The Battle of the Bulge
Methane-producing bacteria. Mutating genes. Hunger-inducing hormones. Understanding the myriad microscopic factors inside our bodies that contribute to weight gain and obesity could help curb the epidemic—and tip the scale toward improved disease prevention.
In the clinic’s waiting room, Jenny M. is looking down, staring at her feet. She is fighting the urge to get up and walk out. The young woman has made appointments before, only to cancel them. But this time, she is determined. She is going to stop the disease that is ravaging her health—because this time she has a baby girl at home and wants to see her grow up. Adrienne Youdim, MD, has seen this many times. She offers assurances and puts her new patient at ease, inviting Jenny to open up about her feelings and fears.
Jenny does not have cancer or heart disease—though she is at risk for both. She has a condition shared by 68 percent of American adults: She is overweight.
We all know someone like Jenny. We also know that weight is a key risk factor in a number of serious health conditions besides heart disease and cancer, including stroke, diabetes, infertility, and Alzheimer’s disease. And we are very well aware that a healthy diet and regular exercise are paramount to good health. But what we did not know until very recently is that what is already inside us—genes, hormones, fat cells, and microbes—may be as important as the food we eat and, in some cases, more so.
Against the obesity epidemic, behavioral and lifestyle changes too often fail to produce any significant lasting changes. To find out why, scientists are taking a microscopic approach to the problem, with research into the molecular and cellular mechanisms that control appetite and weight gain—and their findings could have a sizeable and much-needed impact on disease prevention.
Many of us find it all too easy to ignore the alarms raised about weight gain and disease. We may think that only individuals who are morbidly heavy are at risk. The truth may come as a surprise.
“As little as 10 pounds of excess weight can increase the risk of cardiovascular disease,” says Margo B. Minissian, RN, MSN—a nurse practitioner and board-certified lipid specialist at the Barbra Streisand Women’s Heart Center. Minissian is part of a medical team focused on helping women reduce their risk of heart disease through a preventive approach that includes state-of-the-art screening as well as cardiovascular risk assessments. Helping patients lose weight to improve good cholesterol (HDL) and lower blood pressure is often a priority.
The American Cancer Society estimates that eliminating obesity in America could reduce cancer deaths by 90,000 a year. Excess weight is correlated with cancer of the breast, uterus, colon, kidney, esophagus, pancreas, gallbladder, and liver. Research conducted by Andrew Li, MD, co-director of Women’s Reproductive Cancers and a physician in the Division of Gynecologic Oncology in the Department of Obstetrics and Gynecology, also showed that obesity increases the likelihood of disease recurrence—and death—in women with advanced ovarian cancer.
Excess weight is clearly harmful—and, tragically, often deadly. The connection between weight gain and heart disease was identified decades ago. Excess weight increases the workload for the heart, sometimes to a deadly degree. “But it turns out something more is going on,” says Richard Bergman, PhD, director of the Cedars-Sinai Diabetes and Obesity Research Institute.
Fat cells send out a host of hormonal and chemical signals that help the body maintain its energy balance. When people gain excessive weight, their fat cells plump up, and these oversized cells churn out more of these signals, negatively influencing the body’s production and use of insulin, the hormone that instructs muscles to burn energy and fat cells to store it. “The pancreas has to compensate by making more insulin,” Dr. Bergman explains, “and more insulin can be harmful—not least because it can damage the arteries.”
The complex chemical processes triggered by fat cells in the body are just one of many clues that must be investigated to completely understand the cellular factors at play in weight and disease.
The Weight of Heredity
For the world of medicine, the Human Genome Project was a game-changer. Scientists can now tackle big questions of human biology, such as which genes carry risks for certain diseases and conditions, and how and why they behave as they do. Since 2005, researchers have been able to identify genes specific to weight gain.
“We aren’t talking about the mutation of one or two genes, which would account for very few cases of excess weight,” explains Mark Goodarzi, MD, PhD, director of the Division of Endocrinology and head of the Endocrine Genetics Laboratory at Cedars-Sinai. “We are interested in the common forms of obesity and what role genetics plays in determining someone’s risk. We need to be able to look at thousands of subjects to really get an answer.” Cedars-Sinai participates in the Genetic Investigation of Anthropometric Traits (GIANT) consortium, an international collaboration that receives support from funding agencies worldwide and includes more than 400 scientists.
“We used to believe our genes don’t change,” says Dr. Goodarzi. “Today, we know they do.” The global project makes it possible to study tens of thousands of patients, lending added statistical power to research results. Studies conducted by the GIANT consortium have shown that some 50 genes play a role in the risk of excess weight gain, with each gene contributing only a small piece. “How many of those altered genes does an individual carry? That’s what tells us whether somebody is at low or high risk of becoming obese,” says Dr. Goodarzi.
Weight gain runs in families. Family and twin studies have shown that between 40 percent and 70 percent of susceptibility to obesity is inherited. A study of twins separated at birth—where one was raised by a family of severely overweight people and the other by lean parents—confirmed that genetics plays a strong role.
Surprisingly, our genes are not immutable—they can be altered by lifestyle and environment. That means the health of your children and their children can be affected by what you eat, the traumas you have endured, even what toxins you are exposed to. “We used to believe our genes don’t change,” says Dr. Goodarzi. “Today, we know they do.”
Through a path of inheritance called epigenetics that scientists are only now beginning to understand, we can pass on traits and tendencies acquired during our lifetime. So if a man grows up lean and is the descendant of a long line of thin people but becomes overweight due to lifestyle and/or environmental exposures, he may change his own epigenetic makeup and pass on a risk of obesity to his offspring.
We inherit more than genes, however. As Dr. Bergman says: “We are usually also born into an environment that is largely predetermined for us. We eat the way those around us eat, and we pick up on their lifestyle and habits very early in our lives. Changing behavior is extremely difficult, even if you are motivated.” Getting to the molecular heart of the matter—understanding the cellular factors influencing weight gain—could therefore be a breakthrough in the quest for treatments, picking up where diet and lifestyle often fail to succeed.
Punching Above Their Weight
Like most complex health conditions, obesity and weight gain are rarely attributable to a single cause. To explore their origins, we have to delve deep into a world that until recently was even murkier than the mysterious universe of genes.
Bacteria. Microbes. Viruses. Bugs. Most of us have negative associations with those terms, linking the tiny life forms to dirt and disease. But microorganisms play positive roles as well. “Many people are surprised to hear that there are 10 times as many bacteria as there are cells in the human body,” says Ruchi Mathur, MD, medical director of the Anna and Max Webb & Family Diabetes Outpatient Treatment and Education Center.
Unfortunately, some microbes in the gastrointestinal tract that might have been useful thousands of years ago—when our diets were radically different and food was scarce—can cause problems now that we are no longer hunter-gatherers. Our gastrointestinal evolution has not yet caught up with the modern Western diet, which is high in fats and sugars and changes the composition of our microbe colonies, activating enzymes that promote fat storage. This ability once kept our ancestors alive; now it facilitates obesity.
In one study, Dr. Mathur and her team used animal models to test a specific microorganism, archaea, which produces methane. A portion of the animal models in two groups—those with archaea and those without—was switched to a high-fat diet. Those who received both the microbe and the high-fat diet gained the most weight by far.
Bacteria also produce methane gas. In a study conducted by the Cedars-Sinai GI Motility Program and the Weight Loss Center, researchers found that obese patients who tested positive for methane in their breath had significantly higher BMIs than obese patients who did not.
“It looks like the bacteria that make methane somehow slow the gut down, leading the body to absorb more calories,” explains Dr. Mathur, who took part in the investigation. Her group recently conducted a 700-patient study that again demonstrated the link between methane production and weight gain regardless of the patient’s BMI, age, or gender.
The research suggests that creating a gut profile—analyzing an individual’s microbial makeup, or microbiome, in the same way that scientists create genetic profiles—could help identify those at risk for obesity. Someone with a preponderance of methane-producing microbes in their intestines may be predisposed to harvest calories in a way that increases fat storage, for example. What is clear is that these tiny microorganisms play a much bigger role than previously understood.
The Hunger Games
Despite the power of genetics, microbes, and other forces to make us overweight, many people do succeed in shedding pounds through diet and exercise. Keeping the weight off is another matter.
“We are programmed by thousands of years of evolution to store fat,” says Glenn Braunstein, MD, vice president of Clinical Innovation at Cedars-Sinai. “And for the first time in history, we are living in a society where cheap, high-calorie food, motorized transport, and labor-saving devices are the norm.”
Dr. Youdim, who has worked with hundreds of patients in Cedars-Sinai’s Weight Loss Center, says the reason it is so hard to maintain weight loss is physiological and has little to do with willpower.
The culprits may be the appetite hormones ghrelin, PPY, and GLP-1. Dr. Youdim explains: “When they start losing weight, people develop abnormal changes in levels of ghrelin, PYY, and GLP-1, which causes the brain to keep sending hunger signals. They do not feel full, and a pattern of overeating emerges.” Appetite hormone levels regulate again only if weight is put back on. A large-scale study in the New England Journal of Medicine showed that one year after losing weight, patients still suffered from abnormal levels of all three hormones, so they never felt satiated.
Another adversary is leptin, a substance that tells the brain how much body fat is present. In the same subjects, levels of leptin decreased by two-thirds following initial weight loss. A reduction in leptin leads to increased appetite and slowed metabolism. “It is not surprising that about 90 percent of people who lose large amounts of weight gain it back,” says Dr. Youdim. “And it really is not their fault.”
The Heavy Hitters
Losing weight through diet and exercise does not change this pattern, and therein lies the problem. Bariatric surgery, however, helps regulate those pesky appetite hormones, making it, for now, the most effective treatment for severe obesity, providing durable weight loss.
“The most anatomical changes created by the surgery lead to beneficial hormonal changes,” explains Scott A. Cunneen, MD, co-director of the Weight Loss Center at Cedars-Sinai, which is accredited as a Bariatric Center of Excellence by the American College of Surgeons.
“Over the last decade, we’ve created a system that tracks outcomes, standardizes treatment protocols, and leads to better results,” adds Miguel Burch, MD, associate director of General Surgery and Minimally Invasive Surgery. “Today, the rate of complication for bariatric surgery is even lower than for appendectomies.”
Both gastric bypass surgery (in which surgeons first divide the stomach into a small upper pouch and a larger lower remnant pouch, then re-arrange the small intestine to connect to both) and sleeve gastrectomy (which reduces the size of the stomach) offer an unexpected payoff: They treat diabetes, too, independently of weight loss.
“In other words,” explains Dr. Youdim, “The operation cures the patient of diabetes even before bringing about a significant reduction in weight.” This doesn’t happen, however, with laparoscopic banding (commonly known as the lap band).
Equally good news: In obese patients who do not have Type 2 diabetes, weight-loss surgery substantially reduces the odds of developing the disease. For that matter, Dr. Cunneen sees bariatric surgery as much more than weight-loss surgery. “It is a metabolic treatment that is preventing and reversing life-threatening illnesses.” With more than 20 million Americans suffering from diabetes—mostly Type 2—bariatric surgery could have a dramatic impact on public health.
According to Dr. Burch, gastric bypass surgery may one day become a mainstream approach to diabetes. “If you had a pill that could cure diabetes after a single dose, wouldn’t you take it? We have a surgical procedure that basically has that effect for many people.” More research is needed to understand how and why the procedure works, and to determine which patients would stand to benefit the most.
The Next Frontier
Our growing understanding of the roles of genes, hormones, and microbes in obesity means that new treatment options could soon become available to complement or even replace the need for surgery or drugs. For example, identifying a genetic risk factor for weight gain or obesity early on could help individuals manage their health risks better, learn to make the right lifestyle choices at an early age, and effectively prevent disease.
Now that the outsize role of microorganisms in weight gain is understood, the next frontier may be to manipulate microbes to boost weight loss and tailor the treatment to an individual’s microbiotic makeup—a trend in keeping with the emergence of personalized medicine.
“Someday, we will be talking about different kinds of obesity,” says Dr. Mathur. “Genetic, hormonal, microbebased—it’s not a one-size-fits-all problem.” With that insight, the one-size-fits-all approach to weight loss may soon give way to something radically different: individually tailored, effective, and preventive therapies.
George Orwell wrote, “There’s a thin man inside every fat man.” It turns out there is also a world of knowledge—a once-secret universe of genes, hormones, microbes, and bacteria that holds answers to the greatest health challenge of our time.