Targeting thermogenesis and related pathways in anti-obesity drug discovery

The health consequences of the obesity epidemic are a huge burden on patients and society. Yet it remains an unmet therapeutic need. Lifestyle or behaviour modification, although desirable, seems to benefit only a few and bariatric surgery is not an option for all and not without risks. Nevertheless, bariatric surgery is currently the gold standard in terms of weight loss therapy and any weight loss agent will be in combination with management of lifestyle modification. Sadly, there is a poor history for the pharmacological treatment of obesity and repeated safety concerns have attracted intense regulatory scrutiny. Indeed, recent market withdrawals leave us with just one agent approved for the long term treatment of obesity and that is only mildly efficacious in terms of weight loss, although it is beneficial in terms of metabolic health. There are two broad pharmacological approaches that can be applied in obesity drug discovery: reduce intake (or absorption) or increase expenditure (thermogenesis) of calories. In this review we will look at the latter approach. We will cover regulatory requirements and the rationale for this approach. We believe that post-obese subjects display abnormal metabolic responses to weight loss that almost inevitably leads to weight regain. We will then explore a number of approaches that potentially increase thermogenesis in humans. The challenge we have is in accumulating enough human data to validate this approach using drugs.