Not a One-Size-Fits-All-Problem

The Battle of the Bulge

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 Mark Goodarzi, MD, PhD. "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 Richard Bergman, PhD, 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 Body Mass Index (BMI) 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."

Adrienne Youdim, MD, 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.