Kiran Chada, PhD, professor of biochemistry at Robert Wood Johnson Medical School
Why is Obesity Epidemic?
by Maryann Brinley
Even when people manage to make it to age 30 without gaining excess weight, a National Heart Lung and Blood Institute (NHLBI) study reports that the chance of keeping off middle-age spread, or the kind of excess poundage that will shorten lives and cause disease, is slim. In the U.S., nine out of 10 men and seven out of 10 women are overweight or obese by 59.
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n a bio-molecular level, the answer to the obesity epidemic in the baby boom generation is growing more complicated every day. Poor eating habits, lack of exercise, slowing metabolism and psychology are all factors in body size, of course. But simply pointing the finger at fast food restaurants, sedentary lifestyles, the soft drink industry, the force of gravity on aging bodies, an American love affair with starch-carbs or even micro-organisms and viruses in the gut would be overly simplistic. Perhaps no one knows the intricacies of this human adipocyte puzzle better than Kiran Chada, PhD, in UMDNJ - Robert Wood Johnson Medical School’s Department of Biochemistry. And, it all started 20 years ago with his interest in a “mouse called pygmy, obviously very small,” he says, but also, very significantly free of fat tissue.
“Put two people on the same diet,” Chada say. “One will become obese. The other one won’t. Should you condemn the one who is obese?” he asks. “Of course not.” In fact, a culture of blaming the individual for what is clearly a “complex genetic disease with dire health consequences” may have slowed research up until now. “Obesity research has really mushroomed in the last 10 years but we’re still in the early stages. This is a disease that consists of many genes interacting with each other so we have to be realistic about the pace of our progress.”
Being overweight, just by 15 to 20 pounds, increases the risk of diabetes, heart disease, stroke, hypertension, gallbladder disease, osteoarthritis, sleep apnea and other breathing problems, as well as some forms of cancer including uterine, breast, colorectal, kidney and gallbladder. Carrying around too much bulk on our frames, especially in our abdominal area (where fat concentration will affect blood cholesterol levels more quickly than from hips or thighs) is also associated with high blood cholesterol, menstrual irregularities, hirsutism (excess body hair), stress incontinence, psychological disorders such as depression and increased surgical risk, according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Last August, the Centers for Disease Control (CDC) reported that being even moderately overweight increases the risk of death.
Chada, who calls himself a mouse geneticist and developmental biologist, identified one of the first genetic links to fat cell growth more than five years ago. “That gene is called HMGA2 and there is a human equivalent.” In the absence of HMGA2, or simply by lowering the activity of this gene by 50 percent, you are left with very little fat. Even when you lower the activity of this gene by 50 percent, although you may have a normal amount of fat tissue, you do not gain weight when fed a high fat diet. “Here was a genetic defect that led to a disruption in the expansion of adipose or fat tissue,” he says. “We had previously shown that this was the same gene responsible for fat cell tumors, or lipomas, in humans. Lipomas are the most prevalent tumors in humans but they are usually benign. These two studies are in keeping with HMGA2’s central role in adipocyte biology and its function seems to be to modulate fat cell growth and development.”
What complicates obesity research is that more than 100 genes have now been implicated: some cause weight gain directly while others increase the likelihood of becoming fat. Chada’s own laboratory has identified approximately 100 potential obesity genetic targets. “Now what we are trying to do is identify a drug for each to change their activity.” UMDNJ filed and was granted a patent for Chada’s “HMGI proteins in tumors and obesity” in 2001.
“What biology is teaching us — and it’s something we are finding hard to grasp — is that, like cancer, obesity and weight gain are all about probability,” Chada explains. “It’s naïve to believe that there is one magic solution to the question. Like many complex diseases which involve a number of physiological systems, there’s interplay between genetics and environment,” he says. “Yes, there is an aspect of individual responsibility for obesity but there is also this genetic effect.” He uses the example of the mouse gene called leptin to underscore how genes can trump behavior. “If that gene is not expressed or turned on, no matter what the animal does, it’s still going to get fat.”
This predisposition to obesity can be likened to adult-onset diabetes. Not everyone in a family with hereditary diabetes will actually get the disease itself. “Some diabetics never have to take insulin because they watch their diets carefully. Likewise, you can probably control a genetic propensity to weight gain if you are very careful with your eating and exercise habits.”
Pictured here are four fat cells from their immature stage (top left) to full maturity (center front).
The commercial market for a cure for obesity is about $30 billion, according to Chada’s estimates, and “with all due respect, nothing currently available works. Imagine if there were something that did.” This is where his path differs from other research competitors working on anti-obesity medications. Most current pharmacological approaches concentrate on controlling “the amount of food an individual eats, or what is called satiety,” he explains. But appetite suppressants act on the body’s central nervous system (CNS). “Unfortunately, this has turned out to be problematical,” he points out, because of unwanted side effects. Presently, Xenical (orlistat) is the only drug approved by the Food and Drug Administration (FDA) which does not attempt to turn off the CNS genes linked to satiety. Xenical decreases dietary fat absorption but isn’t without its own set of drawbacks because it can cause diarrhea, cramps and intestinal discomfort.
What should give this obesity geneticist — and millions of baby boomers — hope is that, “All of our obesity targets are aimed at the adipose tissue, on the body’s periphery, so these may well turn out to have fewer potential problems.” Will these potential pharmaceuticals work on already obese people, allowing them to lose weight once and for all? Would a thin person suddenly drop all fat cells? Will the medications be more effective early in life rather than later? “When, in the actual acquiring of this disease, will the drug work best?” Chada himself asks. There are no answers yet. “These are the types of studies we’ll do eventually but to put it simply, it’s a huge project,” he admits. “But this is a huge and devastating problem. And, like everything else, the more resources we can put into it, the quicker the pace will be.”
The Surgical Solution
As millions of baby boomers experience multiple failures in their dieting attempts and serious health consequences pile on, this prescription for obesity is gaining more advocates.
The “two by two” lecture is legendary. After prepping more than 900 patients for bariatric procedures since 1998, Gus Slotman, MD, a School of Osteopathic Medicine (SOM) professor of surgery, can move through his advance warnings for obese patients with lightening speed.
“I say this all day long,” he laughs, joking that as a baby boomer himself, his mantra might just be helping him stay as thin as he was back in school. Without pausing for a single breath, he can rattle off the dietary rules for life after surgery: “Two ounces of protein every two hours, or eight times a day. That’s two by two and take 15 minutes to finish. I tell them they have to commit themselves to eating no more than two ounces at a time. And there will be no room for anything but meat, fish, chicken, vegetables, fruit, dairy products, eggs and other proteins. Say goodbye to bread, potatoes, rice, pasta, noodles, pretzels, chips, cheez doodles, crackers, junk cereal and all those starch-carbs.” About two-thirds of his patients succeed. The others “just can’t get over the drive to eat that led to the bypass.”
Forever after, he warns them, life will be like a cocktail party, where they munch hors d’oeuvres. If these statutes sound formidable enough to scare potential people away, a check around his packed waiting room quickly indicates how desperate so many are to shed unhealthy pounds. Even serious surgery followed by major behavioral modifications doesn’t deter them. Slotman’s waiting room full of patients, by the way, is a study in contrasts because this physician was primarily a head and neck cancer surgeon and a specialist in surgical critical care, before starting a third career in open gastric bypass surgery for weight reduction. He completed his internship followed by a residency and fellowship in surgical oncology at New Jersey Medical School (NJMS) in 1981 and moved to UMDNJ- Robert Wood Johnson affiliate Cooper University Hospital in 1990 after nine years at Brown University. Slotman joined the Department of Surgery at SOM earlier this year. “Half the room is filled with 300, 400 and 500 pound people who want to lose weight while the other half has cancer patients trying not to lose weight. I have 50 patients whose body mass index was greater than 70 before gastric bypass and the same relationship with my obese patients that I have with those who have cancer.”
Gus Slotman, MD, professor of surgery at the School of Osteopathic Medicine
Surgery to jump start significant weight loss may have once seemed like a dramatic alternative but even with the risk of complications such as infections, gastrointestinal leaks, hernias, and deep vein thrombosis, it is fast becoming a legitimate option. When compared to the life-threatening side effects of obesity, however, the overall death rate from surgery, 180 days postoperative, is low at 0.2 percent, according to a study conducted by the Health and Human Services’ Agency for Healthcare Research and Quality released in July 2006. So, along with open gastric bypass, Slotman’s preferred procedure — “I may be a dinosaur but I have the fewest complications” — laparoscopic gastric bypass, vertical banded gastroplasties (the use of staples to reduce stomach size) and lap band adjustable gastric bandings (a newer, less invasive procedure) are also rising. From 1998 to 2002, the number of bariatric surgeries jumped 400 percent. A UMDNJ-University Hospital (UH) report indicates that as a long-term answer, gastric bypass surgery has proven to be the most effective way to control morbid obesity. Even five years after surgery, 95 percent of patients have maintained a loss of more than 50 percent of their excess weight while traditional diet and exercise programs can claim success only 1 percent of the time.
The high health cost of obesity has also created a positive climate for this option because medical expenditures for the overweight exceed $92.5 billion a year in the U.S. now. Even insurance companies, as well as federal agencies like Medicaid, see the therapeutic and financial wisdom in what Slotman has observed in his Bariatric Surgery Center of Excellence at Our Lady of Lourdes Medical Center, a major UMDNJ clinical affiliate in Camden. Last August, Lourdes was certified as a national Center of Excellence by the American Society for Bariatric Surgery.
“The idea is to have patients lose enough weight to get healthy. There is a commonly experienced switch toward better health when a patient has dropped just 30 to 50 pounds,” according to Slotman. Though they may have hundreds more to lose individually, patients start coming off hypertension medication and their diabetes, especially Type 2, is under better control at that point.
The average weight loss after bariatric surgery is two-thirds of the amount the person has been overweight but that reduction takes place over a two year period and is kept off only if patients stick to a diet and exercise program. Slotman acknowledges “a genetic component,” but observes, “I haven’t seen anyone more than 200 pounds overweight who isn’t eating too much. People are just unaware of what they eat.”
Slotman’s office conducts careful pre-op screening to eliminate anyone who may be unable to make lifestyle changes as well as those at high risk for heart, lung or gastrointestinal problems, or with endocrine complications. Baseline criteria for bariatric surgical patients were established by the National Institutes of Health (NIH) 12 years ago: candidates must be more than 100 pounds overweight, with a body mass index over 40 and have failed multiple weight loss attempts using formal programs. “My upper age limit is 55 because anyone over that has been eating the wrong way for so long that it may be impossible to change. Or if they do lose the weight, the high blood pressure, the diabetes and the sleep apnea might not necessarily go away with the lost pounds.”
The drive to eat can certainly become pathological and Slotman believes that as a nation, we’ve become addicted to starch and carbohydrates. “Everyone is different but we have really gotten into bad eating habits.” Age related weight gain typically starts in the 30s with a sedentary lifestyle and loss of muscle mass. In the 40s, middle-age weight will continue to pile on unless regular exercise and a healthy diet stop it. “Surgery is a physical tool that only works best if we can cure the psychological problem,” he insists. “I see my patients akin to recovering alcoholics. There is always going to be an obese person in the back of their heads so they have to beware of crises where old habits return and they eat for emotional comfort.” The good news is that for the majority of his patients, his oft-repeated two by two formula makes mini-meals an opportunity to actually savor the flavors of what they eat. “Some start really tasting food for the first time.”