Therapeutic Strategy

Peripheral Treatment of Obesity

Because of a sedentary lifestyle and excessive calorie consumption, obesity has reached epidemic proportions worldwide, affecting virtually all ages and socioeconomic groups. There are more than 1.4 billion overweight adults, and at least 500 million of them obese1. Being overweight or obese is a major risk factor for chronic diseases, including type 2 diabetes mellitus, cardiovascular disease, and several cancers. Obesity is a source of reduced quality of life, significant mortality, or permanent disability. 300,000 deaths per year in the United States are related to obesity and medical costs amount to $190 billion annually. Current symptomatic medical and behavioral treatments of obesity fail to achieve their long-term therapeutic goals. Recent therapeutic approaches targeting centrally acting mechanisms have resulted in serious adverse reactions, leading to the non-approval or withdrawal of several anti-obesity medications. Despite a market size estimated to reach $8.4 billion globally by 20222, the few marketed anti-obesity medications have had poor uptake by physicians and patients due to limited efficacy and uncertain safety. Consequently, there is a pressing need for novel therapeutic approaches to obesity.

Thermogenesis

The rediscovery of brown adipose tissue (BAT) in adult humans, and the ability to generate brown-like adipocytes (“beige”, or “brite”) in white adipose tissue (WAT) depots, has renewed interest in this area of biology. The interest stems from the fact that, unlike WAT, which stores energy in the form of lipids, BAT is an energy-expending tissue. Increased BAT mass and/or activity should therefore offer a degree of protection from obesity. Relatively limited amounts of BAT would be required to make significant impact on energy balance, since as little as 50g of BAT would account for 20% of daily energy expenditure. Virtanen and co-workers speculated that the estimated 63g of BAT found in one of their study subjects could combust the energy equivalent of 4.1kg of WAT over one year3. In this context, the possibility of a pharmacologically driven switch from WAT to BAT in peripheral tissues is highly attractive for the clinical management of obesity.