Intervening in Obesity

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Simple recommendations such as reducing food intake, changing the composition of one's diet and increasing physical exercise are always appropriate for an obese person. And by themselves, such behavior changes can help individuals lose up to 10 percent of their body weight, although maintaining that weight loss is often difficult.

Bariatric surgery is now performed on hundreds of thousands of patients every year. In general, these operations either tie off part of the stomach with a band to limit its size or actually reroute the gut to both reduce the stomach pouch and bypass part of the intestine. Both procedures are substantially more successful than any current drug therapies at promoting and maintaining weight loss. Recent research also suggests that gastric bypass may cause a reduction in appetite, in part by altering levels of gut hormones such as ghrelin and PYY, which indicates that drugs to accomplish the same end might someday substitute for these operations in many patients.

Any new drug to treat obesity will be held to very high standards of efficacy, tolerability and safety. Because the pathways regulating energy storage are so critical to other processes in the body and brain, developing drug interventions that meet all those criteria is challenging. Unfortunate experiences with past drug candidates that were effective but ultimately proved to be addictive or unsafe could in fact push regulatory agencies to be even more demanding than may seem reasonable. In addition to treating obesity by reducing body fat content, a drug will have to improve obesity-associated complications, such as diabetes and hypertension, or at least not cause them to become worse. Any therapy will also have to be safe for extended use because stopping treatment would likely allow weight to return to previous levels. A high risk exists as well for obesity drugs to be misused by people seeking inappropriately low body weights for nonmedical reasons.

Just recently, a new medication that has been available in Europe for some time, rimonabant, failed to gain approval from U.S. Food and Drug Administration advisers because of concern about increased incidence of depression and anxiety in people taking it. The drug works by blocking activation of a cell-surface receptor in the brain and peripheral tissues known as CB1. This receptor mediates the "munchies" brought on by smoking marijuana, as well as the actions of lipid molecules made in various tissues. The trade-offs between safety and efficacy in using this class of compounds over an extended period are therefore not yet clear.

At present, only two prescription drugs are approved in the U.S. for long-term use to treat obesity. Sibutramine, available since 1997, acts to prolong the exposure of neurons in the brain to the neurotransmitters norepinephrine and serotonin, resulting in reduced appetite and modest weight loss. This drug's use is limited by the fact that blood pressure and pulse tend to rise rather than fall during therapy. Orlistat, available since 1999 and now offered in an over-the-counter form under the brand name alii, lowers an individual's total calorie intake by acting in the gut to reduce fat absorption, with modest effects on weight and obesity complications.

Many other approaches to the development of obesity drugs are being pursued based on the numerous pathways for regulating appetite and weight that have been discovered in recent years. Potential therapies include inhibitors of the appetite-stimulating molecules MCH, NPY and ghrelin, appetite-suppressing mimics of PYY, and activators of the melanocortin 4 and serotonin receptor subtypes. Any of those options would be targeted toward lowering energy intake, as the existing drugs do. But because the body tends to compensate for fat loss by going into energy-conservation mode, complementary drugs that boost the rate at which energy is expended might also be necessary.

Several research groups are looking into ways of increasing the rate at which fat cells release stored energy or of preventing its storage from taking place. One approach focuses on stimulating a class of cell-surface receptors--known as beta3-adrenergic receptors and PPAR nuclear receptors--which trigger tissues' release of a substance called uncoupling protein 1. That signal is a call for energy, which is heard by certain fat cells and increases the rate at which they send triglycerides back into the bloodstream. Yet this technique may work only on a special type of fat tissue known as brown adipose, which is abundant in rodents and in newborn human infants, but by adulthood very few brown adipose cells remain in human fat.

Another promising approach involves blocking enzyme activities that promote fat storage. One example, the enzyme 11 beta HSD-1 (11βHSD1), causes the steroid Cortisol to be converted from a dormant form to a biologically active one inside adipose and liver cells. This locally active Cortisol, in turn, prompts those cells to manufacture more triglyceride. Our laboratory group has shown that experimental mice overproducing 11βHSD1 in their adipose cells also generated excess corticosterone (the mouse version of Cortisol) in those cells and grew to be significantly obese. Interestingly, the mice developed abdominal obesity in particular, as well as diabetes, high blood pressure and high blood lipids, a suite of symptoms resembling the human condition known as metabolic syndrome.

Although studies of obese human subjects have yet to produce such a clear-cut association between llβHSD1 activity and excess fat storage, inhibitors of that enzyme already exist and are in development for use in treating metabolic syndrome. They may prove to be useful interventions for obesity as well.

Many experts believe that successful drug therapy for obesity will eventually involve multiple drugs acting through independent path ways, in combinations tailored to individual patients, as is now the case for treating hypertension and diabetes. Of course, as with other common diseases such as hypertension, it would be preferable to treat people with changes in diet and lifestyle alone. But if that approach fails, and morbid consequences result, safe drug therapies would be no less appropriate for obesity than for other illnesses.