Obesity is a therapeutic area that has broken a lot of hearts (and wallets) over the years. A scroll back through this category will show some of the wreckage, and there's plenty more out there. But hope does that springing-eternal thing that it does, and there's an intriguing new possibility for a target in this area. Alan Saltiel of Michigan (whose group has had a long presence in this sort of research), along with a number of other well-known collaborators, report work on the inflammation connection between diabetes and obesity:
Although the molecular events underlying the relationship between obesity and insulin resistance remain uncertain, numerous studies have implicated an inflammatory link. Obesity produces a state of chronic, low-grade inflammation in liver and fat accompanied by the local secretion of cytokines and chemokines that attenuate insulin action. Knockout or pharmacological inhibition of inflammatory pathways can disrupt the link between genetic- or diet-induced obesity and insulin resistance, suggesting that local inflammation is a key step in the generation of cellular resistance to important hormones that regulate metabolism.
Saltiel's lab had already implicated IKK-epsilon as a kinase involved in this pathway in obese mouse models, and they've been searching for small-molecule inhibitors of it. As it turns out, a known compound (amlexanox) with an uncertain mechanism of action is such an inhibitor. It's best-known, if it's known at all, as a topical canker sore treatment, and has been around since at least the early 1990s.
Administration of this selective TBK1 and IKK-ε inhibitor to obese mice produces reversible weight loss and improved insulin sensitivity, reduced inflammation and attenuated hepatic steatosis without affecting food intake. These data suggest that IKK-ε and TBK1 are part of a counterinflammatory process that sustains energy storage in the context of insulin resistance. Disruption of this process by amlexanox thus increases adaptive energy expenditure and restores insulin sensitivity. Because of the apparent safety of this drug in patients, we propose that it undergo study for the treatment of obesity, type 2 diabetes and nonalcoholic fatty liver disease in patients.
I don't see why not. The compound does seem to be absorbed after oral dosing (most of the topical paste ends up going down into the stomach and intestines), and about 17% is excreted unchanged in the urine. You'd think some sort of oral formulation could be worked out, given those numbers. It looks like a low-micromolar inhibitor, and is selective against a kinase panel, which is good news. And treatment of mice on a high fat diet prevented weight gain, while not altering food intake. Their insulin sensitivity improved, as did the amount of fat in the liver tissue. Giving the compound to already-obese mice (either through diet or genetically predisposed (ob/ob) animals) caused the same effect. Metabolic cage studies showed that increased energy expenditure seemed to be the mechanism (as you'd think - thermodynamics will only give you so many ways of losing weight while eating the same amount of food, and the obvious alternative mechanism might not be very popular).
Just how the compound does all this is somewhat mysterious:
The precise mechanisms by which amlexanox produces these beneficial effects in obese rodents have not yet been completely elucidated. Although amlexanox is known to be a mast cell stabilizer of unknown mechanism20, and depletion of mast cells may have beneficial metabolic effects59, most of the in vivo and in vitro evidence points to a role for the drug in increasing expenditure of energy while reducing its storage in adipocytes and hepatocytes. Furthermore, the lack of a phenotype in wild-type mice reconstituted with Ikbke knockout bone marrow indicates that the role of IKK-ε in bone marrow-derived cells such as mast cells and macrophages is less important than its role in other cell types such as adipocytes and hepatocytes. Although IKK-ε and TBK1 expression is elevated as part of the inflammatory program downstream of NF-κB, the kinase targets of the drug do not seem to be direct participants in the increased inflammatory program. In fact, the reduced inflammation observed in vivo with amlexanox treatment may be an indirect effect of improved metabolic disease or, perhaps, of elimination of a feedback pathway that maintains inflammation at low levels such that inflammation is permitted to resolve. Moreover, despite the fact that administration of amlexanox to obese mice restores insulin sensitivity, these compounds are not direct insulin sensitizers in vitro.
This level of unworkedoutness will surely interest some companies in taking a look at this, and if proof-of-concept can be found with amlexanox itself, a more potent inhibitor would also be something to search for. I have just one worry, though (he said, in his Peter Falk voice).
We were just talking around here about how mouse models of inflammation are probably useless, were we not? So it would be good news if, as speculated above, the inflammation component of this mechanism were to be an effect, not a cause. A direct attack on metabolic syndrome inflammation in mouse models is something that I'd be quite wary of, given the recent reports. But this might well escape the curse. Worth keeping an eye on!