorizes, as do others, that the HPA cycle gets tweaked when stress becomes chronic and then may reshape our taste preferences. There is also clinical evidence that for some obese patients, the drive to overeat palatable food is considered as a form of addiction through the activation of reward systems.

A key suspect is corticotropin-releasing factor (CRF), a family of neuropeptides that Dr. Taché has studied for nearly three decades in relation to its influence on the alterations of gut function. Other studies have shown its implication in a series of other bodily responses, including playing a key role in the neurobiology of addiction. With regard to appetite control, experimental studies showed that CRF inhibits food intake that is normal and beneficial in the context of the “fight-or-flight” response, a primitive, automatic, inborn response that prepares the body to “fight” or “flee” from perceived attack or from harm or threat to our survival. But when stress becomes an everyday experience, CRF-induced chronically elevated glucocorticoids promote the acquisition and redistribution of energy stores into visceral fat. Insulin levels also are increased, leading to insulin resistance. In addition, stressed lab rats, for example, will almost always choose a high-fat option when presented with a choice of meals. Fatty meals lead to ... the answer is obvious.

The process might even begin before birth, when stress-driven insulin loads from the mother can affect the proper development of weight-regulating organs in the in-utero infant. A vicious cycle ensues, often tracking the ups and downs of the parents. Job insecurity leads to anxiety leads to family discord. That causes the child observing all these dips and spikes to develop increased stress-sensitivity, which in turn produces increased feelings of vulnerability. Now consider what happens when this child is presented with comfort foods: They choose foods — and quantities of that food — that take the edge off. They eat. They gain weight. They become obese.

  Psychological and emotional distress on body weight/BMI set-point  
  Proposed step-by-step model of obesity causation. Although the figure only shows reverse causality in the last step, all steps in the model are likely to be more or less bidirectional, especially once severe obesity has been established. Skipping of intermediary steps can also occur.
Graphic: Dr. Erik Hemmingsson/Karolinska University Hospital. Published in Obesity Reviews, June 2014

Dr. Taché and her group may be on to something new, though. CRF, it turns out, has a lesser-known relative, corticotropin-releasing hormone receptor 2 (CRHR2), a protein that seems to restore the balance of some biological disturbance caused by CRF. “They are the yin and yang in aspects of stress response,” Dr. Taché says. CRHR2 presents new opportunities for a breakthrough. “If proper tools can be developed they can help people who are under chronic stress and somehow break that cycle,” she says.
It may eventually involve some kind of pill. But it also will mean having to change one’s ways. Like Dr. Heber, Dr. Taché says there is no way around the fact that a person’s lifestyle matters and not just the eat-less- move-more variety of lifestyle. “Even the way a family eats can make a huge difference,” she says. “The European way of eating — longer meals, smaller portions, few snacks and desserts — might be a good goal. The longer you remain at the table, the more you allow the body’s natural processes to work to feel satiated through the release of gut hormones.”

Gene expression in the gut might be another fruitful avenue for exploration to address obesity issues, suggests Eric Dutson, MD, surgical director of UCLA’s Center for Obesity and Metabolic Health. Following bariatric surgery, Dr. Dutson has noticed that some patients experience an often dramatic change in their food preferences. High-fat, high-sugar foods, for example, disgust them. He posits that in such cases, surgical alteration of the stomach also alters hormonal signaling between the gut and the brain. “The gut,” he says, “is like the second brain, and we know little about how it functions in that regard.”

With gastric-bypass surgery, it appears that areas of the gut with high levels of hormonal-gene expression go silent, leading to decreased hunger signals for high-fat foods. Another factor: bacteria in the gut, known collectively as the microbiome. A growing body of work suggests that shifts in the composition of gut bacteria may fuel weight gain. “We don’t know exactly how that works,” Dr. Dutson says, continuing that he looks forward to the creation of a major center at UCLA to collect and analyze a wide range of bacterial species from the microbiome. “Even if we don’t fully understand the workings of such processes, it’s important for patients to know just how deep-seated are the forces arrayed against them,” he says.

If the gut is our body’s “second brain,” signaling us when and what to eat, it also may be a source contributing to other obesity-related disorders beyond the well-known conditions of heart disease and diabetes. Consider, for instance, inflammatory bowel disease (IBD), which affects about 1.4-million Americans. Two primary conditions fall under the umbrella of IBD: Crohn’s disease and ulcerative colitis. Both are driven by an overactive immune system — the body reacts to food as if it were a toxin, then sends out specialized cells to attack the intruder. In the process, surrounding tissue becomes inflamed, leading to a cascade of ever-worsening intestinal events: diarrhea, cramps, fever, bleeding and fatigue.

IT IS A QUESTION ALMOST EVERY OVERWEIGHT PERSON HAS ASKED: Why is my best friend able to eat the same junk as I do but not gain weight? That question has been as frustrating for science as it is for our expanding selves. While we’ve recognized that genetics plays a role in weight, until recently, we haven’t had the research tools to study something as complicated as individual genetic differences in how we gain weight.

That has changed in the UCLA laboratory of A. “Jake” Lusis, PhD, professor of medicine, microbiology and molecular genetics and vice chair of human genetics. Dr. Lusis has been a force in the growing field of systems biology. Systems biology expands from the idea that most biological responses don’t have a single, clear genetic basis; rather, most involve other genes and other bodily responses to the environment. For example, genes tied to the brain and its hunger signals may link to other genes implicated in diabetes or heart disease. In the case of obesity and diet, the effect of the environment — of fatty and sugary foods, of disease, germs and stress — can differ depending on our genes. The trick, Dr. Lusis says, is figuring out how to measure all the intricate differences within an organism and to see how they fit into the whole. “We want to know how all these pieces act together to produce the different effects we observe,” he says. “Like obesity and diet — how does that really play out?”

One of his lab’s more remarkable achievements in recent years has been the development of a core group of 100 genetically distinct mice — hybrid-mouse diversity panel, or HMDP. Dr. Lusis and his postdoctoral fellows expose the mice to different environments, such as fatty food, and then examine them for their genetically specific responses. The results become meaningful when genes in a specific genetic strain match what is known about obesity genes in humans.

In a recent study, Brian Parks, PhD, a postdoctoral researcher in Dr. Lusis’s lab, did exactly that. The outlines of the experiment were fairly straightforward. “First we had to create a diet similar to a Big Mac and a Coke,” Dr. Parks says. To do that, the lab formulated what might be called fast-food chow pellets — 32 percent of calories from fat and 25 percent of calories from sugar. After feeding the animals a regular chow for eight weeks, Dr. Parks switched them to the junk-food diet for another eight weeks. The differences in gains of body fat were striking. Increases in body-fat percentage ranged from 0 to more than 600 percent in the different strains; many of the suspected fat genes in the mice overlapped with known obesity genes in humans. But there also was a puzzle. “Unlike humans, the amount of food the mice were eating did not change. So we knew there must be something else driving this,” Dr. Parks says.

What might that be? Here is where systems biology, and its ability to parse many factors at once, paid off handsomely. Knowing that different kinds of bacteria in our gut affect weight gain, Drs. Lusis and Parks, and other researchers in the lab, devised a follow-up experiment. After feeding the junk-food pellets to their mouse panel, they tracked the bacterial composition of their guts. “What we found was that the composition of the gut shifted from bacteria that seem to inhibit fat gain to types of bacteria suspected to increase fat gain, “ Dr. Parks says. “And they did this in different degrees, depending on the strain.” It was a classic systems-biology triumph — a dynamic measure of genes, diet, obesity and bacteria. As Dr. Lusis says, “It’s exactly the kind of multilayered findings we want.”

IF THERE WAS EVER A THORNY QUESTION for obesity researchers, it’s that of women and weight gain. And our newest insights again come through systems biology and the work of UCLA’s Karen Reue, PhD. For more than a decade, Dr. Reue, professor of human genetics, has worked to understand one gene, lipin, and its role in fat storage. It’s been a fruitful interrogation: In 2005, she and her associates showed that lipin was implicated in both severe fat loss (known as lipodystrophy) and severe fat gain (obesity). Their discovery fit into her overall research interests. “I’ve long been interested in obesity and homeostasis,” she says. “I truly believe you need a critical amount of fat. But everything is about balance and how our bodies achieve that balance.” That led her to her most-recent quest, to reveal the mechanisms that control female weight gain.

“For a long time, the answer was hormones, hormones, hormones,” Dr. Reue says. “But with what I was seeing with lipin and other genes, I knew it had to be more complicated than that. There had to be something else, a genetic component.” To put the question another way: Why do women, who have two X chromosomes, gain fat so easily, compared with men, who have one X chromosome? How do you discern what part is hormonal and what part is driven by genes?

The answer came via the ingenious methodologies of mouse genetics. Dr. Reue’s colleague in the UCLA College, Arthur P. Arnold, PhD, distinguished professor of integrative biology and physiology, director of the UCLA Laboratory of Neuroendocrinology and editor-in-chief of the journal Biology of Sex Differences, came up with one approach. Like Dr. Lusis, Dr. Arnold built a mouse core — a quartet, in this case — of specially designed mice. Some of the mice had female gonads with either XX or XY sex chromosomes; others had male gonads with either XX or XY sex chromosomes. “That allowed us to tease out the different effects of hormones and sex chromosomes,” Dr. Arnold says. The results were telling; compared with XY mice, XX mice, whether gonadally female or male, had up to twice the increased fat. They also showed greater food intake during daylight hours, when mice are normally inactive. The XX mice also developed fatty livers and registered high blood-fat and insulin levels. The fact that both developed greater obesity, with or without hormones, comes from the presence of the extra X. The second X chromosome, Dr. Reue muses, “may be at the root of many differences between males and females in the development of obesity.”

  Jerry and Ann Moss  
 

Dr. A. “Jake” Lusis (right) uses systems biology to measure differences within an organism to determine how they fit together to influence such
things as obesity and diet, while his colleague Dr. Karen Reue looks at the question of weight gain in women.

It was exactly the kind of new insight that systems biologists crave. “We are always looking at other factors beyond calorie inputs and outputs, and this shows how several factors conspire to change metabolism,” Dr. Reue says. She speculates that more investigation of the X chromosome might identify specific genes that influence behaviors such as night-eating syndrome and propensity to store fat.

All of this is heady stuff for Dr. Heber, who has been fascinated with obesity since the late 1970s, when he was in his residency at UCLA in medicine and endocrinology. After joining the faculty and while studying the problem of malnutrition and starvation in cancer patients, he started to notice an increasing number of patients in the endocrine clinic with type 2 diabetes and obesity. “I looked at this and decided it was the flip side of what I was studying in cancer patients, who were starving,” he says. At the time, obesity was barely on anyone’s radar. “I mean, when I got into it, everyone would ask, ‘Why are you doing that? You’re in a much-better field already.’’’ But the vexing nature of obesity and its treatment was too compelling for him to pass up.

As he mines new veins of obesity research, including the role of gut microflora and the effects of plant substances called polyphenols on fat cells — “Some people say I am a little too far out there,” he says — Dr. Heber also is looking for ways to communicate about the issue. He has written numerous journal articles on diet and nutrition and several mass-market books; one of his best-known books, The L.A. Shape Diet (Harper Collins, 2005), which delves into issues of genetics, protein requirements and nutrition, was republished in 2014. And he’s found a new pet cause: physician education. Although there’s been some improvement over the years, most medical schools still don’t require classes in nutrition science. (At UCLA, nutrition is incorporated throughout the integrated curriculum in the first and second years of medical school.) Dr. Heber wants the subject to be a standard requisite nationwide. “Because obesity-related disorders differ so much from person to person, we’ve got to get better at the doctor-patient interaction on obesity. We must give doctors the necessary tools, both scientific and behavioral, so that they can motivate their patients to change,” he says. After all, whatever the underlying causes of obesity are found to be, it still remains a condition for which the patient must take a measure of responsibility. “Doctors,” Dr. Heber says, “have to get the message across to their patients: If you don’t change your behavior, you’re in big trouble.”

Greg Critser writes about science, nutrition and medicine. He is the author of Fat Land: How Americans Became the Fattest People in the World (Mariner Books, 2004).

 





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