Redundant Pathways of Obesity

Treatments Should Target Multiple Pathways (Part 2)

July 06, 2010

Ken Fujioka, MD

Currently available pharmacotherapies for obesity have been disappointing. Patients taking a pharmacotherapy for weight management lose on average 5% to 10% of their body weight, when most of the patients’ expectations are closer to losing 30% of their body weight.  Furthermore, most currently available pharmacotherapies are centrally acting and the safety and tolerability profile are of concern.  The most important issue with why pharmacotherapies, up to now, have not worked as well as we had hoped is because these drugs only target one pathway.  

Due to the fact that we are built to survive (as part of evolution), our body has a lot of redundant pathways to prevent weight loss.  It is very well accepted that there are a lot of neurohormonal pathways involved in the control of appetite and body weight.  One of the best studied pathways around body weight regulation is leptin.  Leptin is the hormone that comes from fat cells and signals the brain to let it know how much fat is around. We know that after significant weight loss, leptin levels fall as fat mass decreases. This fall in leptin leads to activation of other pathways to drive food intake up, and lower metabolic rate, thus defending the current weight.  Current available therapies targeting only one potential pathway for body weight regulation will run into the problem of the body trying to defend against weight loss.  It is no surprise that current treatments only provide 5% to at most 10% of total body weight loss.

One way of getting around the body’s natural defense of weight is through bariatric surgery.  Bypassing the stomach and putting food directly into the small intestines usually provides 30% total body weight loss after 2 years. This is due to several factors. The bypass decreases food intake, but more importantly, appears to change the normal feedback signals from the gut that control weight in a good way to keep weight off. Although it’s not completely worked out, the bypass appears to increase the signals for satiety and decrease a hormone that drives food intake. Thus, two things are happening that explain the impressive weight loss. First, food intake is restricted, but secondly and more importantly, are the effects on the gut-brain feedback loop known to fight weight loss.

These hormones are actually adjusted by the gastric bypass to help keep the weight off, which apparently demonstrates that multiple targets are being manipulated in the right direction.

It is no surprise that bariatric surgery is arguably the best treatment for morbid obesity. If one looks at the history of medicine it can be seen that many diseases are initially treated with surgery. Later, a drug is often discovered that can do as well as a surgical intervention.  Peptic ulcer disease is a good example.  Surgery was often the first treatment, but as medications such as proton pump inhibitors became available, surgery for peptic ulcers became very rare.

Hopefully obesity will take a similar course. As we learn how bariatric surgery works on multiple levels, we can apply that knowledge to medical, pharmacotherapy treatments. It is quite clear that for most patients targeting a single pathway will not work. Therapies that are able to target multiple pathways will have a much better chance of achieving a weight loss that is acceptable to both the patient and the physician.  

Dr. Fujioka is the Director of the Nutrition and Metabolic Research Center, and a member of the Division of Diabetes and Endocrinology, at the Scripps Clinic - Del Mar in San Diego, California.

For more related articles, click Obesity Perspectives.