Some very interesting papers from the obesity research field have been published in the last few months. There have been a number of these over the years, and (as is widely apparent), none of them have quite lived up to their initial promise. This latest mechanism has been written up by both academic groups and industrial ones, which leads to some speculation about the state of the field - read on.
First, some background: GLP-1 (glucagon-like peptide 1) is a very important metabolic regulator. Peptides that mimic it at its receptor (but with a longer half-life) are marketed diabetes therapies (Byetta (exenatide), liraglutide, and others), and the DPP-IV inhibitors, like Januvia (sitagliptin) and its upcoming competition do something similar by inhibiting the enzyme that normally breaks the peptide down.
In addition to glycemic control, GLP-1 and related ligands also have complex effects on appetite in rodent models. These are still being unraveled, and depend on which peptide you use, and whether it's given out in the periphery or into the brain. More than one mechanism seems to be involved.
Glucagon is another key player in regulating glucose - it's another peptide hormone with its own receptor, and its most noticeable effect is as sort of counterweight to insulin in glucose control. It stimulates the liver to break down glycogen and release glucose, among other things, and people have tried (so far, without success) to develop glucagon blockers as a treatment for diabetes.
There are several other important signaling peptides in this space, such as GLP-2 and oxyntomodulin, and it's been clear for a few years now that there's some sort of opportunity to come up with a mixed-activity ligand that might hit these various piano keys to produce the right chord. (Several such have been reported in the diabetes field). These peptides are all part of the gut-to-brain signaling system, which is rather complex and has been the target of a number of obesity research programs over the years. Signals for satiety, hunger, glucose handling, and energy expenditure are all tangled together there, but in ways that we don't understand well, so it's been a very attractive minefield. For the most part, compounds targeting these systems have been stabilized forms of peptides themselves, and thus have to be given by injection. Small-molecule ligands for these receptors have been much harder to come by.
Now for the new results. A team from Indiana, Kentucky, and Cincinnati reported back in July in Nature Chemical Biology that dual agonist peptides acting at both the GLP-1 and glucagon receptors do a tremendous job on obese rodents. (Here's a PDF from one of the authors). They took two of them into diet-induced-obese mice, and saw very significant weight loss, which appears to have been almost entirely body fat, and was driven by simultaneously higher energy expenditure coupled with lower food intake.
There would indeed be a market for that, and you can bet that the possibility hasn't escaped the metabolics groups at the large companies. At almost the same time, in fact, a group at Merck published a very similar study in obese mice with their own dual-agonist peptide, and saw the same sort of thing: weight loss, improvement in metabolic markers, decreased fat mass, the whole deal.
Now, what does all this mean for the state of the art? Merck wouldn't publish such interesting results without a good reason - you have to wonder if they're far enough along that they felt safe talking about such things, or (alternately) if there are clear problems with the approach that will keep this mechanism from ever being used. Nothing's shown up in the open literature about the latter possibility, as far as I can see. So the race would appear to be on. Is it?