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Through Thick and Thin

  How fat became a recipe for disease  

By Veronica Meade-Kelly • Illustration by James Steinberg

Relationships are complicated. The relationship between fat and the human body? Let’s just say there’s a lot of history there. In the ancient past, our ancestors relied on fat to keep them alive. But today, it’s hard to think of the relationship as anything but troubled. After all, obesity has been linked to more than 20 chronic diseases that have been sharply on the rise in recent decades, including type 2 diabetes, cardiovascular disease, hypertension and stroke.

In light of this, humanity’s relationship with fat may best be viewed as a once-glorious partnership now gone tragically awry — a tale of need and betrayal, dependence and survival.

Our relationship with fat was admittedly always a one-fsided affair. We consumed fat and used it to our evolutionary advantage. Its energy fueled our active, free-roaming lifestyle, empowering us to hunt for food and migrate across continents. It helped us compete with our enemies — giving us the strength to fend off predators and rivals and to fight microorganisms that cause infection. Fat even supported our intellectual growth, powering our fortuitously large primate brains.

What we didn’t burn for energy, we stored. Humans, like all mammals, have adipocytes, fat cells, which store calories until we need them. Adipose tissue – what we commonly think of as “body fat” — serves as an energy reserve. We appreciated having fat around. It kept us warm at night; it saw us through life’s ups and downs.

“For hundreds of thousands of years, fat helped us get through hardship and famine, natural disasters, starvation,” explains Kamyar Kalantar-Zadeh, MD, MPH, PhD, professor of epidemiology in the Jonathan and Karin Fielding School of Public Health at UCLA and principal investigator in the Harbor-UCLA Medical Center Biomedical Research Institute. “Who survived? Those who were able to maintain their fat reserves.”

Those among us who possessed genes that favored this accumulation of fat had a massive advantage in hostile climates and inhospitable terrain. They survived their environment, passing their fat-hoarding genes on to future generations. Those who didn’t possess that advantage died off.

  Drs. Simon Beaven, Peter Tontonoz and Charalabos “Harry” Pothoulakis  
  (From left) Drs. Simon Beaven and Peter Tontonoz have led studies examining the role of obesity in liver disease, while Dr. Charalabos “Harry” Pothoulakis has found evidence that the fat that lies close to the intestines plays a role in inflammatory bowel disease.
Photo: Ann Johansson

FOR YEARS, FAT HELPED US THRIVE, but the good times weren’t to last. Things changed after industrialization. As human ingenuity generated ways to automate agriculture, food became plentiful, and improved methods for transportation and storage made it easier, in the developed world, to get the food we wanted anywhere and anytime we liked. Instead of hunting, we had factory farms; gathering became a quick stop at the local food store. We developed a taste for new things, like fast food and complex carbohydrates.

It is estimated that the average American consumes, on average, 500 more calories per day than 50 years ago. To make matters worse, we’ve become more sedentary, so even as we’re consuming more calories, we’re burning less. It’s a familiar story; we’ve changed, but fat hasn’t. Fat is still in the same place, doing the same job. It’s clinging to us, acting as if nothing has happened.

The problem, says hepatologist and gastroenterologist Simon Beaven, MD (FEL ’08), PhD ’10, is straightforward physiology. “Everything you eat gets processed in the liver, then packaged and sent to appropriate places in the body,” he explains. “When you eat an excessive meal and you don’t need it all for energy, the liver sends the excess to be stored in the adipose tissue around your waist and elsewhere.”

Our modern excess has led much of what we consume to be stored in these “fat depots,” and obesity has reached critical mass. More than one-third of adults and 17 percent of children in the U.S. now weigh in as obese. Because of its connection to numerous chronic diseases, obesity has become the primary public-health concern of the 21st century.

It is clear from this that our relationship with fat has grown very unhealthy, indeed. To understand what went wrong, it’s important to recognize that fat has never been a passive partner. It doesn’t just loaf around waiting to be burned; it’s an active participant in our biological systems. Fat secretes hormones and other substances that affect metabolism, and these products play a role in disease — roles that researchers are still trying to understand.

For example, metabolic syndrome — a cluster of risk factors associated with heart disease, type 2 diabetes and stroke, among others — involves several biological features that tend to go hand-in- hand with obesity, including high triglycerides, cholesterol, blood sugar and blood pressure and a large waistline. While the exact mechanisms by which these biological processes are causing disease are unclear, scientists are amassing solid evidence that fat is a major player in varied disease states.

Recently, Steven Horvath, PhD, ScD, professor of human genetics and biostatistics, used an “epigenetic clock” — a time-keeping mechanism that monitors DNA activity to measure age in human tissue — to show that obesity accelerates aging in the liver. This premature aging could account for the frequent early onset of age-related liver disease in those who are obese.

Dr. Beaven, director of UCLA’s Metabolic Syndrome Program in the Division of Digestive Diseases, and Peter Tontonoz, MD, PhD, professor of pathology and laboratory medicine, also have led studies examining the role of obesity in liver disease. Among other findings, they’ve shown that lipid-fat metabolism plays a role in activating stellate cells — star-shaped cells that, once stimulated, cause scarring in the liver. The findings have serious implications in a time when fatty liver disease is on the rise — in large part because of the obesity epidemic. Fatty liver disease can lead to more serious conditions including cirrhosis and liver cancer that require liver transplantation. Ironically, the increasing prevalence of fatty liver disease in the population also is reducing the number of viable organs for transplant.

This active signaling between fat and other cell types has also been noted by Charalabos “Harry” Pothoulakis, MD, director of basic research at the UCLA Center for Inflammatory Bowel Diseases in the Division of Digestive Diseases. His lab has found evidence that mesenteric fat, the fat that lies close to the intestines, participates in the pathogenesis of inflammatory bowel disease (IBD). The team noted that the molecules secreted from fat cells during IBD can activate inflammatory pathways in the colonic mucosa of patients with ulcerative colitis and Crohn’s disease and that the makeup of the signals these fat cells secreted is distinct in each disease.

  Drs. Gregg Fonarow and Tamara Horwich  
  Research by Drs. Gregg Fonarow (left) and Tamara Horwich has shown that in some instances, obesity can benefit some patients and
protect them from the adverse effects of disease.
Photo: Ann Johansson

“WE KNOW THAT FAT CELLS are not inert; they function like little organs, excreting all kinds of chemicals,” Dr. Pothoulakis says. For patients with IBD who also are obese, this process can have a major impact. He and his colleagues have observed that disease progression for obese patients can be significantly more dramatic than for thinner patients, and the symptoms are much worse.

“This suggests that symptom-making products from the fat depots surrounding the intestine during gut inflammation may directly affect the pathophysiology and the extent of disease,” Dr. Pothoulakis says. “We now know that this is happening in the intestines of IBD patients, but it is also highly likely to be happening in other diseases.”

Understanding how these mechanisms exacerbate disease could point the way to treatments targeting the biological pathways involved. It may be better, however, to stop obesity from triggering disease in the first place. That means focusing on restoring the balance between the calories we consume and those we burn. This may involve drug therapies that, akin to bariatric surgery, stem our insatiable appetites. It may also be possible to design therapies that increase the base rate at which we burn calories, even while we’re at rest.

However, the most straightforward approach remains to rely on diet and exercise to keep fat under control. “There’s no free lunch; you can either eat less or burn more,” Dr. Tontonoz says. “There’s not likely to be a magic bullet that will allow a person to eat infinite amounts of food and not have any consequences.”

FOR THE OBJECTIVE OBSERVER — one who wasn’t around for the good times, when we had a healthier relationship with fat — it might be tempting to ask: Why not just kick fat to the curb? Why not solve the obesity problem by getting rid of adipose tissue altogether? Dr. Tontonoz says it isn’t that simple.

“What is often unappreciated is that fat is actually ‘a good guy,’” he says. “You need a place to store calories for energy, and if you don’t have adipose tissue, those calories will go to other tissue and may cause even more problems.”

To make his point, Dr. Tontonoz, who also is an investigator with the Howard Hughes Medical Institute, points to those who lack adipose tissue due to a genetic defect. These individuals paradoxically share symptoms in common with type 2 diabetes patients. They have excess lipids floating around in the body, and if those lipids can’t find a home in adipocytes, they deposit in other tissue, wreaking havoc in the body. “People without adipose tissue are extraordinarily sick,” Dr. Tontonoz says.

Fat has also been shown to play an unexpected beneficial role in chronic disease, suggesting that it may be able to help us through at least some of the messes it creates. “Obesity is, without question, a key risk factor for many chronic diseases,” explains Gregg Fonarow, MD ’87 (RES ’90, FEL ’93), Eliot Corday Chair in Cardiovascular Medicine and Science and director of the Ahmanson-UCLA Cardiomyopathy Center. “But once that disease state has surfaced, obesity may then paradoxically play a different role; it appears to provide protective or survival advantages.”

DR. FONAROW AND HIS COLLEAGUE, Tamara Horwich, MD (RES ’02, FEL ’06), began to look into the relationship between body mass index (BMI) — the most common measurement used to assess obesity — and outcomes for heart-failure patients. The expectation was that they would see shorter survival rates for individuals with pre-existing heart failure who were also obese. For both men and women in the study, that meant a BMI ranging from 25 to 29 (overweight) to 30 or higher (obese) with a waist circumference of 40 inches or greater for men and 37 inches or greater for women. There was a hope — and an expectation — that advising patients to lose weight might improve their heart-failure state and help them survive.

“When I was compiling the data and doing my analyses, I thought I was doing something wrong because I was getting the opposite result from what we expected,” Dr. Horwich says. “I was finding that patients, both men and women, who were overweight or even obese were having better outcomes. They were living longer.” On the other hand, men and women with a normal BMI and waist circumference were shown to be at a substantially higher risk for adverse outcomes, such as the need for a heart transplant, placement of a ventricular-assist device — or death.

Their findings were published in 2012 in the American Journal of Cardiology, and this phenomenon has come to be known as the “obesity paradox.”

Dr. Horwich, associate professor of medicine and cardiologist at the Ahmanson-UCLA Cardiomyopathy Center, says that BMI has often been considered a questionable measure of obesity, since it can’t discriminate between fat and muscle mass. There was some suspicion that the so-called obesity paradox they had identified was an artifact of this and other confounding factors.

Dr. Horwich started to measure her heart patients’ waist circumference, possibly a better indicator of fat composition, and later measured fat by bioelectrical impedance analysis, a special scale that uses sound waves to determine how much weight is due to fat mass and how much is from muscle. With every method she and her team have used, they’ve found that excess fat consistently correlates with better health outcomes in heart-failure patients.

  Brad Jones, Why I Give  
 

Brad Jones
Photo: Courtesy of Brad Jones

WHY I GIVE

Brad Jones is a founding partner of Redpoint Ventures. He focuses on technology opportunities in Southern California and has managed successful investments in fields ranging from biotechnology to wireless communications. A longtime supporter of the UCLA Division of Digestive Diseases, Mr. Jones has championed the work of Simon Beaven, MD (FEL ’08), PhD.

“Obesity has clearly emerged as a public-health crisis. It’s imperative to me to support the scientists who are spearheading discoveries that will, ultimately, put this nation on the road to better health. I am happy to be a part of this important effort.”

– Brad Jones

 

OTHER STUDIES HAVE SHOWN the obesity paradox also to exist in other types of cardiovascular disease — in patients with coronary artery disease, in those recovering from heart attacks, in patients undergoing bypass surgery. It has also been seen in a wide variety of other diseases — chronic kidney disease and kidney cancer; chronic obstructive pulmonary disease; and HIV/AIDS, to name a few. Research published early last year, led by Katherine Flegal, PhD, of the U.S. Centers for Disease Control and Prevention, even suggested that, for those over the age of 65, being overweight may confer as much as a 10-percent survival advantage.

The assumption is that this excess fat provides a large, metabolic reserve that provides chronically ill patients with the energy to fight disease, giving them an advantage over their normal-weight counterparts. The finding has made for some uncomfortable conversations in the public-health community, where many would prefer we cut fat out of our lives completely.

“The concept of the obesity paradox has continued to face opposition for some very good reasons,” explains Dr. Kalantar-Zadeh, who has observed and written extensively on the paradox in chronic kidney disease. “The public-health community is focused on fighting obesity, so to say that there’s a chance that obesity in some people is good complicates what some feel should be a streamlined public-health campaign against obesity.”

“WHAT IS CRITICAL AND SHOULD NOT BE CONFUSED is that obesity is clearly a risk factor for a number of severe chronic diseases. No one should feel that it is a good idea to become overweight or obese with the thought that, should they eventually develop heart failure or one of these other disease states, it may protect them. To do so would be putting themselves at far-greater risk for developing these disease states in the first place,” Dr. Fonarow says, echoing sentiments shared by Dr. Kalantar-Zadeh, Dr. Horwich and other clinicians who have studied the paradox.

All three doctors do recommend that this complex relationship with fat be taken into account by clinicians when making health recommendations for aging populations and for those with chronic disease. “Doctors’ office notes often default to say ‘lose weight,’ but that may not be good for all patients,” Dr. Horwich says. “What the obesity paradox shows is that we can’t take a set of guidelines from one population — for instance, healthy populations — and extrapolate to sick populations and expect that the guidelines should be the same for everybody. That’s really the basic tenet of personalized medicine.”

Given the increase in the number of people suffering from chronic disease and the swelling population of the aged and elderly, a shift in approach has the potential to affect tens of millions of people, and emerging research on the obesity paradox suggests that the official position on obesity may need to be refined for some select populations.

“In this day and age, we don’t have starvation and natural disasters to the same degree. Getting older, chronic diseases, cancer, these are the hardships that we deal with now,” Dr. Kalantar-Zadeh says. “In the past, it was fat that helped us through our hardships; in the same way fat protected us for many thousands of years, it continues, in some instances, to protect us today.”

Veronica Meade-Kelly is a science writer at The Broad Institute of MIT and a frequent contributor to Harvard Medicine magazine.

 

 

 





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